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Review

Management of Chronic Congestive Heart Failure Caused by Myxomatous Mitral Valve Disease in Dogs: A Narrative Review from 1970 to 2020

by
Mara Bagardi
*,†,
Viola Zamboni
†,
Chiara Locatelli
,
Alberto Galizzi
,
Sara Ghilardi
and
Paola G. Brambilla
Department of Veterinary Medicine, University of Milan, Via dell’Università n. 6, 26900 Lodi, Italy
*
Author to whom correspondence should be addressed.
†
These authors contributed equally to this work.
Animals 2022, 12(2), 209; https://doi.org/10.3390/ani12020209
Submission received: 22 December 2021 / Revised: 12 January 2022 / Accepted: 13 January 2022 / Published: 16 January 2022
(This article belongs to the Special Issue Cardiovascular Disease in Companion Animals—Dogs, Cats and Horses: Diagnosis, Prognosis and Therapy)
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Abstract

:

Simple Summary

Myxomatous mitral valve disease (MMVD) is the most common acquired cardiovascular disease in dogs. The progression of the disease and the increasing severity of valvular regurgitation cause a volume overload of the left heart, leading to left atrial and ventricular remodeling and congestive heart failure (CHF). The treatment of chronic CHF secondary to MMVD in dogs has not always been the same over time. In the last fifty years, the drugs utilized have considerably changed, as well as the therapeutic protocols. Some drugs have also changed their intended use. An analysis of the literature concerning the therapy of chronic heart failure in dogs affected by this widespread degenerative disease is not available; a synthesis of the published literature on this topic and a description of its current state of art are needed. To the authors’ knowledge, a review of this topic has never been published in veterinary medicine; therefore, the aim of this study is to overview the treatments of chronic CHF secondary to MMVD in dogs from 1970 to 2020 using the general framework of narrative reviews.

Abstract

The treatment of chronic congestive heart failure (CHF), secondary to myxomatous mitral valve disease (MMVD) in dogs, has considerably changed in the last fifty years. An analysis of the literature concerning the therapy of chronic CHF in dogs affected by MMVD is not available, and it is needed. Narrative reviews (NRs) are aimed at identifying and summarizing what has been previously published, avoiding duplications, and seeking new study areas that have not yet been addressed. The most accessible open-access databases, PubMed, Embase, and Google Scholar, were chosen, and the searching time frame was set in five decades, from 1970 to 2020. The 384 selected studies were classified into categories depending on the aim of the study, the population target, the pathogenesis of MMVD (natural/induced), and the resulting CHF. Over the years, the types of studies have increased considerably in veterinary medicine. In particular, there have been 43 (24.29%) clinical trials, 41 (23.16%) randomized controlled trials, 10 (5.65%) cross-over trials, 40 (22.60%) reviews, 5 (2.82%) comparative studies, 17 (9.60%) case-control studies, 2 (1.13%) cohort studies, 2 (1.13%) experimental studies, 2 (1.13%) questionnaires, 6 (3.40%) case-reports, 7 (3.95%) retrospective studies, and 2 (1.13%) guidelines. The experimental studies on dogs with an induced form of the disease were less numerous (49–27.68%) than the studies on dogs affected by spontaneous MMVD (128–72.32%). The therapy of chronic CHF in dogs has considerably changed in the last fifty years: in the last century, some of the currently prescribed drugs did not exist yet, while others had different indications.

1. Introduction

Myxomatous mitral valve disease (MMVD) is the most common acquired cardiovascular disease in dogs [1]. It is estimated that approximately 10% of dogs presented to primary care veterinary practices have heart disease and that MMVD is the most common among them (75% of canine cases of heart disease) [2,3]. Mitral regurgitation (MR) is the earliest hemodynamic event. The progression of the disease and the increasing severity of valvular regurgitation generate a volume overload of the left heart, leading to left atrial and ventricular remodeling and congestive heart failure (CHF) [1,4]. Particularly, remodeling secondary to MMVD is associated with characteristic histopathologic features, such as the expansion of the extracellular matrix with glycosaminoglycans and proteoglycans, the alteration of the valvular interstitial cell, and the attenuation or loss of the collagen-laden fibrosa layer. These lead to malformation of the mitral apparatus, biomechanical dysfunction, and mitral incompetence. Mitral regurgitation is the most common manifestation of MMVD and, in advanced stages, associated volume overload promotes progressive valvular regurgitation, left atrial and left ventricular remodeling, atrial tears, chordal rupture, and CHF, as stated before [5]. Dogs with MMVD present left-sided CHF clinical signs and a history of tachypnea, restlessness, respiratory distress, or cough [3]. Dogs with acute CHF need hospitalization, while patients with chronic CHF can be managed at home. The treatment of chronic CHF secondary to MMVD in dogs has not always been the same. In the last fifty years, the drugs utilized have considerably changed, and some have changed their intended use. The therapeutic protocols have also substantially changed over time. In 1970, the research and the literature were human medicine oriented, CHF in dogs was usually experimentally induced, and dogs were considered experimental animals. Later, the health and wellness of dogs have become primary endpoints; therefore, the research has been carried out on dogs as patients, and the therapy of CHF secondary to MMVD has been studied mainly on the spontaneous disease.
An analysis of the literature concerning the therapy of CHF in dogs affected by MMVD from 1970 to 2020 is not available, and a synthesis of the published literature on this topic, as well as a description of its current state of art, are needed.
The review on a specific subject can be systematic (SR) or non-systematic (narrative review—NR) and may include studies with different levels of evidence, different objectives, methods, and application areas [5]. Generally, an NR describes and appraises published articles that may be organized in chronological order, and the general framework includes different sections: introduction, literature search, central body/discussion, conclusion, and abstract.
To the authors’ knowledge, an NR on the therapeutic management of CHF secondary to MMVD in dogs has not yet been published in veterinary medicine, and the aim of this study is to overview the treatments of this disease in dogs from 1970 to 2020 using the general framework of narrative reviews.

2. Materials and Methods

2.1. Search Strategy

The identification of the research engines was the first step of the literature selection process [5]. The most accessible open-access databases, PubMed, Embase, and Google Scholar, were chosen, and the searching time frame was set in five decades, from 1970 to 2020. Then the key concept “therapy of chronic congestive heart failure caused by mitral valve disease in dogs” was transformed into keywords through the thesaurus system used to index articles for PubMed (Medical Subject Heading—MSH). The most distinctive terms were “therapy”, “chronic congestive heart failure”, “dogs”, and “mitral valve disease”, and they were entered into the search bar [5]. Then the categories of the most used cardioactive drugs (i.e., diuretics, ACE-inhibitors, inodilator, inotropes) were also included in the searching string.
The three basic Boolean operators, AND, OR, and NOT, were employed to focus the search. Since our topic contains multiple search terms, the operators were essential to connect various pieces of information to find exactly what we were looking for.
In accordance with the study design proposed by Ranganathan [6] and Röhrig, [7] the publications were classified as descriptive (case reports, case series, cross-sectional studies) or analytical, such as observational (cross-sectional studies, case-control studies, cohort studies) and experimental studies (clinical trials, randomized controlled trials, comparative studies, retrospective studies), or as questionnaires, reviews, and guidelines.

2.2. Inclusion/Exclusion Criteria

Inclusion criteria were full text and/or abstract available in the English language, better both, or at least the abstract, and studies focusing on the treatment of CHF secondary to MMVD in dogs published from 1970 to 2020. Furthermore, the selection also considered the origin of the CHF secondary to spontaneous or experimental-induced MMVD (MMVDEI).
Studies concerning the therapy of acute CHF, right CHF, Bernheim Syndrome and ventricular interdependence, chronic CHF secondary to heart diseases different from MMVD, research on animals different from the dog, and studies dealing with surgical therapy of MMVD were excluded from this study.
The inclusion and exclusion criteria were applied, and the resulting flowchart is reported in Figure 1.
The selected studies were subsequently classified into categories depending on the aim of the study, the population target, the pathogenesis of MMVD (natural occurring or induced), and the resulting CHF. Three sets of studies were obtained: dogs as a model for humans (DMH), dogs as a model for dogs (MMVDEI) (DMD), and dogs affected by naturally acquired MMVD as a model for diseased dogs (DNAD) (Table 1).
The studies were also distinguished depending on the target of the journal (human medicine and veterinary medicine) (Table 1) [8].

3. Results

3.1. General Considerations

The research engines provided 384 studies concerning the therapy of chronic CHF in dogs. PubMed proved to be more useful than Embase and Google Scholar for the search of older studies because it included more studies that better fitted our inclusion criteria (full text and/or abstract in English) (Figure 2 and Figure 3).
The studies published in veterinary medicine journals resulted in 43 (24.29%) clinical trials, 41 (23.16%) randomized controlled trials, 10 (5.65%) cross-over trials, 40 (22.60%) reviews, 5 (2.82%) comparative studies, 17 (9.60%) case-control studies, 2 (1.13%) cohort studies, 2 (1.13%) experimental studies, 2 (1.13%) questionnaires, 6 (3.40%) case-reports, 7 (3.95%) retrospective studies, and 2 (1.13%) guidelines (Figure 4).
In the fifty years considered, however, the experimental studies published in veterinary medicine journals (DMD) were less numerous (49–27.68%) than the studies on dogs affected by spontaneous MMVD (128–72.32%) (Figure 5).
Experimental studies in which the CHF was induced in healthy dogs to test the therapeutic efficacy (human or canine) show the highest timeframe variability in the distribution (Figure 6).

3.2. 1970–1979

In the 1970s, the literature search performed on the 3 research engines resulted in 11 studies, all of them published in human medicine journals [9,10,11,12,13,14,15,16,17,18,19]. The mitral valve incompetence was always experimentally induced in dogs, surgically and/or pharmacologically, to obtain a low cardiac output. The goal of these studies was to test drugs for the treatment of CHF in humans. The database that proved most useful for finding the oldest studies was PubMed (Figure 3).
In this decade, only one case report describing spontaneous CHF in dogs was published [20]. Thus, it can be inferred that pharmacologic management of canine CHF secondary to MMVD was not yet thoroughly investigated in this decade.
Furthermore, the milestone of therapy of the canine spontaneous chronic CHF due to MMVD was reported in a book [21]; therefore, it was not accessible to most of the researchers [18]. The therapeutic protocol included the same drugs used today but with very different intents, as reported in Figure 7 [21].

3.3. 1980–1989

During the 1980s, canine experimental studies increased compared to the 1970s [22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56,57,58,59], and they were mostly published in human medicine journals (DMH); in this decade, this type of study was still the most common (Figure 3). However, an experimental study carried out on dogs, that was then published in a veterinary medicine journal (DMD), was identified [60].
In addition to the above-mentioned experimental studies, five others were published on CHF management in dogs affected by spontaneous MMVD. Two studies tested the use of hydralazine [61,62], one tested milrinone [63] and the two others tested digitalis glycosides [64,65]. In the 1970s and 1980s, the digitalis glycosides were considered the standard therapy of the canine CHF, and the studies were mostly focused on finding the appropriate and individual therapeutic dosage; in fact, in some cases, the same dosage provided different results. For example, in one of the two publications, the digoxin dosage administered in 10 patients was 0.01 mg/kg lean body mass twice daily; however, serum digoxin concentrations in patients differed.

3.4. 1990–1999

The 1990s registered the highest number of experimental studies published in human medicine journals [66,67,68,69,70,71,72,73,74,75,76,77,78,79,80,81,82,83,84,85,86,87,88,89,90,91,92,93,94,95,96,97,98,99,100,101,102,103,104,105,106,107,108,109,110,111,112,113,114,115,116,117,118,119,120,121,122,123,124,125,126,127,128,129,130,131,132,133,134,135,136,137,138]. This highlights that the research concerning the therapy of human CHF was a key point along this period and that the dog was considered one of the most common and useful experimental animals. Furthermore, the number of experimental studies published in veterinary medicine journals also increased compared to the previous decade [139,140,141,142,143,144]. The efficacy of the therapy of CHF in dogs affected by spontaneous MMVD was evaluated, and the published studies were more numerous than in the previous twenty years. Many of the studies tested the effect and the efficacy of ACE inhibitors (captopril, enalapril, quinapril, ramipril, and benazepril), and over these ten years, they were introduced in the standard therapy of chronic CHF in dogs affected by MMVD [145,146,147,148,149,150,151,152,153,154,155,156]. In particular, it is important to mention the COVE study [147], the IMPROVE study [148], the BENCH study [156], and the LIVE study [155], which significantly contributed to the evaluation of the efficacy and effect of enalapril and benazepril. The ACE inhibitors were administered at different dosages: benazepril from a minimum of 0.25 mg/kg once daily, captopril 0.5 mg/kg three times daily, quinapril 0.5 mg/kg once daily, enalapril from 0.38 mg/kg twice daily to 0.5 mg/kg once or twice daily, and ramipril 0.125 mg/kg once or twice daily. Moreover, two studies have been published on milrinone [157,158] (which was administered at a dosage of 0.5 to 1 mg/kg twice daily), two on propentophylline [159,160], and one on the effect of fish oil when added to the diet of dogs with CHF [161]. These studies were isolated, and the research on these molecules has not been followed up in veterinary medicine. In 1991 and 1998, the first two systematic reviews, one on the management of chronic CHF in dogs [162] and one on afterload reducing agents [163], were published.
In 1995, the results of the first documented experience of a cardiological survey in veterinary medicine were published [164]. The questionnaire was submitted to veterinarians, and the aim was to analyze the preferences on the medications prescribed to treat heart diseases in dogs [164]. Interestingly, diuretics appeared to be the most common category (74%), while positive inotropic agents (digitalis glycoside), which were the milestone of the therapy of CHF in dogs up to the 1980s, were the least used drugs (20%). Thus, from this decade on, the use of digitalis glycoside as the main therapeutic agent started decreasing [164].

3.5. 2000–2009

During the 2000s, the experimental studies that tested in dogs the efficacy of drugs used for CHF in humans (DMH) were fewer than in the previous decades [165,166,167,168,169,170,171,172,173,174,175,176,177,178,179,180,181,182,183,184,185,186,187,188,189,190,191,192,193,194,195,196,197,198,199,200,201,202,203,204,205,206,207,208,209,210,211,212,213,214,215]. In contrast, there was an increase in studies published in veterinary medicine journals that evaluated the treatment of CHF in dogs, both experimental [216,217,218,219,220,221,222,223,224,225,226,227,228,229,230,231] and carried out in patients with spontaneous MMVD. The scientific publications on drugs tested in dogs with CHF secondary to MMVD (DNAD) were more numerous than in previous years, and many studies were performed on ACE inhibitors [232,233,234,235], β-blockers [236,237,238], sildenafil [239,240], amiodarone [241], diuretics [242], isosorbide 5-mononitrate [243], and amlodipine [244]. In particular, the different ACE inhibitors were administered at different dosages: quinapril and enalapril at 0.5 mg/kg once daily, ramipril at 0.125 mg/kg once daily, perindopril at 0.2 mg/kg once daily, benazepril from 0.25 to 1 mg/kg/day. Pimobendan was also introduced in the standard therapeutic protocol of CHF secondary to MMVD [245,246,247,248,249]. Some studies compared pimobendan and ACE inhibitors, such as the QUEST study [250], and the results showed that pimobendan, in combination with the standard therapy (diuretics and digoxin), administered at a dosage of 0.4–0.6 mg/kg/day prolonged the expectancy and quality of life in patients affected by CHF secondary to MMVD [251]. Digitalis glycosides definitively changed their intended use, and, differently from their previous indication, they were administered to decrease the excitability of the atrioventricular node and the ventricular rate in presence of atrial fibrillation (AF) [252]. At the end of this decade, guidelines for the diagnosis and treatment of canine chronic valvular heart disease were published for the first time [2]; the recommended drugs were furosemide, ACE-I, and pimobendan. The majority of the panelists recommended the administration of β-blockers, digoxin, or diltiazem as antiarrhythmics, and cough suppressants and bronchodilators in the presence of cough. In this decade, the attention to dogs’ diets increased, with particular interest for sodium restriction [253,254,255,256,257]. The reviews published in these ten years are much more numerous than in previous years because more studies were carried out to evaluate the therapy of CHF secondary to MMVD in dogs [237,247,258,259,260,261,262,263,264]; these data are important because the reviews identify, evaluate, and summarize the outcomes of the studies carried out in a specific period.

3.6. 2010–2020

From 2010 to 2020, as well as in the early 2000s, there was a decrease in experimental studies carried out on dogs published in human medicine journals and an increase in studies published in veterinary medicine journals. DMH studies were 34 [265,266,267,268,269,270,271,272,273,274,275,276,277,278,279,280,281,282,283,284,285,286,287,288,289,290,291,292,293,294,295,296,297,298], the DMD studies were 25 [299,300,301,302,303,304,305,306,307,308,309,310,311,312,313,314,315,316,317,318,319,320,321,322,323,324], and 69 studies concerning the therapy of CHF secondary to spontaneous MMVD have been found in the literature. The research was profuse, and the drugs tested were numerous; in fact, the reviews published in these ten years regarding the therapy of CHF secondary to MMVD in dogs are 25 [325,326,327,328,329,330,331,332,333,334,335,336,337,338,339,340,341,342,343,344,345,346,347,348,349]. As in the previous decade, many studies have been published and many drugs have been tested on dogs with spontaneous disease, such as sildenafil [350,351,352,353], imatinib [354], atorvastatin [355,356], coenzyme q10 [357,358], amlodipine [359], BNP1–32 [360], and angiotensin receptor antagonists [361]. In this decade, several studies have been published on diuretics, with particular regard to torasemide (such as the TEST study [362] and the CARPODIEM study [363]). In these papers, the diuretic has been administered over a dose range of 0.13 mg/kg/day to 0.5 mg/kg/day, and spironolactone (an aldosterone receptor antagonist) has been administered at dosages from 0.49 mg/kg once daily to 2 mg/kg once daily. These drugs are very useful in the therapy of CHF secondary to MMVD in dogs [362,363,364,365,366,367,368,369].
Studies focused on other standard therapy drugs (pimobendan or ACE inhibitors, such as the QUEST and the EPIC studies [370,371], respectively, which focused on symptomatic and asymptomatic dogs with cardiac remodeling) or drugs used in case of complications related to this syndrome (such as β-blockers, amlodipine, and digoxin) [372,373,374,375,376,377,378,379,380,381,382,383,384] have also been published. In the QUEST and EPIC studies, pimobendan was administered over a dose range of 0.4 to 0.6 mg/kg/daily and benazepril over a dose range of 0.25 to 1 mg/kg/daily. The addition of the ACE inhibitor ramipril to pimobendan and furosemide has been demonstrated not to have any beneficial effect on survival time in dogs with CHF secondary to MMVD [384].
In 2019, the newly updated guidelines were published according to the most recent results [3]. The recommended diuretic was not only furosemide but also torasemide. Moreover, spironolactone was recommended in addition to the classic triple therapy for its aldosterone-antagonist effect [3].
Other studies evaluated the clinical findings and the survival time following the administration of the drugs [385], X-ray and ultrasound images after the treatment [386], and the “aldosterone breakthrough” following the administration of ACE inhibitors [387]. Furthermore, a study on a myostatin antagonist used to counteract cardiac cachexia secondary to CHF has also been published [388]. In recent years, the evaluation of NT-pro BNP levels following the cardiological treatment has gained a lot of interest; in fact, low levels of this molecule indicate a better prognosis [389,390]. Cohort studies in veterinary medicine are rarely carried out because of high costs and long-time needing; in the period considered for this narrative review, only two have been found in the literature [391,392]. A questionnaire published in 2015 was also very interesting since it is useful to compare how dogs’ CHF therapy has changed from that which was used twenty years earlier [393].

3.7. 2021—Last Minute Update

The never-ending story of the medical strategies for the treatment of MMVD in dogs is far from the conclusion.
In 2021, the last clinical trial, named the BESST study, has been published after the conclusion of this narrative review [394]. The BESST is a multicentric double-blind study that compared the combination of benazepril and spironolactone in the management of CHF in dogs affected by MMVD [394]. Particularly, the results of this study show that the combination of spironolactone and benazepril is effective, safe, and superior to benazepril alone when used with furosemide for the management of mild, moderate, or severe CHF caused by MMVD in dogs.

4. Discussion

The therapy of chronic CHF in dogs has considerably changed in the last fifty years. In the last century, some of the currently prescribed drugs did not exist yet, while others had different indications [21]. Digitalis glycosides are the oldest medication used for the treatment of chronic CHF in dogs, and despite the risks of intoxication or death secondary to their overdose, the drug is still used. For a very long time, digitalis glycosides have been administrated because of their positive inotropic and negative chronotropic effect, and their dromotropic action. Furthermore, they were used to relieve clinical signs as cough, dyspnea (secondary to pulmonary edema), and ascites, frequently found in severe CHF. Currently, their clinical use has changed: the presence of AF, quite a common complication of MMVD, especially in medium- and large-breed dogs, is the first indication of adding the digitalis glycosides to the therapeutic protocol. Nevertheless, digoxin is the most common drug used to ensure adequate control of the ventricular rate in patients with AF, alone or associated with diltiazem, as reported by the literature [252,377].
Diuretics are another pivotal category of drugs that makes the history of the cardioactive protocols. In 1970, diuretics were administered only if therapy with glycosides alone failed. Nowadays, they are one of the most useful drugs used for the treatment of chronic CHF in dogs. The oldest diuretics were mercurials, thiazides, furosemide, spironolactone, and ethacrynic acid. Furosemide was administered in case of the development of resistance to thiazides, so it was not the first diuretic of choice [348]. To the present day, the therapeutic protocol of chronic CHF in dogs includes furosemide, the most widely used diuretic.
Interestingly, the role of spironolactone in cardiac protocols changed its use: in the last century, it was administered in association with thiazides to avoid hypokalemia, while it is now one of the main drugs for the treatment of chronic CHF because of its antagonist activity to mineralocorticoid receptors. Spironolactone, added to the therapy with pimobendan, diuretic, and an ACE inhibitor, has been shown to increase survival time in dogs with chronic CHF secondary to MMVD [362]. The main antiarrhythmics drugs used in the 1970s were quinidine sulphate, procainamide, and lidocaine. Currently, as previously mentioned, the digoxin–diltiazem protocol is well tolerated, and β-blocker antiarrhythmics can be used [215,219]. ACE inhibitors were introduced into dogs’ treatment protocol in the early 1990s, while pimobendan was introduced in the 2000s.
The renin–angiotensin–aldosterone system (RAAS) activation can be compensatory in the early stages of cardiovascular and renal diseases, but its long-term activation is maladaptive [345]. In patients with heart failure, relative increases in plasma renin activity and the blood aldosterone concentration are considered markers of, and contributors to, the hemodynamic and anatomic derangements of this syndrome [345]. However, the literature shows that the more we learn about this system, the broader and more complex it becomes. Continuous research into this complex system is necessary to improve medical therapies for cardiovascular and renal diseases, allowing us to modulate this system and improve clinical outcomes more adeptly [345].
Following this research, other considerations emerge: fifty years ago, the research was mainly focused on the therapy of human CHF and, in the studies published in human medicine journals that tested drugs on dogs, the syndrome was induced in different ways, surgically or pharmacologically. Different pathologies that cause CHF, such as the surgical procedure or the drug used to induce a low cardiac output, were not particularly taken into consideration.
Studies published in veterinary journals were only a few in the 1970s; however, over the years, their number increased until they were more than the studies published in human journals where the dog was used as a laboratory animal. Furthermore, regarding the studies published in veterinary medicine journals, it should be noted that the experimental studies (DMD) are fewer than the studies carried out on dogs with spontaneous pathology.
As can be seen from Figure 2, over the years, the types of studies have increased considerably in veterinary medicine, and reviews have always had an increasing trend over the five decades. It is important to remember that reviews should be published every 4–5 years as they are useful to understand the direction of the research; however, systematic reviews are restricted in veterinary medicine. Cohort studies are not very numerous in veterinary medicine due to their high cost, long duration, and potential numerous losses of subjects during the study. Over the past two decades, randomized controlled trials have become more and more numerous; they have the advantage of selecting a group of patients through defined criteria, administering the treatment randomly, and thus reducing bias.
The databases chosen for the research of the studies to be included in this narrative review were PubMed, Google Scholar, and Embase. PubMed was the database that provided the greatest number of studies and, in particular, the oldest ones. It is a very wide database and, thanks to the use of Mesh terms and Boolean operators, allows the researcher to identify the most pertinent studies easily and quickly. Google Scholar is a very intuitive and easy-to-use database. The results obtained are conspicuous as there are also books, citations, meetings, and symposiums; however, it is more generic compared to PubMed, and sometimes some results are irrelevant. It is important to remember that Google Scholar is the only free access database among these three; not all information may be accessible without an institutional account, but it allows anyone to search. Embase is a database that allows precise searches, although fewer old studies have been found compared to PubMed.
This review is a narrative review (NR) or non-systematic review: NRs are aimed at identifying and summarizing what has been previously published, avoiding duplications, and seeking new study areas that have not yet been addressed. An NR does not have the strict rules of a systematic review; therefore, an NR potentially leads to biases because of subjectivity in the study selection [5].

5. Conclusions

The treatments of chronic CHF secondary to MMVD in dogs have considerably changed in the last fifty years, and some drugs have changed their intended use, such as digitalis glycosides and spironolactone. In the 1970s, the research and the literature were human medicine oriented, CHF in dogs was usually experimentally induced, and dogs were considered experimental animals. Later, the health and wellness of dogs have become primary endpoints; therefore, the research has been carried out on dogs as patients, and the therapy of CHF secondary to MMVD has been studied mainly on the spontaneous disease. This NR has been aimed at identifying and summarizing what has been previously published, avoiding duplications, with the intent to be a useful tool for the clinicians approaching this topic.

Author Contributions

Conceptualization, P.G.B., M.B. and V.Z.; methodology, V.Z. and M.B.; software, V.Z.; validation, P.G.B., M.B., V.Z., C.L., A.G. and S.G.; formal analysis, V.Z.; investigation, V.Z. and M.B.; resources, P.G.B.; data curation, V.Z. and M.B.; writing—original draft preparation, M.B., V.Z. and P.G.B.; writing—review and editing, M.B., V.Z., P.G.B., C.L., A.G. and S.G.; visualization, M.B., V.Z. and P.G.B.; supervision, P.G.B.; project administration, P.G.B. and M.B.; funding acquisition, M.B. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Institutional Review Board Statement

Not applicable.

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. Fox, P.R. Pathology of myxomatous mitral valve disease in the dog. J. Vet. Cardiol. 2012, 14, 103–126. [Google Scholar] [CrossRef]
  2. Atkins, C.; Bonagura, J.; Ettinger, S.; Fox, P.; Gordon, S.; Haggstrom, J.; Stepien, R. Guidelines for the Diagnosis and Treatment of Canine Chronic Valvular Heart Disease. J. Vet. Intern. Med. 2009, 23, 1142–1150. [Google Scholar] [CrossRef]
  3. Keene, B.W.; Atkins, C.E.; Bonagura, J.D.; Fox, P.R.; Häggström, J.; Luis Fuentes, V.; Oyama, M.A.; Rush, J.E.; Stepien, R.; Uechi, M. ACVIM consensus guidelines for the diagnosis and treatment of myxomatous mitral valve disease in dogs. J. Vet. Intern. Med. 2019, 33, 1127–1140. [Google Scholar] [CrossRef] [PubMed]
  4. Yancy, C.W.; Jessup, M.; Bozkurt, B.; Butler, J.; Casey, D.E., Jr.; Drazner, M.H.; Fonarow, G.C.; Geraci, S.A.; Horwich, T.; Januzzi, J.L.; et al. 2013 ACCF/AHA Guideline for the Management of Heart Failure. JACC 2013, 62, 147–239. [Google Scholar] [CrossRef] [Green Version]
  5. Ferrari, R. Writing narrative style literature reviews. Med. Writ. 2015, 24, 230–235. [Google Scholar] [CrossRef]
  6. Ranganathan, P.; Aggarwal, R. Study designs: Part 1—An overview and classification. Perspect. Clin. Res. 2018, 9, 184–186. [Google Scholar] [PubMed]
  7. Röhrig, B.; Du Prel, J.B.; Wachtlin, D.; Blettner, M. Types of study in medical research: Part 3 of a series on evaluation of scientific publications. Dtsch. Arztebl. Int. 2009, 106, 262–268. [Google Scholar]
  8. Bottarelli, E.; Ostanello, F. Compiti e scopi dell’epidemiologia. In Epidemiologia-Teoria ed Esempi di Medicina Veterinaria, 1st ed.; Edagricole: Milan, Italy, 2011; pp. 29–75. [Google Scholar]
  9. Kumar, B.; Hood, W.B., Jr.; Joison, J.; Gilmour, D.P.; Norman, J.C.; Abelmann, W.H. Experimental myocardial infarction: VI. Efficacy and toxicity of digitalis in acute and healing phase in intact conscious dogs. J. Clin. Investig. 1970, 49, 358–364. [Google Scholar] [CrossRef] [Green Version]
  10. Vatner, S.F.; Higgins, C.B.; Franklin, D.; Braunwald, E. Effects of a Digitalis Glycoside on Coronary and Systemic Dynamics in Conscious Dogs. Circ. Res. 1971, 28, 470–479. [Google Scholar] [CrossRef] [Green Version]
  11. Higgins, C.B.; Vatner, S.F.; Braunwald, E. Regional Hemodynamic Effects of a Digitalis Glycoside in the Conscious Dog with and without Experimental Heart Failure. Circ. Res. 1972, 30, 406–417. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  12. Sakai, K.; Sugano, S.; Isono, C. Effects of oxyfedrine and ouabain on the heart-lung preparation of the dog. Naunyn Schmiedebergs Arch. Pharmacol. 1973, 277, 89–102. [Google Scholar] [CrossRef] [PubMed]
  13. Vatner, S.F.; Higgins, C.B.; Braunwald, E. Effects of norepinephrine on coronary circulation and left ventricular dynamics in the conscious dog. Circ. Res. 1974, 34, 812–823. [Google Scholar] [CrossRef] [Green Version]
  14. Vatner, S.F.; Mc Ritchie, R.J.; Maroko, P.R.; Patrick, T.A.; Braunwald, E. Effects of Catecholamines, Exercise, and Nitroglycerin on the Normal and Ischemic Myocardium in Conscious Dogs. J. Clin. Investig. 1974, 54, 563–575. [Google Scholar] [CrossRef]
  15. Vatner, S.F.; Mc Ritchie, R.J.; Braunwald, E. Effects of Dobutamine on Left Ventricular Performance, Coronary Dynamics, and Distribution of Cardiac Output in Conscious Dogs. J. Clin. Investig. 1974, 53, 1265–1273. [Google Scholar] [CrossRef] [Green Version]
  16. Kim, Y.I.; Noble, R.J.; Zipes, D.P. Dissociation of the inotropic effect of digitalis from its effect on atrioventricular conduction. Am. J. Cardiol. 1975, 36, 459–467. [Google Scholar] [CrossRef]
  17. Cummings, J.R.; Beaulieu, G. Positive inotropic and antiarrhythmic actions of actodigin in dogs (1). Arch. Int. Pharmacodyn. Ther. 1977, 228, 92–98. [Google Scholar] [PubMed]
  18. Kirk, E.S.; Lejemtel, T.H.; Nelson, G.R.; Sonnenblick, E.H. Mechanisms of beneficial effects of vasodilators and inotropic stimulation in the experimental failing ischemic heart. Am. J. Med. 1978, 65, 189–196. [Google Scholar] [CrossRef]
  19. O’Keeffe, B.; Hayler, A.M.; Holt, D.W.; Medd, R.K. Cardiac consequences and treatment intoxication: Experimental evaluation of disopyramide in dogs. Cardiovasc. Res. 1979, 13, 630–634. [Google Scholar] [CrossRef]
  20. Atwell, R.B. The use of alpha blockade in the treatment of congestive heart failure associated with dirofilariasis and mitral valvular incompetence. Vet. Rec. 1979, 104, 114–116. [Google Scholar] [CrossRef]
  21. Ettinger, S.J.; Suter, P.F. Digitalis and the Cardiac Glicosides. In Canine Cardiology, 1st ed.; W.B. Saunders Company: Toronto, ON, Canada, 1970; pp. 224–261. [Google Scholar]
  22. Ek, L.; Björkman, J.A.; Carlsson, E.; Johansson, B. The haemodynamic effects of intravenous prenalterol and ouabain in conscious dogs. Acta Med. Scand. Suppl. 1982, 659, 39–52. [Google Scholar] [CrossRef]
  23. Engler, R.; Pouleur, H.; Link, J.; Printz, M.; Covell, J.W. Changes in control of renin release in congestive heart failure in dogs: Response to acute and chronic vasodilator therapy. Clin. Exp. Hypertens A 1982, 4, 639–659. [Google Scholar] [CrossRef]
  24. O’Rourke, R.A.; Badke, F.R.; Forst, D. Comparative hemodynamic effects of digoxin vs nitroprusside in conscious dogs with aortocaval fistula-induced chronic left ventricular volume overload and normal systolic performance. Am. Heart J. 1982, 103, 489–497. [Google Scholar] [CrossRef]
  25. Satoh, K.; Kawada, M.; Taira, N. Improvement by trapidilod cardiac function of the dog heart-lung preparation depressed by pentobarbital. Jpn. Heart J. 1983, 24, 399–405. [Google Scholar] [CrossRef] [Green Version]
  26. Pouleur, H.; Rousseau, M.F.; van Mechelen, H.; Roncoroni, L.; Ries, A.; Charlier, A.A. Cardiovascular effects of AR-L115 BS in conscious dogs with and without chronic congestive heart failure. J. Cardiovasc. Pharmacol. 1982, 4, 409–418. [Google Scholar] [CrossRef]
  27. Alousi, A.A.; Canter, J.M.; Montenaro, M.J.; Fort, D.J.; Ferrari, R.A. Cardiotonic activity of milrinone, a new and potent cardiac bipyridine, on the normal and failing heart of experimental animals. J. Cardiovasc. Pharmacol. 1983, 5, 792–803. [Google Scholar] [CrossRef]
  28. Carmines, P.K.; Rosivall, L.; Till, M.F.; Navar, L.G. Renal hemodynamic effects of captopril in anesthetized sodium-restricted dogs. Relative contributions of prostaglandin stimulation and suppressed angiotensin activity. Ren. Physiol. 1983, 6, 281–287. [Google Scholar] [PubMed]
  29. Fennell, W.H.; Taylor, A.A.; Young, J.B.; Brandon, T.A.; Ginos, J.Z.; Goldberg, L.I.; Mitchell, J.R. Propylbutyldopamine: Hemodynamic Effects in Conscious Dogs, Normal Human Volunteers and Patients with Heart Failure. Circulation 1983, 67, 829–836. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  30. Leddy, C.L.; Wilen, M.; Franciosa, J.A. Effects of a new angiotensin converting enzyme inhibitor, enalapril, in acute and chronic left ventricular failure in dogs. J. Clin. Pharmacol. 1983, 23, 189–198. [Google Scholar] [CrossRef]
  31. MacCannell, K.L.; Giraud, G.D.; Hamilton, P.L.; Groves, G. Haemodynamic responses to dopamine and dobutamine infusions as a function of duration of infusion. Pharmacology 1983, 26, 29–39. [Google Scholar] [CrossRef]
  32. Morita, T.; Satoh, K.; Taira, N. Improvement of cardiac performance by AR-L 115 BS, a new cardiotonic drug, in the experimental failing dog heart. Jpn. Heart J. 1984, 25, 439–445. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  33. Engler, R.L.; Freeman, G.L.; Covell, J.W. Regional venous return: Nitroprusside effect in normal and chronically congested dogs. Am. J. Physiol. 1983, 245, 814–823. [Google Scholar] [CrossRef] [PubMed]
  34. Pastelìn, G.; Mendez, R. Cardiac effects of six actodigin (AY-22,241)-related semisynthetic glycosides. Life Sci. 1983, 32, 1905–1909. [Google Scholar] [CrossRef]
  35. Pastelin, G.; Mendez, R.; Kabela, E.; Farah, A. The search for a digitalis substitute II milrinone (Win 47203). Its action on the heart-lung preparation of the dog. Life Sci. 1983, 33, 1787–1796. [Google Scholar] [CrossRef]
  36. Porter, C.B.; Walsh, R.A.; Badke, F.R.; O’Rourke, R.A. Differential effects of diltiazem and nitroprusside on left ventricular function in experimental chronic volume overload. Circulation 1983, 68, 685–692. [Google Scholar] [CrossRef] [Green Version]
  37. Pouleur, H.; Engler, R.L.; Link, J.; Printz, M.P.; Covell, J.W. Changes in plasma renin activity and haemodynamics during vasodilator therapy in conscious dogs with myocardial infarction or chronic volume overload. Eur. J. Clin. Investig. 1983, 13, 331–338. [Google Scholar] [CrossRef]
  38. Pouleur, H.; Marechal, G.; Balasim, H.; Van Mechelen, H.; Ries, A.; Rousseau, M.F.; Charlier, A.A. Effects of dobutamine and sulmazol (AR-L115 BS) on myocardial metabolism and coronary, femoral, and renal blood flows: A comparative study in normal dogs and in dogs with chronic volume overload. J. Cardiovasc. Pharmacol. 1983, 5, 861–867. [Google Scholar] [CrossRef] [Green Version]
  39. Prasad, K.; O’Neil, C.L.; Bharadwaj, B. Effects of chronic digoxin treatment on cardiac function, electrolytes, and sarcolemmal ATPase in the canine failing heart due to chronic mitral regurgitation. Am. Heart J. 1984, 108, 1487–1494. [Google Scholar] [CrossRef]
  40. Riegger, G.A.; Liebau, G.; Holzschuh, M.; Witkowski, D.; Steilner, H.; Kochsiek, K. Role of the renin-angiotensin system in the development of congestive heart failure in the dog as assessed by chronic converting-enzyme blockade. Am. J. Cardiol. 1984, 53, 614–618. [Google Scholar] [CrossRef]
  41. Braunwald, E. Effects of Digitalis on the Normal and the Failing Heart. J. Am. Coll. Cardiol. 1985, 5, 51–59. [Google Scholar] [CrossRef] [Green Version]
  42. Kosugi, I.; Gonga, T.; Okada, K.; Tajimi, K.; Moriyasu, N.; Fukatsu, O. Effects of amrinone on hemodynamics, oxygen consumption and plasma catecholamine levels in anesthetized dogs. Masui 1985, 34, 429–433. [Google Scholar]
  43. Nunoki, K.; Goto, T.; Satoh, K.; Taira, N. Improvement by denopamine (TA-064) of pentobarbital-induced cardiac failure in the dog heart-lung preparation. Heart Vessels 1985, 1, 216–219. [Google Scholar] [CrossRef] [PubMed]
  44. Hori, M.; Inoue, M.; Tamai, J.; Koretsune, Y.; Kitakaze, M.; Iwai, K.; Ito, H.; Kitabatake, A.; Kamada, T. Cardiotonic activity of a new inotropic agent, 3,4-dihydro-6-[4-(3,4-dimethoxybenzoyl)-1-piperazinyl]-2(1H)-quinolinone (OPC-8212), in the dogs with and without b-blocker and Ca++ antagonist pretreatment. Jpn. Circ. J. 1986, 50, 37–44. [Google Scholar] [CrossRef] [Green Version]
  45. Goto, T.; Nunoki, K.; Satoh, K.; Taira, N. Amelioration of heart failure by MDL 17043 and MDL 19205, novel positive inotropic drugs, in dog heart-lung preparations. Jpn. Heart J. 1985, 26, 1011–1018. [Google Scholar] [CrossRef] [Green Version]
  46. Prasad, K.; O’Neil, C.L.; Bharadwaj, B. Effect of chronic prazosin treatment on the cardiac function and electrolytes in failing heart due to chronic mitral insufficiency. Can. J. Cardiol. 1985, 1, 107–112. [Google Scholar]
  47. Prasad, K.; O’Neil, C.L.; Bharadwaj, B. Effect of prazosin treatment on the cardiac sarcolemmal ATPase in failing heart due to mitral insufficiency in dogs. Cardiovasc. Res. 1985, 19, 406–410. [Google Scholar] [CrossRef]
  48. Weyl, J.D.; Snyder, R.W.; Hanson, R.C. Differential cardioprotective properties of the l- and d- enantiomers of bucindolol in a canine model of heart failure. Arch. Int. Pharmacodyn. Ther. 1985, 275, 4–12. [Google Scholar]
  49. Ikeo, T.; Nagao, T.; Murata, S.; Yabana, H.; Sato, M.; Nakajima, H. Cardiovascular effects of the new positive inotropic agent denopamine with special reference to species difference and the effect on failing heart. Arzneimittelforschung 1986, 36, 1063–1068. [Google Scholar] [PubMed]
  50. Sonoki, H.; Uchida, Y.; Masuo, M.; Tomaru, T.; Katoh, A.; Sugimoto, T. Effects of forskolin on canine congestive heart failure. Nihon Yakurigaku Zasshi 1986, 88, 389–394. [Google Scholar] [CrossRef] [Green Version]
  51. Petein, M.; Heppner, B.; Bache, R.J.; Cohn, J.N.; Pierpont, G.L. Hemodynamic and regional blood flow response to piroximone (MDL 19205) in dogs with congestive heart failure: A comparison with dobutamine. J. Pharmacol. Exp. Ther. 1987, 241, 956–960. [Google Scholar] [PubMed]
  52. Goldberg, E.; Berdoff, R.; Spivack, G.; Haimowitz, A.; Tay, S. Evaluation of the vasodilator vs inotropic effect of milrinone using an animal model of left ventricular failure: Reversal of disopyramide depression of the myocardium with milrinone. Angiology 1987, 38, 657–662. [Google Scholar] [CrossRef]
  53. Imagawa, J.; Nabata, H.; Sakai, K. Comparison of cardiovascular effects of SGB-1534 and prazosin, selective a-adrenoceptor antagonists, in anesthetized dogs. Jpn. J. Pharmacol. 1987, 44, 35–41. [Google Scholar] [CrossRef] [Green Version]
  54. Satoh, K.; Nunoki, K.; Goto, T.; Hosono, M.; Hashimoto, H.; Sato, Y.; Taira, N. Improvement of pentobarbital-induced heart failure by MCL-154, a novel and potent cardiotonic agent, in the dog heart-lung preparation. Jpn. J. Pharmacol. 1988, 47, 189–195. [Google Scholar] [CrossRef]
  55. Sonoki, H.; Uchida, Y.; Tomaru, T.; Sugimoto, T. Effects of prazosin, SGB-1534, dobutamine and isoproterenol on congestive heart failure in dogs. Nihon Yakurigaku Zasshi 1988, 92, 119–126. [Google Scholar] [CrossRef] [Green Version]
  56. Hittinger, L.; Shannon, R.P.; Kohin, S.; Lader, A.S.; Manders, W.T.; Patrick, T.A.; Kelly, P.; Vatner, S.F. Isoproterenol-Induced Alterations in Myocardial Blood Flow, Systolic and Diastolic Function in Conscious Dogs With Heart Failure. Circulation 1989, 80, 658–668. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  57. Pouleur, H.; Hanet, C.; Schröder, E.; Col, J.; Van Mechelen, H.; Etienne, J.; Rousseau, M.F. Effects of pimobendan (UD-CG 115 BS) on left ventricular inotropic state in conscious dogs and in patients with heart failure. J. Cardiovasc. Pharmacol. 1989, 14, 18–22. [Google Scholar]
  58. Sahashi, T.; Ito, H.; Nagata, K.; Hirose, I.; Wada, H.; Takai, K.; Hirakawa, S. Effects of ace inhibitor (captopril) on canine systemic capacitance vessels: A study with the measurement of mean circulatory pressure. Acta Sch. Med. Univ. Gifu 1989, 37, 1011–1023. [Google Scholar]
  59. Van Meel, J.C.; Diederen, W. Hemodynamic profile of the cardiotonic agent pimobendan. J. Cardiovasc. Pharmacol. 1989, 14, S1–S6. [Google Scholar]
  60. Kittleson, M.D.; Hamlin, R.L. Hydralazine pharmacodynamics in the dog. Am. J. Vet. Res. 1983, 44, 1501–1505. [Google Scholar]
  61. Hamlin, R.L.; Kittleson, M.D. Clinical experience with hydralazine for treatment of otherwise intractable cough in dogs with apparent left-side heart failure. J. Am. Vet. Med. Assoc. 1982, 180, 1327–1329. [Google Scholar] [PubMed]
  62. Kittleson, M.D.; Johnson, L.E.; Oliver, N.B. Acute hemodynamic effects of hydralazine in dogs with chronic mitral regurgitation. J. Am. Vet. Med. Assoc. 1985, 187, 258–261. [Google Scholar]
  63. Kittleson, M.D.; Pipers, F.S.; Knauer, K.W.; Keister, D.M.; Knowlen, G.G.; Miner, W.S. Echocardiographic and clinical effects of milrinone in dogs with myocardial failure. Am. J. Vet. Res. 1985, 46, 1659–1664. [Google Scholar] [PubMed]
  64. Tobias, A.H.; Bland-van den Berg, P.; Kruse, M.M.; Tubbesing, U.H.; Berry, W.L. Serum digoxin concentrations in canine congestive heart failure. J. S. Afr. Vet. Assoc. 1989, 60, 11–14. [Google Scholar] [PubMed]
  65. Staudacher, G. Individual glycoside therapy using serum concentration determination in canine heart failure. Dtsch. Tierarztl. Wochenschr. 1989, 96, 308–310. [Google Scholar]
  66. Barrett, J.A.; Woltmann, R.F.; Swillo, R.S.; Kasiewski, C.; Faith, W.C.; Campbell, H.F.; Perrone, M.H. Pharmacology of RG W-2938: A cardiotonic agent with vasodilator activity. J. Cardiovasc. Pharmacol. 1990, 16, 537–545. [Google Scholar] [CrossRef]
  67. Blackford, L.W.; Golden, A.L.; Bright, J.M.; Bright, R.M.; Gompf, R.E. Captopril provides sustained hemodynamic benefits in dogs with experimentally induced mitral regurgitation. Vet. Surg. 1990, 19, 237–242. [Google Scholar] [CrossRef]
  68. Carlyle, P.F.; Cohn, J.N. Systemic and regional hemodynamic effects of alpha-adrenoceptor blockade in chronic left ventricular dysfunction in the conscious dog. Am. Heart J. 1990, 120, 619–624. [Google Scholar] [CrossRef]
  69. Elsner, D.; Kromer, E.P.; Riegger, A.J. Hemodynamic, hormonal, and renal effects of the prostacyclin analogue iloprost in conscious dogs with and without heart failure. J. Cardiovasc. Pharmacol. 1990, 16, 601–608. [Google Scholar] [CrossRef]
  70. Holtz, J.; Munzel, T.; Sommer, O.; Bassenge, E. Converting enzyme inhibition by enalapril in experimental heart failure. Nephron 1990, 55, 73–76. [Google Scholar] [CrossRef] [PubMed]
  71. Lavine, S.J.; Campbell, C.A.; Held, A.C.; Johnson, V. Effect of inotropic and vasodilator therapy on left ventricular diastolic filling in dogs with severe left ventricular dysfunction. J. Am. Coll. Cardiol. 1990, 15, 1165–1172. [Google Scholar] [CrossRef] [Green Version]
  72. Riegger, G.A.; Elsner, D.; Forssmann, W.G.; Kromer, E.P. Effects of ANP-(95-126) in dogs before and after induction of heart failure. Am. J. Physiol. 1990, 259, 1643–1648. [Google Scholar] [CrossRef] [PubMed]
  73. Gosgnach, M.; Gérard, J.L.; Berdeaux, A.; Giudicelli, J.F. Compared peripheral vascular responses to intravenous and intra-arterial administrations of positive inotropic agents in conscious dogs. Fundam. Clin. Pharmacol. 1991, 5, 709–718. [Google Scholar] [CrossRef]
  74. Ichihara, K.; Abiko, Y. The effect of pimobendan on myocardial mechanical function and metabolism in dogs: Comparison with dobutamine. J. Pharm. Pharmacol. 1991, 43, 583–588. [Google Scholar] [CrossRef] [PubMed]
  75. Riegger, A.J. ACE inhibition: Mechanisms of cardioprotection in chronic experimental heart failure. Klin. Wochenschr. 1991, 69, 20–23. [Google Scholar] [PubMed]
  76. Dogterom, P.; Zbinden, G.; Reznik, G.K. Cardiotoxicity of vasodilators and positive inotropic/vasodilating drugs in dogs: An overview. Crit. Rev. Toxicol. 1992, 22, 203–241. [Google Scholar] [CrossRef]
  77. Elsner, D.; Müntze, A.; Kromer, E.P.; Riegger, G.A. Prostaglandin E2 in dogs with heart failure: Hemodynamic, hormonal, and renal effects. J. Cardiovasc. Pharmacol. 1992, 20, 547–553. [Google Scholar] [CrossRef] [PubMed]
  78. Elsner, D.; Müntze, A.; Kromer, E.P.; Riegger, G.A. Prostaglandin I2 versus prostaglandin E2 in dogs with and without low cardiac output. Differential effects on renal function. Am. J. Hypertens 1992, 5, 175–179. [Google Scholar] [CrossRef] [PubMed]
  79. Sudo, Y.; Takai, M.; Esumi, K. Improved heart failure protection by FK664, a novel positive inotropic agent, in dog heart-lung preparations. Life Sci. 1992, 51, 41–46. [Google Scholar] [CrossRef]
  80. Brands, M.W.; Alonso-Galicia, M.; Mizelle, H.L.; Montani, J.P.; Hildebrandt, D.A.; Hall, J.E. Chronic angiotensin-converting-enzyme inhibition improves cardiac output and fluid balance during heart failure. Am. J. Physiol. 1993, 264, 414–422. [Google Scholar] [CrossRef]
  81. Pagel, P.S.; Hettrick, D.A.; Warltier, D.C. Amrinone enhances myocardial contractility and improves left ventricular diastolic function in conscious and anesthetized chronically instrumented dogs. Anesthesiology 1993, 79, 753–765. [Google Scholar] [CrossRef]
  82. Sabbah, H.N.; Levine, T.B.; Gheorghiade, M.; Kono, T.; Goldstein, S. Hemodynamic response of a canine model of chronic heart failure to intravenous dobutamine, nitroprusside, enalaprilat, and digoxin. Cardiovasc. Drugs Ther. 1993, 7, 349–356. [Google Scholar] [CrossRef]
  83. Satoh, K.; Satoh, Y.; Imagawa, J.; Taira, N. Improvement of cardiac performance by pimobendan, a new cardiotonic drug, in the experimental failing dog heart. Jpn. Heart J. 1993, 34, 213–219. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  84. Seymour, A.A.; Asaad, M.M.; Lanoce, V.M.; Langenbacher, K.M.; Fennell, S.A.; Rogers, W.L. Systemic hemodynamics, renal function and hormonal levels during inhibition of neutral endopeptidase 3.4.24.11 and angiotensin-converting enzyme in conscious dogs with pacing-induced heart failure. J. Pharmacol. Exp. Ther. 1993, 266, 872–883. [Google Scholar] [PubMed]
  85. McDonald, K.M.; Francis, G.S.; Matthews, J.; Hunter, D.; Cohn, J.N. Long-Term Oral Nitrate Therapy Prevents Chronic Ventricular Remodeling in the Dog. J. Am. Coll. Cardiol. 1993, 21, 514–522. [Google Scholar] [CrossRef]
  86. Moe, G.W.; Montgomery, G.; Howard, R.J.; Grima, E.A.; Armstrong, P.W. Left ventricular myocardial blood flow, metabolism, and effects of treatment with enalapril: Further insights into the mechanisms of canine experimental pacing-induced heart failure. J. Lab. Clin. Med. 1993, 121, 294–301. [Google Scholar]
  87. Wang, J.; Zhao, G.; Shen, W.; Ochoa, M.; Moore, D.; Hubbard, J.W.; Hintze, T.H. Effects of an orally active NO-releasing agent, CAS 936, and its active metabolite, 3754, on cardiac and coronary dynamics in normal conscious dogs and after pacing-induced heart failure. J. Cardiovasc. Pharmacol. 1993, 22, 51–58. [Google Scholar] [CrossRef]
  88. Asanoi, H.; Ishizaka, S.; Kameyama, T.; Ishise, H.; Sasayama, S. Disparate inotropic and lusitropic responses to pimobendan in conscious dogs with tachycardia-induced heart failure. J. Cardiovasc. Pharmacol. 1994, 23, 268–274. [Google Scholar] [CrossRef] [PubMed]
  89. Forster, C.; Naik, G.O.; Larosa, G. Myocardial beta-adrenoceptors in pacing-induced heart failure: Regulation by enalapril? Can. J. Physiol. Pharmacol. 1994, 72, 667–672. [Google Scholar] [CrossRef] [PubMed]
  90. Himura, Y.; Liang, C.S.; Delehanty, J.M.; Hood, W.B., Jr. Nitroprusside infusion improves arterial baroreflex control of heart rate in dogs with chronic congestive heart failure. J. Cardiovasc. Pharmacol. 1994, 24, 702–706. [Google Scholar] [CrossRef]
  91. Ishimori, T.; Gotanda, K.; Sasaki, T.; Shinbo, A.; Asano, H.; Miyazawa, K.; Miyasaka, K. Cardiac effects of the novel pyridazinone derivative 6-[4-[2-[3-(5-chloro-2-cyanophenoxy)-2-hydroxypropylamino]-2-methylpropylamino]phenyl]-4,5-dihydro-5-methyl-3(2H) pyridazinone monoethyl maleate and its metabolite in isolated heart preparations of guinea pigs and dogs. Arzneimittelforschung 1994, 44, 583–588. [Google Scholar]
  92. Levett, J.M.; Marinelli, C.C.; Lund, D.D.; Pardini, B.J.; Nader, S.; Scott, B.D.; Augelli, N.V.; Kerber, R.E.; Schmid, P.G., Jr. Effects of beta-blockade on neurohumoral responses and neurochemical markers in pacing-induced heart failure. Am. J. Physiol. 1994, 266, 468–475. [Google Scholar] [CrossRef]
  93. Ogilvie, R.I.; Zborowska-Sluis, D. Effect of captopril treatment on total and central vascular capacitance in dogs with chronic heart failure. J. Cardiovasc. Pharmacol. 1994, 24, 358–364. [Google Scholar] [CrossRef] [PubMed]
  94. Kono, T.; Sabbah, H.N.; Rosman, H.; Shimoyama, H.; Alam, M.; Goldstein, S. Divergent effects of intravenous dobutamine and nitroprusside on left atrial contribution to ventricular filling in dogs with chronic heart failure. Am. Heart J. 1994, 127, 874–880. [Google Scholar] [CrossRef]
  95. Pagel, P.S.; Harkin, C.P.; Hettrick, D.A.; Warltier, D.C. Levosimendan (OR-1259), a myofilament calcium sensitizer, enhances myocardial contractility but does not alter isovolumic relaxation in conscious and anesthetized dogs. Anesthesiology 1994, 81, 974–987. [Google Scholar] [CrossRef] [PubMed]
  96. Tsutsui, H.; Spinale, F.G.; Nagatsu, M.; Schmid, P.G.; Ishihara, K.; DeFreyte, G.; Cooper, G.; Carabello, B.A. Effects of Chronic B-Adrenergic Blockade on the Left Ventricular and Cardiocyte Abnormalities of Chronic Canine Mitral Regurgitation. J. Clin. Investig. 1994, 93, 2639–2648. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  97. Sabbah, H.N.; Shimoyama, H.; Kono, T.; Gupta, R.C.; Sharov, V.G.; Scicli, G.; Levine, T.B.; Goldstein, S. Effects of Long-term Monotherapy with Enalapril, Metoprolol, and Digoxin on the Progression of Left Ventricular Dysfunction and Dilation in Dogs With Reduced Ejection Fraction. Circulation 1994, 89, 2852–2859. [Google Scholar] [CrossRef] [Green Version]
  98. Evans, M.A.; Burnett, J.C., Jr.; Redfield, M.M. Effect of Low Dose Aspirin on Cardiorenal Function and Acute Hemodynamic Response to Enalaprilat in a Canine Model of Severe Heart Failure. J. Am. Coll. Cardiol. 1995, 25, 1445–1450. [Google Scholar] [CrossRef] [Green Version]
  99. Harkin, C.P.; Pagel, P.S.; Tessmer, J.P.; Warltier, D.C. Systemic and coronary hemodynamic actions and left ventricular functional effects of levosimendan in conscious dogs. J. Cardiovasc. Pharmacol. 1995, 26, 179–188. [Google Scholar] [CrossRef] [PubMed]
  100. Ogilvie, R.I.; Zborowska-Sluis, D. Effect of perindopril in pacing-induced canine models of acute and chronic heart failure. Can. J. Cardiol. 1995, 11, 934–940. [Google Scholar]
  101. Murakami, M.; Suzuki, H.; Naitoh, M.; Matsumoto, A.; Kageyama, Y.; Tsujimoto, G.; Saruta, T. Blockade of the renin-angiotensin system in heart failure in conscious dogs. J. Hypertens. 1995, 13, 1405–1412. [Google Scholar] [CrossRef]
  102. Shimoyama, H.; Sabbah, H.N.; Rosman, H.; Alam, M.; Goldstein, S. Effect of B-blockade on left atrial contribution to ventricular filling in dogs with moderate heart failure. Am. Heart J. 1996, 131, 772–777. [Google Scholar] [CrossRef]
  103. Shimoyama, H.; Sabbah, H.N.; Rosman, H.; Kono, T.; Alam, M.; Goldstein, S. Effects of Long-Term Therapy with Enalapril on Severity of Functional Mitral Regurgitation in Dogs with Moderate Heart Failure. J. Am. Coll. Cardiol. 1995, 25, 768–772. [Google Scholar] [CrossRef] [Green Version]
  104. Kinugawa, T.; Dibner-Dunlap, M.E. Altered vagal and sympathetic control of heart rate in left ventricular dysfunction and heart failure. Am. J. Physiol. 1995, 268, 310–316. [Google Scholar] [CrossRef] [PubMed]
  105. Fujiki, H.; Mori, T.; Tominaga, M. Effects of OPC-18790 on hemodynamics and the β-adrenergic receptor pathway during long-term infusion in conscious dogs: A comparison to dobutamine. Prev. Manag. Congest. Heart Fail. 1996, 2, 12–20. [Google Scholar]
  106. Itoh, S.; Mori, T.; Fujiki, H.; Tominaga, M. Effects of toborinone on myocardial oxygen consumption in pacing-induced heart failure dogs. Arzneimittelforschung 1996, 46, 1105–1109. [Google Scholar]
  107. McConnell, P.I.; Wang, W.; Zucker, I.H. Effects of an orally effective endothelin-A receptor antagonist in dogs with pacing-induced heart failure. Neb. Med. J. 1996, 81, 349–355. [Google Scholar]
  108. McMahon, W.S.; Holzgrefe, H.H.; Walker, J.D.; Mukherjee, R.; Arthur, S.R.; Cavallo, M.J.; Child, M.J.; Spinale, F.G. Cellular Basis for Improved Left Ventricular Pump Function After Digoxin Therapy in Experimental Left Ventricular Failure. J. Am. Coll. Cardiol. 1996, 28, 495–505. [Google Scholar] [CrossRef]
  109. Pagel, P.S.; Hettrick, D.A.; Warltier, D.C. Influence of levosimendan, pimobendan, and milrinone on the regional distribution of cardiac output in anaesthetized dogs. Br. J. Pharmacol. 1996, 119, 609–615. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  110. Pagel, P.S.; Hettrick, D.A.; Warltier, D.C. Comparison of the effects of levosimendan, pimobendan, and milrinone on canine left ventricular-arterial coupling and mechanical efficiency. Basic Res. Cardiol. 1996, 91, 296–307. [Google Scholar] [CrossRef]
  111. Shimoyama, H.; Sabbah, H.N.; Borzak, S.; Tanimura, M.; Shevlyagin, S.; Scicli, G.; Goldstein, S. Short-term hemodynamic effects of endothelin receptor blockade in dogs with chronic heart failure. Circulation 1996, 94, 779–784. [Google Scholar] [CrossRef]
  112. Nozaki, J.; Kitahata, H.; Tanaka, K.; Kawahito, S.; Oshita, S. The effects of acute normovolemic hemodilution on left ventricular systolic and diastolic function in the absence or presence of beta-adrenergic blockade in dogs. Anest. Analg. 2002, 94, 1120–1126. [Google Scholar] [CrossRef]
  113. Shannon, R.P.; Friedrich, S.; Mathier, M.; Knight, D.R. Effects of renin inhibition compared to angiotensin converting enzyme inhibition in conscious dogs with pacing-induced heart failure. Cardiovasc. Res. 1997, 34, 464–472. [Google Scholar] [CrossRef] [Green Version]
  114. Teramura, S.; Yamakado, T.; Maeda, M.; Nakano, T. Effects of MCI-154, a calcium sensitizer, on left ventricular systolic and diastolic function in pacing-induced heart failure in the dog. Circulation 1997, 95, 732–739. [Google Scholar] [CrossRef]
  115. Dell’Italia, L.J.; Balcells, E.; Meng, Q.C.; Su, X.; Schultz, D.; Bishop, S.P.; Machida, N.; Straeter-Knowlen, I.M.; Hankes, G.H.; Dillon, R.; et al. Volume-overload cardiac hypertrophy is unaffected by ACE inhibitor treatment in dogs. Am. J. Physiol. 1997, 273, 961–970. [Google Scholar] [CrossRef] [PubMed]
  116. King, J.N.; Maurer, M.; Morrison, C.A.; Mauron, C.; Kaiser, G. Pharmacokinetics of the angiotensin-converting-enzyme inhibitor, benazepril, and its active metabolite, benazeprilat, in dog. Xenobiotica 1997, 27, 819–829. [Google Scholar] [CrossRef] [PubMed]
  117. Stanley, W.C.; Li, B.; Bonhaus, D.W.; Johnson, L.G.; Lee, K.; Porter, S.; Walker, K.; Martinez, G.; Eglen, R.M.; Whiting, R.L.; et al. Catecholamine modulatory effects of nepicastat (RS-25560-197), a novel, potent and selective inhibitor of dopamine-b-hydroxylase. Br. J. Pharmacol. 1997, 121, 1803–1809. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  118. Ohte, N.; Cheng, C.P.; Suzuki, M.; Little, W.C. The Cardiac Effects of Pimobendan (But Not Amrinone) Are Preserved at Rest and During Exercise in Conscious Dogs with Pacing-Induced Heart Failure. J. Pharmacol. Exp. Ther. 1997, 282, 23–31. [Google Scholar]
  119. Araki, S.; Uematsu, T.; Nagashima, S.; Matsuzaki, T.; Gotanda, K.; Ochiai, H.; Hashimoto, H.; Nakashima, M. Cardiac and Hemodynamic Effects of TZC-5665, a Novel Pyridazinone Derivative, and Its Metabolite in Humans and Dogs. Gen. Pharmacol. 1997, 28, 545–553. [Google Scholar] [CrossRef] [Green Version]
  120. Wada, A.; Tsutamoto, T.; Fukai, D.; Ohnishi, M.; Maeda, K.; Hisanaga, T.; Maeda, Y.; Matsuda, Y.; Kinoshita, M. Comparison of the Effects of Selective Endothelin ETA and ETB Receptor Antagonists in Congestive Heart Failure. J. Am. Coll. Cardiol. 1997, 30, 1385–1392. [Google Scholar] [CrossRef] [Green Version]
  121. Goussev, A.; Sharov, V.G.; Shimoyama, H.; Tanimura, M.; Lesch, M.; Goldstein, S.; Sabbah, H.N. Effects of ACE inhibition on cardiomyocyte apoptosis in dogs with heart failure. Am. J. Physiol. 1998, 275, 626–631. [Google Scholar] [CrossRef]
  122. Panchal, A.R.; Stanley, W.C.; Kerner, J.; Sabbah, H.N. Beta-Receptor Blockade Decreases Carnitine Palmitoyl Transferase I Activity in Dogs with Heart Failure. J. Card. Fail. 1998, 4, 121–126. [Google Scholar] [CrossRef]
  123. Lai, L.P.; Raju, V.S.; Delehanty, J.M.; Yatani, A.; Liang, C.S. Altered Sarcoplasmic Reticulum Ca2+ ATPase Gene Expression in Congestive Heart Failure: Effect of Chronic Norepinephrine Infusion. J. Mol. Cell. Cardiol. 1998, 30, 175–185. [Google Scholar] [CrossRef]
  124. Ohnishi, M.; Wada, A.; Tsutamoto, T.; Fukai, D.; Kinoshita, M. Comparison of the acute effects of a selective endothelin ET-a and a mixed ET-a /ET-b receptor antagonist in heart failure. Cardiovasc. Res. 1998, 39, 617–624. [Google Scholar] [CrossRef] [Green Version]
  125. Ohnishi, M.; Wada, A.; Fukai, D.; Sawaki, M.; Maeda, Y.; Kinoshita, M. Chronic effects of a novel, orally active endothelin receptor antagonist, T-0201, in dogs with congestive heart failure. J. Cardiovasc. Pharmacol. 1998, 31, 236–238. [Google Scholar] [CrossRef]
  126. Ogilvie, R.I.; Zborowska-Sluis, D. Captopril and angiotensin II receptor antagonist therapy in a pacing model of heart failure. Can. J. Cardiol. 1998, 14, 1025–1033. [Google Scholar]
  127. Moe, G.W.; Albernaz, A.; Naik, G.O.; Kirchengast, M.; Stewart, D.J. Beneficial effects of long-term selective endothelin type A receptor blockade in canine experimental heart failure. Cardiovasc. Res. 1998, 39, 571–579. [Google Scholar] [CrossRef] [Green Version]
  128. Yi, G.H.; Burkhoff, D.; Zhang, H.; Zhu, S.M.; Zwas, D.; Wang, J. Hemodynamic Effects of a Calcium Channel Promoter, BAY y 5959, are Preserved after Chronic Administration in Ischemic Heart Failure in Conscious Dogs. J. Pharmacol. Exp. Ther. 1998, 286, 760–766. [Google Scholar]
  129. Borgeson, D.D.; Grantham, J.A.; Williamson, E.E.; Luchner, A.; Redfield, M.M.; Opgenorth, T.J.; Burnett, J.C., Jr. Chronic Oral Endothelin Type A Receptor Antagonism in Experimental Heart Failure. Hypertension 1998, 31, 766–770. [Google Scholar] [CrossRef] [Green Version]
  130. Amati, B.; Littlewood, T.D.; Evan, G.I.; Land, H. The c-Myc protein induces cell cycle progression and apoptosis through dimerization with Max. EMBO J. 1993, 12, 5083–5087. [Google Scholar] [CrossRef] [PubMed]
  131. Shen, Y.T.; Woltmann, R.F.; Appleby, S.; Prahalada, S.; Krause, S.M.; Kivilghn, S.D.; Johnson, R.G.; Siegl, P.K.; Lynch, J.J. Lack of beneficial effects of growth hormone treatment in conscious dogs during development of heart failure. Am. J. Physiol. 1998, 274, 456–466. [Google Scholar] [CrossRef] [PubMed]
  132. Todaka, K.; Wang, J.; Yi, G.H.; Gu, A.; Zhu, S.M.; Zhang, H.; Burkhoff, D. Effect of BAY y 5959 on myocardial function and metabolism in normal and failing hearts. Am. J. Physiol. 1998, 274, 1560–1568. [Google Scholar] [CrossRef]
  133. Kovacevic, A. Some drugs in the therapy of cardiac failure of dogs and cats. Farm. Glas. 1999, 55, 235–238. [Google Scholar]
  134. Straeter-Knowlen, I.M.; Dell’Italia, L.J.; Dai, J.; Hankes, G.H.; Dillon, A.R.; Cartee, R.E.; Pohost, G.M.; Ku, D.D. ACE inhibitors in HF restore canine pulmonary endothelial function and ANG II vasoconstriction. Am. J. Physiol. 1999, 277, 1924–1930. [Google Scholar] [CrossRef] [PubMed]
  135. Mital, S.; Loke, K.E.; Slater, J.P.; Addonizio, L.; Gersony, W.M.; Hintze, T.H. Synergy of Amlodipine and Angiotensin-Converting Enzyme Inhibitors in Regulating Myocardial Oxygen Consumption in Normal Canine and Failing Human Hearts. Am. J. Cardiol. 1999, 83, 92–98. [Google Scholar] [CrossRef]
  136. Yatsu, T.; Tomura, Y.; Tahara, A.; Wada, K.; Kusayama, T.; Tsukada, J.; Tokioka, T.; Uchida, W.; Inagaki, O.; Iizumi, Y.; et al. Cardiovascular and renal effects of conivaptan hydrochloride (YM087), a vasopressin V1a and V2 receptor antagonist, in dogs with pacing-induced congestive heart failure. Eur. J. Pharmacol. 1999, 376, 239–246. [Google Scholar] [CrossRef]
  137. Tanimura, M.; Sharov, V.G.; Shimoyama, H.; Mishima, T.; Levine, T.B.; Goldstein, S.; Sabbah, H.N. Effects of AT1-receptor blockade on progression of left ventricular dysfunction in dogs with heart failure. Am. J. Physiol. 1999, 276, 1385–1392. [Google Scholar] [CrossRef]
  138. Zhang, X.; Recchia, F.A.; Zhang, X.; Recchia, F.A.; Bernstein, R.; Xu, X.; Nasjletti, A.; Hintze, T.H. Kinin-mediated coronary nitric oxide production contributes to the therapeutic action of angiotensin-converting enzyme and neutral endopeptidase inhibitors and amlodipine in the treatment in heart failure. J. Pharmacol. Exp. Ther. 1999, 288, 742–751. [Google Scholar]
  139. Koch, J.; Pedersen, H.D.; Jensen, A.L.; Flagstad, A.; Poulsen, K.; Bie, P. Short term effects of acute inhibition of the angiotensin-converting enzyme on the renin-angiotensin system and plasma atrial natriuretic peptide in healthy dogs fed a low-sodium diet versus a normal-sodium diet. Zent. Vet. A 1994, 41, 121–127. [Google Scholar] [CrossRef] [PubMed]
  140. Allworth, M.S.; Church, D.B.; Maddison, J.E.; Einstein, R.; Brennan, P.; Abdul Hussein, N.; Matthews, R. Effect of enalapril in dogs with pacing-induced heart failure. Am. J. Vet. Res. 1995, 56, 85–94. [Google Scholar]
  141. King, J.N.; Mauron, C.; Kaiser, G. Pharmacokinetics of the active metabolite of benazepril, benazeprilat, and inhibition of plasma angiotensin-converting enzyme activity after single and repeated administrations to dogs. Am. J. Vet. Res. 1995, 56, 1620–1628. [Google Scholar] [PubMed]
  142. Smal, J.; Haapala, O.; Marvola, M.; Kuusela, S.; Happonen, I. Prolonged-release hard gelatin capsules of furosemide for the treatment of dogs. J. Vet. Pharmacol. Ther. 1995, 18, 17–23. [Google Scholar] [CrossRef]
  143. Hamlin, R.L.; Benitz, A.M.; Ericsson, G.F.; Cifelli, S.; Daurio, C.P. Effects of Enalapril on Exercise Tolerance and Longevity in Dogs with Heart Failure Produced by Iatrogenic Mitral Regurgitation. J. Vet. Intern. Med. 1996, 10, 85–87. [Google Scholar] [CrossRef]
  144. Hamlin, R.L.; Nakayama, T. Comparison of Some Pharmacokinetic Parameters of 5 Angiotensin-Converting Enzyme Inhibitors in Normal Beagles. J. Vet. Intern. Med. 1998, 12, 93–95. [Google Scholar] [CrossRef] [Green Version]
  145. Roudebush, P.; Allen, T.A.; Kuehn, N.F.; Magerkurth, J.H.; Bowers, T.L. The Effect of Combined Therapy with Captopril, Furosemide, and a Sodium-Restricted Diet on Serum Electrolyte Concentrations and Renal Function in Normal Dogs and Dogs with Congestive Heart Failure. J. Vet. Intern. Med. 1994, 8, 337–342. [Google Scholar] [CrossRef]
  146. Morisse, B.; Kersten, U. Treatment of heart failure in dogs with ACe inhibitors: Comparison of quinapril and captopril. Tierarztl. Prax. 1995, 23, 489–496. [Google Scholar] [PubMed]
  147. The COVE Study Group. Controlled Clinical Evaluation of Enalapril in Dogs with Heart Failure: Results of the Cooperative Veterinary Enalapril Study Group. J. Vet. Intern. Med. 1995, 9, 243–252. [Google Scholar] [CrossRef] [PubMed]
  148. The IMPROVE Study Group. Acute and Short-Term Hemodynamic, Echocardiographic, and Clinical Effects of Enalapril Maleate in Dogs with Naturally Acquired Heart Failure: Results of the Invasive Multicenter PROspective Veterinary Evaluation of Enalapril Study. J. Vet. Intern. Med. 1995, 9, 234–242. [Google Scholar] [CrossRef]
  149. DeFrancesco, T.C.; Atkins, C.E.; Keene, B.W. Myocardial infarction complicating management of congestive heart failure in a dog. J. Am. Anim. Hosp. Assoc. 1996, 32, 68–72. [Google Scholar] [CrossRef]
  150. Häggström, J.; Hansson, K.; Karlberg, B.E.; Kvart, C.; Madej, A.; Olsson, K. Effects of long-term treatment with enalapril or hydralazine on the renin-angiotensin-aldosterone system and fluid balance in dogs with naturally acquired mitral valve regurgitation. Am. J. Vet. Res. 1996, 57, 1645–1652. [Google Scholar] [PubMed]
  151. Hofmann, S.; Kersten, U. The effectiveness and tolerance of ramipril in comparison to captopril for heart failure in dogs. Dtsch. Tierärztliche Wochenschr. 1996, 103, 159–163. [Google Scholar]
  152. Kitagawa, H.; Wakamiya, H.; Kitoh, K.; Kuwahara, Y.; Ohba, Y.; Isaji, M.; Iwasaki, T.; Nakano, M.; Sasaki, Y. Efficacy of monotherapy with benazepril, an angiotensin converting enzyme inhibitor, in dogs with naturally acquired chronic mitral insufficiency. J. Vet. Med. Sci. 1997, 59, 513–520. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  153. Biller, B.; Hörauf, A.; Kraft, W. Treatment of mitral valve insufficiency in dogs with the ACE inhibitor enalapril. A clinical progress study. Tierarztl Prax Ausg K Kleintiere Heimtiere 1998, 26, 21–30. [Google Scholar]
  154. Uehara, Y.; Takahashi, M. Hemodynamic changes during administration of drugs for mitral regurgitation in dogs. J. Vet. Med. Sci. 1998, 60, 213–218. [Google Scholar] [CrossRef] [Green Version]
  155. Ettinger, S.J.; Benitz, A.M.; Ericsson, G.F.; Cifelli, S.; Jernigan, A.D.; Longhofer, S.L.; Trimboli, W.; Hanson, P.D. Effects of enalapril maleate on survival of dogs with naturally acquired heart failure. The Long-Term Investigation of Veterinary Enalapril (LIVE) Study Group. J. Am. Vet. Med. Assoc. 1998, 213, 1573–1577. [Google Scholar] [PubMed]
  156. The BENCH Study Group. The effect of benazepril on survival times and clinical signs of dogs with congestive heart failure: Results of a multicenter, prospective, randomized, double-blinded, placebo-controlled, long-term clinical trial. J. Vet. Cardiol. 1999, 1, 7–18. [Google Scholar] [CrossRef]
  157. Keister, D.M.; Kittleson, M.D.; Bonagura, J.D.; Pipers, F.S.; Knauer, K.W. Milrinone: A Clinical Trial in 29 Dogs with Moderate to Severe Congestive Heart Failure. J. Vet. Intern. Med. 1990, 4, 79–86. [Google Scholar] [CrossRef]
  158. Kittleson, M.D. The efficacy and safety of milrinone for treating heart failure in dogs. Vet. Clin. N. Am. Small Anim. Pract. 1991, 21, 905–918. [Google Scholar] [CrossRef]
  159. Ynaraja, R.E.; Montoya, A.A. Propentophylline: Its use in dogs with congestive heart failure. Part I. Med. Vet. 1998, 15, 399–408. [Google Scholar]
  160. Ynaraja, R.E.; Montoya, A.A. Propentophylline: Can be use as general treatment for ageing dogs. Med. Vet. 1998, 15, 462–480. [Google Scholar]
  161. Freeman, L.M.; Rush, J.E.; Kehayias, J.J.; Ross, J.N., Jr.; Meydani, S.N.; Brown, D.J.; Dolnikowski, G.G.; Marmor, B.N.; White, M.E.; Dinarello, C.A.; et al. Nutritional Alterations and the Effect of Fish Oil Supplementation in Dogs with Heart Failure. J. Vet. Intern. Med. 1998, 12, 440–448. [Google Scholar] [CrossRef] [Green Version]
  162. Bright, J.M.; Mears, E. Chronic Heart Disease and Its Management. Vet. Clin. N. Am. Small Anim. Pract. 1998, 27, 1305–1329. [Google Scholar] [CrossRef]
  163. Sisson, D. Evidence for or Against the Efficacy of Afterload Reducers for Management of Heart Failure in Dogs. Vet. Clin. N. Am. Small Anim. Pract. 1991, 21, 945–955. [Google Scholar] [CrossRef]
  164. Watson, A.D.; Church, D.B. Preferences of veterinarians for drugs to treat heart disease in dogs and cats. Aust. Vet. J. 1995, 72, 401–403. [Google Scholar] [CrossRef] [PubMed]
  165. Chen, H.H.; Grantham, J.A.; Schirger, J.A.; Jougasaki, M.; Redfield, M.M.; Burnett, J.C., Jr. Subcutaneous Administration of Brain Natriuretic Peptide in Experimental Heart Failure. J. Am. Coll. Cardiol. 2000, 63, 1706–1712. [Google Scholar] [CrossRef] [Green Version]
  166. Lainchbury, J.G.; Burnett, J.C., Jr.; Meyer, D.; Redfield, M.M. Effects of natriuretic peptides on load and myocardial function in normal and heart failure dogs. Am. J. Physiol.-Heart Circ. Physiol. 2000, 278, 33–40. [Google Scholar] [CrossRef]
  167. Mishima, T.; Tanimura, M.; Suzuki, G.; Todor, A.; Sharov, V.G.; Goldstein, S.; Sabbah, H.N. Effects of Long-Term Therapy with Bosentan on the Progression of Left Ventricular Dysfunction and Remodeling in Dogs with Heart Failure. J. Am. Coll. Cardiol. 2000, 35, 222–229. [Google Scholar] [CrossRef] [Green Version]
  168. Sabbah, H.N.; Sharov, V.G.; Gupta, R.C.; Todor, A.; Singh, V.; Goldstein, S. Chronic Therapy with Metoprolol Attenuates Cardiomyocyte Apoptosis in Dogs with Heart Failure. J. Am. Coll. Cardiol. 2000, 36, 1698–1705. [Google Scholar] [CrossRef] [Green Version]
  169. Solter, P.; Sisson, D.; Thomas, W.; Goetze, L. Intrarenal Effects of Ecadotril during Acute Volume Expansion in Dogs with Congestive Heart Failure. J. Pharmacol. Exp. Ther. 2000, 293, 989–995. [Google Scholar]
  170. Shen, Y.T.; Buie, P.S.; Lynch, J.J.; Krause, S.M.; Ma, X.L. Chronic therapy with an ET receptor antagonist in conscious dogs A/B during progression of congestive heart failure 21 Intracellular Ca regulation and nitric oxide mediated coronary relaxation. Cardiovasc. Res. 2000, 48, 332–345. [Google Scholar] [CrossRef] [Green Version]
  171. Sabbah, H.N.; Stanley, W.C.; Sharov, V.G.; Mishima, T.; Tanimura, M.; Benedict, C.R.; Hegde, S.; Goldstein, S. Effects of Dopamine b-Hydroxylase Inhibition with Nepicastat on the Progression of Left Ventricular Dysfunction and Remodeling in Dogs With Chronic Heart Failure. Circulation 2000, 102, 1990–1995. [Google Scholar] [CrossRef] [Green Version]
  172. Tanimura, M.; Mishima, T.; Steinberg, M.I.; Borzak, S.; Goldstein, S.; Sabbah, H.N. Hemodynamic effects of a novel sodium channel activator in dogs with chronic heart failure. Cardiovasc. Drugs Ther. 2000, 14, 77–82. [Google Scholar] [CrossRef]
  173. Li, D.; Shinagawa, K.; Pang, L.; Leung, T.K.; Cardin, S.; Wang, Z.; Nattel, S. Effects of Angiotensin-Converting Enzyme Inhibition on the Development of the Atrial Fibrillation Substrate in Dogs With Ventricular Tachypacing–Induced Congestive Heart Failure. Circulation 2001, 104, 2608–2614. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  174. Oikawa, Y.; Maehara, K.; Saito, T.; Tamagawa, K.; Maruyama, Y. Attenuation of Angiotensin II-Mediated Coronary Vasoconstriction and Vasodilatory Action of Angiotensin-Converting Enzyme Inhibitor in Pacing-Induced Heart Failure in Dogs. J. Am. Coll. Cardiol. 2001, 38, 1188–1194. [Google Scholar] [CrossRef] [Green Version]
  175. Sabbah, H.N.; Haddad, W.; Mika, Y.; Nass, O.; Aviv, R.; Sharov, V.G.; Maltsev, V.; Felzen, B.; Undrovinas, A.I.; Goldstein, S.; et al. Cardiac contractility modulation with the impulse dynamics signal: Studies in dogs with chronic heart failure. Heart Fail. Rev. 2001, 6, 45–53. [Google Scholar] [CrossRef]
  176. Nemoto, S.; Hamawaki, M.; De Freitas, G.; Carabello, B.A. Differential Effects of the Angiotensin-Converting Enzyme Inhibitor Lisinopril Versus the Beta- Adrenergic Receptor Blocker Atenolol on Hemodynamics and Left Ventricular Contractile Function in Experimental Mitral Regurgitation. J. Am. Coll. Cardiol. 2002, 40, 149–154. [Google Scholar] [CrossRef] [Green Version]
  177. Mishima, T.; Tanimura, M.; Suzuki, G.; Todor, A.; Sharov, V.G.; Tanhehco, E.J.; Goldstein, S.; Sabbah, H.N. Effects of chronic neutral endopeptidase inhibition on the progression of left ventricular dysfunction and remodeling in dogs with moderate heart failure. Cardiovasc. Drugs Ther. 2002, 16, 209–214. [Google Scholar] [CrossRef] [PubMed]
  178. Morita, H.; Suzuki, G.; Mishima, T.; Chaudhry, P.A.; Anagnostopoulos, P.V.; Tanhehco, E.J.; Sharov, V.G.; Goldstein, S.; Sabbah, H.N. Effects of long-term monotherapy with metoprolol CR/XL on the progression of left ventricular dysfunction and remodeling in dogs with chronic heart failure. Cardiovasc. Drugs Ther. 2002, 16, 443–449. [Google Scholar] [CrossRef]
  179. Suzuki, G.; Morita, H.; Mishima, T.; Sharov, V.G.; Todor, A.; Tanhehco, E.J.; Rudolph, A.E.; McMahon, E.G.; Goldstein, S.; Sabbah, H.N. Effects of Long-Term Monotherapy With Eplerenone, a Novel Aldosterone Blocker, on Progression of Left Ventricular Dysfunction and Remodeling in Dogs With Heart Failure. Circulation 2002, 106, 2967–2972. [Google Scholar] [CrossRef] [Green Version]
  180. Sabbah, H.N.; Chandler, M.P.; Mishima, T.; Suzuki, G.; Chaudhry, P.; Nass, O.; Biesiadecki, B.J.; Blackburn, B.; Wolff, A.; Stanley, W.C. Ranolazine, a Partial Fatty Acid Oxidation (pFOX) Inhibitor, Improves Left Ventricular Function in Dogs With Chronic Heart Failure. J. Card. Fail. 2002, 8, 416–422. [Google Scholar] [CrossRef]
  181. Xu, X.; Zeng, G.; Yang, Y.; Liu, H.X. Recombinant human brain natriuretic peptide on the cardiac hemodynamics and renal function in dogs with heart failure. Yao Xue Xue Bao 2002, 37, 758–762. [Google Scholar]
  182. Chandler, M.P.; Stanley, W.C.; Morita, H.; Suzuki, G.; Roth, B.A.; Blackburn, B.; Wolff, A.; Sabbah, H.N. Short-Term Treatment with Ranolazine Improves Mechanical Efficiency in Dogs With Chronic Heart Failure. Circ. Res. 2002, 91, 278–280. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  183. Yamamoto, T.; Wada, A.; Ohnishi, M.; Tsutamoto, T.; Fujii, M.; Matsumoto, T.; Takayama, T.; Wang, X.; Kurokawa, K.; Kinoshita, M. Chronic administration of phosphodiesterase type 5 inhibitor suppresses renal production of endothelin-1 in dogs with congestive heart failure. Clin. Sci. 2002, 103, 258–262. [Google Scholar] [CrossRef] [PubMed]
  184. Koji, T.; Onishi, K.; Dohi, K.; Okamoto, R.; Tanabe, M.; Kitamura, T.; Ito, M.; Isaka, N.; Nobori, T.; Nakano, T. Addition of Angiotensin II Receptor Antagonist to an ACE Inhibitor in Heart Failure Improves Cardiovascular Function by a Bradykinin-Mediated Mechanism. J. Cardiovasc. Pharmacol. 2003, 41, 632–639. [Google Scholar] [CrossRef] [PubMed]
  185. Tonduango, D.; Hittinger, L.; Ghaleh, B.; Le Corvoisier, P.; Sambin, L.; Champagne, S.; Badoual, T.; Vincent, F.; Berdeaux, A.; Crozatier, B.; et al. Chronic Infusion of Bradykinin Delays the Progression of Heart Failure and Preserves Vascular Endothelium- Mediated Vasodilation in Conscious Dogs. Circulation 2004, 109, 114–119. [Google Scholar] [CrossRef] [Green Version]
  186. Morita, H.; Suzuki, G.; Haddad, W.; Mika, Y.; Tanhehco, E.J.; Sharov, V.G.; Goldstein, S.; Ben-Haim, S.; Sabbah, H.N. Cardiac Contractility Modulation With Nonexcitatory Electric Signals Improves Left Ventricular Function in Dogs With Chronic Heart Failure. J. Card. Fail. 2003, 9, 69–75. [Google Scholar] [CrossRef]
  187. Sun, W.; Liu, J. Effects of ginsenoside Rg2 on heart failure induced by pentobarbital sodium in dogs. Chin. Pharmacol. Bull. 2003, 19, 671–674. [Google Scholar]
  188. Suzuki, G.; Mishima, T.; Tanhehco, E.J.; Sharov, V.G.; Todor, A.; Rostogi, S.; Gupta, R.C.; Chaudhry, P.A.; Anagnostopoulos, P.V.; Nass, O.; et al. Effects of the AT1-receptor antagonist eprosartan on the progression of left ventricular dysfunction in dogs with heart failure. Br. J. Pharmacol. 2003, 138, 301–309. [Google Scholar] [CrossRef]
  189. Cataliotti, A.; Boerrigter, G.; Costello-Boerrigter, L.C.; Schirger, J.A.; Tsuruda, T.; Heublein, D.M.; Chen, H.H.; Malatino, L.S.; Burnett, J.C., Jr. Brain Natriuretic Peptide Enhances Renal Actions of Furosemide and Suppresses Furosemide-Induced Aldosterone Activation in Experimental Heart Failure. Circulation 2004, 109, 1680–1685. [Google Scholar] [CrossRef] [Green Version]
  190. Funabiki, K.; Onishi, K.; Dohi, K.; Koji, T.; Imanaka-Yoshida, K.; Ito, M.; Wada, H.; Isaka, N.; Nobori, T.; Nakano, T. Combined angiotensin receptor blocker and ACE inhibitor on myocardial fibrosis and left ventricular stiffness in dogs with heart failure. Am. J. Physiol.-Heart Circ. Physiol. 2004, 287, 2487–2492. [Google Scholar] [CrossRef] [PubMed]
  191. Onishi, K.; Dohi, K.; Koji, T.; Funabiki, K.; Kitamura, T.; Imanaka-Yoshida, K.; Ito, M.; Nobori, T.; Nakano, T. Candesartan Prevents Myocardial Fibrosis during Progression of Congestive Heart Failure. J. Cardiovasc. Pharmacol. 2004, 43, 860–867. [Google Scholar] [CrossRef]
  192. Okuda, S.; Yano, M.; Doi, M.; Oda, T.; Tokuhisa, T.; Kohno, M.; Kobayashi, S.; Yamamoto, T.; Ohkusa, T.; Matsuzaki, M. Valsartan Restores Sarcoplasmic Reticulum Function with No Appreciable Effect on Resting Cardiac Function in Pacing-Induced Heart Failure. Circulation 2004, 109, 911–919. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  193. Amado, L.C.; Saliaris, A.P.; Raju, S.V.; Lehrke, S.; St John, M.; Xie, J.; Stewart, G.; Fitton, T.; Minhas, K.M.; Brawn, J.; et al. Xanthine oxidase inhibition ameliorates cardiovascular dysfunction in dogs with pacing-induced heart failure. J. Mol. Cell. Cardiol. 2005, 39, 531–536. [Google Scholar] [CrossRef] [PubMed]
  194. Nemoto, S.; Razeghi, P.; Ishiyama, M.; De Freitas, G.; Taegtmeyer, H.; Carabello, B.A. PPAR-y agonist rosiglitazone ameliorates ventricular dysfunction in experimental chronic mitral regurgitation. Am. J. Physiol.-Heart Circ. Physiol. 2005, 288, 77–82. [Google Scholar] [CrossRef] [Green Version]
  195. Tachibana, H.; Cheng, H.; Ukai, T.; Igawa, A.; Zhang, Z.S.; Little, W.C.; Cheng, C.P. Levosimendan improves LV systolic and diastolic performance at rest and during exercise after heart failure. Am. J. Physiol.-Heart Circ. Physiol. 2005, 288, 914–922. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  196. Lin, Y.; Xu, C.; Deng, Y.L.; Chen, L.; Huang, H.; Du, J. Effects of tetramethylpyrazine on fibrosis of atrial tissue and atrial fibrillation in a canine model of congestive heart failure induced by ventricular tachypacing. Zhong Xi Yi Jie He Xue Bao 2006, 4, 35–38. [Google Scholar] [CrossRef] [PubMed]
  197. Morita, H.; Khanal, S.; Rastogi, S.; Suzuki, G.; Imai, M.; Todor, A.; Sharov, V.G.; Goldstein, S.; O’Neill, T.P.; Sabbah, H.N. Selective matrix metalloproteinase inhibition attenuates progression of left ventricular dysfunction and remodeling in dogs with chronic heart failure. Am. J. Physiol.-Heart Circ. Physiol. 2006, 290, 2522–2527. [Google Scholar] [CrossRef]
  198. Papp, J.G.; Pollesello, P.; Varró, A.; Végh, A.; Udvary, E. The Effect of Levosimendan during Long-Term Amiodarone Treatment in Dogs. Basic Clin. Pharmacol. Toxicol. 2006, 99, 27–32. [Google Scholar] [CrossRef]
  199. Shroff, S.C.; Ryu, K.; Martovitz, N.L.; Hoit, B.D.; Stambler, B.S. Selective aldosterone blockade suppresses atrial tachyarrhythmias in heart failure. J. Cardiovasc. Electrophysiol. 2006, 17, 534–541. [Google Scholar] [CrossRef]
  200. Undrovinas, A.I.; Belardinelli, L.; Undrovinas, N.A.; Sabbah, H.N. Ranolazine improves abnormal repolarization and contraction in left ventricular myocytes of dogs with heart failure by inhibiting late sodium current. J. Cardiovasc. Electrophysiol. 2006, 17, 169–177. [Google Scholar] [CrossRef] [Green Version]
  201. Cheng, Y.; George, I.; Yi, G.H.; Reiken, S.; Gu, A.; Tao, Y.K.; Muraskin, J.; Qin, S.; He, K.L.; Hay, I.; et al. Bradycardic therapy improves left ventricular function and remodeling in dogs with coronary embolization-induced chronic heart failure. J. Pharmacol. Exp. Ther. 2007, 321, 469–476. [Google Scholar] [CrossRef] [Green Version]
  202. Imai, M.; Rastogi, S.; Sharma, N.; Chandler, M.P.; Sharov, V.G.; Blackburn, B.; Belardinelli, L.; Stanley, W.C.; Sabbah, H.N. CVT-4325 Inhibits Myocardial Fatty Acid Uptake and Improves Left Ventricular Systolic Function without Increasing Myocardial Oxygen Consumption in Dogs with Chronic Heart Failure. Cardiovasc. Drugs Ther. 2007, 21, 9–15. [Google Scholar] [CrossRef]
  203. Rastogi, S.; Mishra, S.; Zacà, V.; Alesh, I.; Gupta, R.C.; Goldstein, S.; Sabbah, H.N. Effect of Long-term Monotherapy with the Aldosterone Receptor Blocker Eplerenone on Cytoskeletal Proteins and Matrix Metalloproteinases in Dogs with Heart Failure. Cardiovasc. Drugs Ther. 2007, 21, 415–422. [Google Scholar] [CrossRef] [PubMed]
  204. Zacà, V.; Rastogi, S.; Imai, M.; Wang, M.; Sharov, V.G.; Jiang, A.; Goldstein, S.; Sabbah, H.N. Chronic Monotherapy With Rosuvastatin Prevents Progressive Left Ventricular Dysfunction and Remodeling in Dogs With Heart Failure. J. Am. Coll. Cardiol. 2007, 50, 551–557. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  205. Sabbah, H.N.; Imai, M.; Cowart, D.; Amato, A.; Carminati, P.; Gheorghiade, M. Hemodynamic Properties of a New-Generation Positive Luso-Inotropic Agent for the Acute Treatment of Advanced Heart Failure. Am. J. Cardiol. 2007, 99, 41–46. [Google Scholar] [CrossRef]
  206. Shiroshita-Takeshita, A.; Brundel, B.; Burstein, B.; Leung, T.K.; Mitamura, H.; Ogawa, S.; Nattel, S. Effects of simvastatin on the development of the atrial fibrillation substrate in dogs with congestive heart failure. Cardiovasc. Res. 2007, 74, 75–84. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  207. Suzuki, G.; Khanal, S.; Rastogi, S.; Morita, H.; Mishima, T.; Anagnostopoulos, P.V.; Nass, O.; Sharov, V.G.; Tanhehco, E.J.; Goldstein, S.; et al. Long-term Pharmacological Activation of PPARg Does not Prevent Left Ventricular Remodeling in Dogs with Advanced Heart Failure. Cardiovasc. Drugs Ther. 2007, 21, 29–36. [Google Scholar] [CrossRef]
  208. Imai, M.; Rastogi, S.; Gupta, R.C.; Mishra, S.; Sharov, V.G.; Stanley, W.C.; Mika, Y.; Rousso, B.; Burkhoff, D.; Ben-Haim, S.; et al. Therapy With Cardiac Contractility Modulation Electrical Signals Improves Left Ventricular Function and Remodeling in Dogs With Chronic Heart Failure. J. Am. Coll. Cardiol. 2007, 49, 2120–2128. [Google Scholar] [CrossRef] [Green Version]
  209. Masutani, S.; Cheng, H.; Hyttilä-Hopponen, M.; Levijoki, J.; Heikkilä, A.; Vuorela, A.; Little, W.C.; Cheng, C.P. Orally available levosimendan dose-related positive inotropic and lusitropic effect in conscious chronically instrumented normal and heart failure dogs. J. Pharmacol. Exp. Ther. 2008, 325, 236–247. [Google Scholar] [CrossRef] [Green Version]
  210. Rastogi, S.; Sharov, V.G.; Mishra, S.; Gupta, R.C.; Blackburn, B.; Belardinelli, L.; Stanley, W.C.; Sabbah, H.N. Ranolazine combined with enalapril or metoprolol prevents progressive LV dysfunction and remodeling in dogs with moderate heart failure. Am. J. Physiol.-Heart Circ. Physiol. 2008, 295, 2149–2155. [Google Scholar] [CrossRef] [Green Version]
  211. Rastogi, S.; Imai, M.; Sharov, V.G.; Mishra, S.; Sabbah, H.N. Darbepoetin-alpha prevents progressive left ventricular dysfunction and remodeling in nonanemic dogs with heart failure. Am. J. Physiol.-Heart Circ. Physiol. 2008, 295, 2475–2482. [Google Scholar] [CrossRef] [Green Version]
  212. Pat, B.; Killingsworth, C.; Denney, T.; Zheng, J.; Powell, P.; Tillson, M.; Dillon, A.R.; Dell’Italia, L.J. Dissociation between cardiomyocyte function and remodeling with beta-adrenergic receptor blockade in isolated canine mitral regurgitation. Am. J. Physiol.-Heart Circ. Physiol. 2008, 295, 2321–2327. [Google Scholar] [CrossRef] [Green Version]
  213. Yang, S.; Han, W.; Zhou, H.Y.; Dong, G.; Wang, B.C.; Huo, H.; Wei, N.; Cao, Y.; Zhou, G.; Xiu, C.H.; et al. Effects of spironolactone on electrical and structural remodeling of atrium in congestive heart failure dogs. Chin. Med. J. 2008, 121, 38–42. [Google Scholar] [CrossRef] [PubMed]
  214. Sasaki, H.; Asanuma, H.; Fujita, M.; Takahama, H.; Wakeno, M.; Ito, S.; Ogai, A.; Asakura, M.; Kim, J.; Minamino, T.; et al. Metformin Prevents Progression of Heart Failure in Dogs Role of AMP-Activated Protein Kinase. Circulation 2009, 119, 2568–2577. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  215. Zacà, V.; Rastogi, S.; Mishra, S.; Wang, M.; Sharov, V.G.; Gupta, R.C.; Goldstein, S.; Sabbah, H.N. Atenolol Is Inferior to Metoprolol in Improving Left Ventricular Function and Preventing Ventricular Remodeling in Dogs with Heart Failure. Cardiology 2009, 112, 294–302. [Google Scholar]
  216. Sawangkoon, S.; Miyamoto, M.; Nakayama, T.; Hamlin, R.L. Acute cardiovascular effects and pharmacokinetics of carvedilol in healthy dogs. Am. J. Vet. Res. 2000, 61, 57–60. [Google Scholar] [CrossRef]
  217. Olivier, N.B.; Kutas, S.M.; Beals, S.; Hanson, B.; Windram, S. Short-term effects of ecadotril in dogs with induced congestive heart failure. Am. J. Vet. Res. 2000, 61, 333–338. [Google Scholar] [CrossRef]
  218. Asano, K.; Masuda, K.; Okumura, M.; Kadosawa, T.; Fujinaga, T. Association between exogenous atrial natriuretic peptide and hemodynamics in dogs with congestive heart failure produced by experimental mitral regurgitation. J. Vet. Med. Sci. 2001, 63, 243–250. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  219. Uechi, M.; Sasaki, T.; Ueno, K.; Yamamoto, T.; Ishikawa, Y. Cardiovascular and renal effects of carvedilol in dogs with heart failure. J. Vet. Med. Sci. 2002, 64, 469–475. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  220. Uechi, M.; Matsuoka, M.; Kuwajima, E.; Kaneko, T.; Yamashita, K.; Fukushima, U.; Ishikawa, Y. The effects of the loop diuretics furosemide and torasemide on diuresis in dogs and cats. J. Vet. Med. Sci. 2003, 65, 1057–1061. [Google Scholar] [CrossRef] [Green Version]
  221. Arsenault, W.G.; Boothe, D.M.; Gordon, S.G.; Miller, M.W.; Chalkley, J.R.; Petrikovics, I. Pharmacokinetics of carvedilol after intravenous and oral administration in conscious healthy dogs. Am. J. Vet. Res. 2005, 66, 2172–2176. [Google Scholar] [CrossRef]
  222. Abbott, J.A.; Broadstone, R.V.; Ward, D.L.; Pyle, R.L. Hemodynamic effects of orally administered carvedilol in healthy conscious dogs. Am. J. Vet. Res. 2005, 66, 637–641. [Google Scholar] [CrossRef] [PubMed]
  223. Gordon, S.G.; Arsenault, W.G.; Longnecker, M.; Boothe, D.M.; Miller, M.W.; Chalkley, J. Pharmacodynamics of Carvedilol in Conscious, Healthy Dogs. J. Vet. Intern. Med. 2006, 20, 297–304. [Google Scholar] [CrossRef]
  224. Nakayama, T.; Nishijima, Y.; Miyamoto, M.; Hamlin, R.L. Effects of 4 Classes of Cardiovascular Drugs on Ventricular Function in Dogs with Mitral Regurgitation. J. Vet. Intern. Med. 2007, 21, 445–450. [Google Scholar] [CrossRef]
  225. Atkins, C.E.; Rausch, W.P.; Gardner, S.Y.; Defrancesco, T.C.; Keene, B.W.; Levine, J.F. The effect of amlodipine and the combination of amlodipine and enalapril on the renin-angiotensin-aldosterone system in the dog. J. Vet. Pharmacol. Ther. 2007, 30, 394–400. [Google Scholar] [CrossRef] [PubMed]
  226. Kanno, N.; Kuse, H.; Kawasaki, M.; Hara, A.; Kano, R.; Sasaki, Y. Effects of pimobendan for mitral valve regurgitation in dogs. J. Vet. Med. Sci. 2007, 69, 373–377. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  227. Chetboul, V.; Lefebvre, H.; Sampedrano, C.C.; Gouni, V.; Saponaro, V.; Serres, F.; Concodert, D.; Nicolle, A.P.; Pouchelon, J. Comparative Adverse Cardiac Effects of Pimobendan and Benazepril Monotherapy in Dogs with Mild Degenerative Mitral Valve Disease: A Prospective, Controlled, Blinded, and Randomized Study. J. Vet. Intern. Med. 2007, 21, 742–753. [Google Scholar] [CrossRef] [PubMed]
  228. Hori, Y.; Takusagawa, F.; Ikadai, H.; Uechi, M.; Hoshi, F.; Higuchi, S. Effects of oral administration of furosemide and torsemide in healthy dogs. Am. J. Vet. Res. 2007, 68, 1058–1063. [Google Scholar] [CrossRef] [PubMed]
  229. Beddies, G.; Fox, P.R.; Papich, M.D.; Kanikanti, V.R.; Krebber, R.; Keene, B.W. Comparison of the pharmacokinetic properties of bisoprolol and carvedilol in healthy dogs. Am. J. Vet. Res. 2008, 69, 1659–1663. [Google Scholar] [CrossRef]
  230. Hori, Y.; Katou, A.; Tsubaki, M.; Kanai, K.; Nakao, R.; Hoshi, F.; Itoh, N.; Higuchi, S. Assessment of diuretic effects and changes in plasma aldosterone concentration following oral administration of a single dose of furosemide or azosemide in healthy dogs. Am. J. Vet. Res. 2008, 69, 1664–1669. [Google Scholar] [CrossRef]
  231. Sayer, M.B.; Atkins, C.E.; Fujii, Y.; Adams, A.K.; Defrancesco, T.C.; Keene, B.W. Acute effect of pimobendan and furosemide on the circulating renin-angiotensin-aldosterone system in healthy dogs. J. Vet. Intern. Med. 2009, 23, 1003–1006. [Google Scholar] [CrossRef]
  232. Atkins, C.E.; Brown, W.A.; Coats, J.R.; Crawford, M.A.; Defrancesco, T.C.; Edwards, J.; Fox, P.R.; Keene, B.W.; Lehmkhul, L.; Luethy, M.; et al. Effects of long-term administration of enalapril on clinical indicators of renal function in dogs with compensated mitral regurgitation. J. Am. Vet. Med. Assoc. 2002, 221, 654–658. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  233. The BENCH Study Group. Long-term tolerability of benazepril in dogs with congestive heart failure. J. Vet. Cardiol. 2004, 6, 7–13. [Google Scholar] [CrossRef]
  234. Amberger, C.; Chetboul, V.; Bomassi, E.; Rougier, S.; Woehrlé, F.; Thoulon, F.; FIRST Group. Comparison of the effects of imidapril and enalapril in a prospective, multicentric randomized trial in dogs with naturally acquired heart failure. J. Vet. Cardiol. 2004, 6, 9–16. [Google Scholar] [CrossRef]
  235. Besche, B.; Chetboul, V.; Lachaud Lefay, M.P.; Grandemange, E. Clinical evaluation of imidapril in congestive heart failure in dogs: Results of the EFFIC study. J. Small Anim. Pract. 2007, 48, 265–270. [Google Scholar] [CrossRef] [PubMed]
  236. Rush, J.E.; Freeman, L.M.; Hiler, C.; Brown, D.J. Use of metoprolol in dogs with acquired cardiac disease. J. Vet. Cardiol. 2002, 4, 23–28. [Google Scholar] [CrossRef]
  237. Abbott, J.A. Beta-blockade in the management of systolic dysfunction. Vet. Clin. N. Am. Small Anim. Pract. 2004, 34, 1157–1170. [Google Scholar] [CrossRef] [PubMed]
  238. Marcondes-Santos, M.; Tarasoutchi, F.; Mansur, A.P.; Strunz, C.M.C. Effects of Carvedilol Treatment in Dogs with Chronic Mitral Valvular Disease. J. Vet. Intern. Med. 2007, 21, 996–1001. [Google Scholar] [CrossRef] [PubMed]
  239. Bach, J.F.; Rozanski, E.A.; MacGregor, J.; Betkowski, J.M.; Rush, J.E. Retrospective Evaluation of Sildenafil Citrate as a Therapy for Pulmonary Hypertension in Dogs. J. Vet. Intern. Med. 2006, 20, 1132–1135. [Google Scholar] [CrossRef]
  240. Kellum, H.B.; Stepien, R.L. Sildenafil Citrate Therapy in 22 Dogs with Pulmonary Hypertension. J. Vet. Intern. Med. 2007, 21, 1258–1264. [Google Scholar] [CrossRef] [PubMed]
  241. Saunders, A.B.; Miller, M.W.; Gordon, S.G.; Van De Wiele, C.M. Oral Amiodarone Therapy in Dogs with Atrial Fibrillation. J. Vet. Intern. Med. 2006, 20, 921–926. [Google Scholar] [CrossRef] [PubMed]
  242. Caro-Vadillo, A.; Ynaraja-Ramirez, E.; Montoya-Alonso, J.A. Effect of torsemide on serum and urine electrolyte levels in dogs with congestive heart failure. Vet. Rec. 2007, 160, 847–848. [Google Scholar] [CrossRef]
  243. Adin, D.B.; Kittleson, M.D.; Hornof, W.J.; Kass, P.H. Efficacy of a Single Oral Dose of Isosorbide 5 Mononitrate in Normal Dogs and in Dogs with Congestive Heart Failure. J. Vet. Intern. Med. 2001, 15, 105–111. [Google Scholar] [CrossRef] [PubMed]
  244. Thomason, J.D.; Fallaw, T.L.; Carmichael, K.P.; Radlinsky, M.A.; Calvert, C.A. Gingival Hyperplasia Associated with the Administration of Amlodipine to Dogs with Degenerative Valvular Disease (2004–2008). J. Vet. Intern. Med. 2009, 23, 39–42. [Google Scholar] [CrossRef] [PubMed]
  245. Tissier, R.; Chetboul, V.; Moraillon, R.; Nicolle, A.; Carlos, C.; Enriquez, B.; Pouchelon, J.L. Increased Mitral Valve Regurgitation and Myocardial Hypertrophy in Two Dogs With Long-Term Pimobendan Therapy. Cardiovasc. Toxicol. 2005, 5, 43–51. [Google Scholar] [CrossRef]
  246. Smith, P.J.; French, A.T.; Van Israël, N.; Smith, S.G.W.; Swift, S.T.; Lee, A.J.; Corcoran, B.M.; Dukes-McEwan, J. Efficacy and safety of pimobendan in canine heart failure caused by myxomatous mitral valve disease. J. Small Anim. Pract. 2005, 46, 121–130. [Google Scholar] [CrossRef]
  247. Gordon, S.G.; Miller, M.W.; Saunders, A.B. Pimobendan in heart failure therapy—A silver bullet? J. Am. Anim. Hosp. Assoc. 2006, 42, 90–93. [Google Scholar] [CrossRef]
  248. Caro, A.; Ynaraja, E.; Montoya, J.A. Effects of Short-term Treatment with Pimobendan in Dogs with Myxomatous Valve Disease. J. Appl. Anim. Res. 2009, 35, 113–117. [Google Scholar] [CrossRef]
  249. Atkinson, K.J.; Fine, D.M.; Thombs, L.A.; Gorelick, J.J.; Durham, H.E. Evaluation of Pimobendan and N-Terminal Probrain Natriuretic Peptide in the Treatment of Pulmonary Hypertension Secondary to Degenerative Mitral Valve Disease in Dogs. J. Vet. Intern. Med. 2009, 23, 1190–1196. [Google Scholar] [CrossRef]
  250. Häggström, J.; Boswood, A.; O’Grady, M.; Jöns, O.; Smith, S.; Swift, S.; Borgarelli, M.; Gavaghan, B.; Kresken, J.G.; Patteson, M.; et al. Effect of Pimobendan or Benazepril Hydrochloride on Survival Times in Dogs with Congestive Heart Failure Caused by Naturally Occurring Myxomatous Mitral Valve Disease: The QUEST Study. J. Vet. Intern. Med. 2008, 22, 1124–1135. [Google Scholar] [CrossRef]
  251. Lombard, C.W.; Jöns, O.; Bussadori, C.M. Clinical efficacy of pimobendan versus benazepril for the treatment of acquired atrioventricular valvular disease in dogs. J. Am. Anim. Hosp. Assoc. 2006, 42, 249–261. [Google Scholar] [CrossRef]
  252. Gelzer, A.R.M.; Kraus, M.S.; Rishniw, M.; Moïse, N.S.; Pariaut, R.; Jesty, S.A.; Hemsley, S.A. Combination Therapy with Digoxin and Diltiazem Controls Ventricular Rate in Chronic Atrial Fibrillation in Dogs Better than Digoxin or Diltiazem Monotherapy: A Randomized Crossover Study in 18 Dogs. J. Vet. Intern. Med. 2009, 23, 499–508. [Google Scholar] [CrossRef]
  253. Chandler, M.L. Pet food safety: Sodium in pet foods. Top. Companion. Anim. Med. 2008, 23, 148–153. [Google Scholar] [CrossRef] [PubMed]
  254. Rush, J.E.; Freeman, L.M.; Brown, D.J.; Brewer, B.P.; Ross, J.N.; Markwell, P.J. Clinical, Echocardiographic, and Neurohormonal Effects of a Sodium-Restricted Diet in Dogs with Heart Failure. J. Vet. Intern. Med. 2000, 14, 513–520. [Google Scholar] [CrossRef] [PubMed]
  255. Martinez-Alcaine, M.A.; Ynaraja, E.; Corbera, J.A.; Montoya, J.A. Effect of short-term treatment with bumetanide, quinapril and low-sodium diet on dogs with moderate congestive heart failure. Aust. Vet. J. 2001, 79, 102–105. [Google Scholar] [CrossRef]
  256. Freeman, L.M.; Rush, J.E.; Cahalane, A.K.; Markwell, P.J. Dietary Patterns of Dogs with Cardiac Disease. J. Nutr. 2002, 132, 1632–1633. [Google Scholar] [CrossRef] [Green Version]
  257. Caro-Vadillo, A.; Ynaraja-Ramirez, E.; Montoya-Alonso, J.A. Effect of Short-term Treatment with Perindopril, Torsemide and Restricted sodium Diet in Dogs with Atrioventricular Valvular Insufficiency. J. Appl. Anim. Res. 2006, 29, 105–108. [Google Scholar] [CrossRef]
  258. Martin, M.W.S. Treatment of congestive heart failure—A neuroendocrine disorder. J. Small Anim. Pract. 2003, 44, 154–160. [Google Scholar] [CrossRef]
  259. Häggström, J.; Duelund Pedersen, H.; Kvart, C. New insights into degenerative mitral valve disease in dogs. Vet. Clin. N. Am. Small Anim. Pract. 2004, 34, 1209–1226. [Google Scholar] [CrossRef] [PubMed]
  260. Smith, P. Management of chronic degenerative mitral valve disease in dogs. Practice 2006, 28, 376–383. [Google Scholar] [CrossRef] [Green Version]
  261. Lefebvre, H.P.; Brown, S.A.; Chetboul, V.; King, J.N.; Puchelon, J.L.; Toutain, P.L. Angiotensin-converting enzyme inhibitors in veterinary medicine. Curr. Pharm. Des. 2007, 13, 1347–1361. [Google Scholar] [CrossRef]
  262. Häggström, J.; Höglund, K.; Borgarelli, M. An update on treatment and prognostic indicators in canine myxomatous mitral valve disease. J. Small Anim. Pract. 2009, 50, 25–33. [Google Scholar] [CrossRef]
  263. Stepien, R.L. Pulmonary arterial hypertension secondary to chronic left-sided cardiac dysfunction in dogs. J. Small Anim. Pract. 2009, 50, 34–43. [Google Scholar] [CrossRef]
  264. Oyama, M.A. Neurohormonal activation in canine degenerative mitral valve disease: Implications on pathophysiology and treatment. J. Small Anim. Pract. 2009, 50, 3–11. [Google Scholar] [CrossRef]
  265. Takahama, H.; Asanuma, H.; Sanada, S.; Fujita, M.; Sasaki, H.; Wakeno, M.; Kim, J.; Asakura, M.; Takashima, S.; Minamino, T.; et al. A histamine H2 receptor blocker ameliorates development of heart failure in dogs independently of b-adrenergic receptor blockade. Basic Res. Cardiol. 2010, 105, 787–794. [Google Scholar] [CrossRef] [PubMed]
  266. Onogawa, T.; Sakamoto, Y.; Nakamura, S.; Nakayama, S.; Fujiki, H.; Yamamura, Y. Effects of Tolvaptan on Systemic and Renal Hemodynamic Function in Dogs with Congestive Heart Failure. Cardiovasc. Drugs Ther. 2011, 25, 67–76. [Google Scholar] [CrossRef]
  267. Sabbah, H.N.; Wang, M. Long-term therapy with a partial adenosine A1-Receptor agonist improves left ventricular systolic function and prevents progressive ventricular remodeling in dogs with chronic heart failure. Circulation 2011, 124, 21. [Google Scholar]
  268. Boerrigter, G.; Soergel, D.G.; Violin, J.D.; Lark, M.W.; Burnett, J.C. TRV120027, a Novel β-Arrestin Biased Ligand at the Angiotensin II Type I Receptor, Unloads the Heart and Maintains Renal Function When Added to Furosemide in Experimental Heart Failure. Circ. Heart Fail. 2012, 5, 627–634. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  269. Speranza, L.; Franceschelli, S.; Riccioni, G. The Biological Effects of Ivabradine in Cardiovascular Disease. Molecules 2012, 17, 4924–4935. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  270. Sakabe, M.; Fujiki, A.; Sakamoto, T.; Nakatani, Y.; Mizumaki, K.; Inoue, H. Xanthine Oxidase Inhibition Prevents Atrial Fibrillation in a Canine Model of Atrial Pacing-Induced left Ventricular Dysfunction. J. Cardiovasc. Electrophysiol. 2012, 23, 1130–1135. [Google Scholar] [CrossRef] [PubMed]
  271. Zhou, S.; Fang, C.; Zheng, S.; Zhang, Y.; Lei, J.; Wang, J. Effect of amiodarone on dispersion of ventricular repolarization in a canine congestive heart failure model. Clin. Exp. Pharmacol. Physiol. 2012, 39, 241–246. [Google Scholar] [CrossRef] [PubMed]
  272. Chello, M.; Spadaccio, C. Pleiotropic effects of long-term monotherapy with rosuvastatin in dogs with moderate heart failure. Cardiology 2013, 124, 36–37. [Google Scholar] [CrossRef]
  273. Esposito, C.T.; Varahan, S.; Jeyaraj, D.; Lu, Y.; Stambler, B.S. Spironolactone improves the arrhythmogenic substrate in heart failure by preventing ventricular electrical activation delays associated with myocardial interstitial fibrosis and inflammation. J. Cardiovasc. Electrophysiol. 2013, 24, 806–812. [Google Scholar] [CrossRef]
  274. Nakatani, Y.; Nishida, K.; Sakabe, M.; Kataoka, N.; Sakamoto, T.; Yamaguchi, Y.; Iwamoto, J.; Mizumaki, K.; Fujiki, A.; Inoue, H. Tranilast Prevents Atrial Remodeling and Development of Atrial Fibrillation in a Canine Model of Atrial Tachycardia and Left Ventricular Dysfunction. J. Am. Coll. Cardiol. 2013, 61, 582–588. [Google Scholar] [CrossRef] [Green Version]
  275. Sabbah, H.N.; Gupta, R.C.; Kohli, S.; Wang, M.; Rastogi, S.; Zhang, K.; Zimmermann, K.; Diedrichs, N.; Albrecht-Küpper, B.E. Chronic Therapy with a Partial Adenosine A1 Receptor Agonist, Improves Left Ventricular Function and Remodeling in Dogs with Advanced Heart Failure. Circ. Heart Fail. 2013, 6, 563–571. [Google Scholar] [CrossRef] [Green Version]
  276. Wang, M.; Gupta, R.C.; Rastogi, S.; Johli, S.; Sabbah, M.S.; Zhang, K.; Mohyi, P.; Hogie, M.; Fischer, Y.; Sabbah, H.N. Effects of acute intravenous infusion of apelin on left ventricular function in dogs with advanced heart failure. J. Card. Fail. 2013, 19, 509–516. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  277. Hamabe, L.; Kawamura, K.; Kim, S.; Yoshiyuki, R.; Fukuyama, T.; Shimizu, M.; Fukushima, R.; Tanaka, R. Comparative Evaluation of Calcium-Sensitizing Agents, Pimobendan and SCH00013, on the Myocardial Function of Canine Pacing–Induced Model of Heart Failure. J. Pharmacol. Sci. 2014, 124, 386–393. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  278. Li, Y.; Ji, Y.; Zhou, X.; Jiang, T.; Hong, Y.; Li, J.; Zing, Q.; Ziong, J.; Yusufuaji, Y.; Tang, B. Effects of Ivabradine on Cardiac Electrophysiology in Dogs with Age-Related Atrial Fibrillation. Med. Sci. Monit. 2015, 21, 1414–1420. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  279. Mochel, J.P.; Danhof, M. Chronobiology and Pharmacologic Modulation of the Renin-Angiotensin-Aldosterone System in Dogs: What Have We Learned? Rev. Physiol. Biochem. Pharmacol. 2015, 169, 43–69. [Google Scholar] [PubMed]
  280. Sabbah, H.N.; Gupta, R.C. Long-term therapy with Bendavia (MTP-131), a novel mitochondria-targeting peptide, normalizes Complex-I Activity and reduces the NADH/NAD ratio in left ventricular myocardium of dogs with advanced heart failure. Mitochondrion 2015, 24, 21–22. [Google Scholar] [CrossRef]
  281. Trappanese, D.M.; Liu, Y.; McCormick, R.C.; Cannavo, A.; Nanayakkara, G.; Baskharoun, M.M.; Jarrett, H.; Woitek, F.J.; Tillson, D.M.; Dillon, A.R.; et al. Chronic β1-adrenergic blockade enhances myocardial β3-adrenergic coupling with nitric oxide-cGMP signaling in a canine model of chronic volume overload: New insight into mechanisms of cardiac benefit with selective β1-blocker therapy. Basic Res. Cardiol. 2015, 110, 456. [Google Scholar] [CrossRef] [Green Version]
  282. Gupta, R.C.; Singh-Gupta, V.; Zhang, K.; Xu, J.; Sabbah, H.N. Elamipretide (Bendavia™) restores 4-hydroxy-2-nonenal protein adducts and aldehyde dehydrogenase-2 activity and mRNA expression in left ventricular myocardium of dogs with advanced heart failure. Circulation 2016, 134, A12949. [Google Scholar]
  283. Gupta, R.C.; Singh-Gupta, V.; Sabbah, H.N. Long-term therapy with elamipretide normalizes protein levels of the signal transducer and activator of transcription 3 (STAT3) in mitochondria of left ventricular myocardium of dogs with chronic heart failure. Circulation 2016, 134, A12984. [Google Scholar]
  284. Panthee, N.; Okada, J.; Washio, T.; Mochizuki, Y.; Suzuki, R.; Koyama, H.; Ono, M.; Hisada, T.; Sugiura, S. Tailor-made heart simulation predicts the effect of cardiac resynchronization therapy in a canine model of heart failure. Med. Image Anal. 2016, 31, 46–62. [Google Scholar] [CrossRef] [PubMed]
  285. Sabbah, H.N.; Gupta, R.C.; Kohli, S.; Wang, M.; Hachem, S.; Zhang, K. Chronic Therapy with Elamipretide (MTP-131), a Novel Mitochondria-Targeting Peptide, Improves Left Ventricular and Mitochondrial Function in Dogs with Advanced Heart Failure. Circ. Heart Fail. 2016, 9, e002206. [Google Scholar] [CrossRef] [Green Version]
  286. Sabbah, H.N.; Gupta, R.C. Long-term therapy with elamipretide normalizes ATP synthase activity in left ventricular myocardium of dogs with advanced heart failure. J. Card. Fail. 2016, 22, 23. [Google Scholar] [CrossRef]
  287. Ames, M.K.; Atkins, C.E.; Lanyis, A.C.; zum Brunnen, J. Evaluation of subacute change in RAAS activity (as indicated by urinary aldosterone:creatinine, after pharmacologic provocation) and the response to ACE inhibition. J. Renin-Angiotensin-Aldosterone Syst. 2016, 17, 1470320316633897. [Google Scholar] [CrossRef] [Green Version]
  288. Gupta, R.C.; Singh-Gupta, V.; Sabbah, H.N. Long-term therapy with elamipretide normalizes activation of the mitochondrial signal transducer and activator of transcription 3 (mstat3) in of left ventricular myocardium of dogs with chronic heart failure. J. Am. Coll. Cardiol. 2017, 69, 923. [Google Scholar] [CrossRef]
  289. Sabbah, H.N.; Gupta, R.C. Long-term therapy with elamipretide reverses abnormalities of cardiolipin synthesis and remodeling in left ventricular myocardium of dogs with chronic heart failure. J. Card. Fail. 2017, 23, 25–26. [Google Scholar] [CrossRef]
  290. Gupta, R.C.; Singh-Gupta, V.; Castle, K.; Sabbah, H.N. Long-term therapy with elamipretide normalizes sirtuin-3 protein levels in isolated mitochondria of left ventricular myocardium of dogs with chronic heart failure. J. Am. Coll. Cardiol. 2018, 71, 11. [Google Scholar] [CrossRef]
  291. Gupta, R.C.; Singh-Gupta, V.; Zhang, K.; Xu, J.; Sabbah, H.N. Elamipretide restores protein and mRNA expression levels of S100A1 in left ventricular myocardium of dogs with chronic heart failure. Eur. J. Heart Fail. 2018, 20, 150. [Google Scholar]
  292. Sabbah, H.N.; Gupta, R.C.; Singh-Gupta, V.; Zhang, K.; Lanfear, D.E. Abnormalities of Mitochondrial Dynamics in the Failing Heart: Normalization Following Long-Term Therapy with Elamipretide. Cardiovasc. Drugs Ther. 2018, 32, 319–328. [Google Scholar] [CrossRef] [Green Version]
  293. Gao, B.; Qu, Y.; Sutherland, W.; Chui, R.W.; Hoagland, K.; Vargas, H.M. Decreased contractility and altered responses to inotropic agents in myocytes from tachypacing-induced heart failure canines. J. Pharmacol. Toxicol. Methods 2018, 93, 98–107. [Google Scholar] [CrossRef] [PubMed]
  294. Zhang, X.; Zhang, Z.; Li, T.; Cheng, H.-J.; Deal, D.D.; Jordan, J.E.; Adams, J.; Cheng, C.P. Apd418, a selective beta-adrenergic receptor antagonist enhances cardiac positive inotropic and lusitropic responses to dobutamine in conscious, chronically-instrumented dogs with pacing-induced heart failure: Assessment by pressure-volume analysis. Circulation 2018, 138, A10553. [Google Scholar]
  295. Tsujino, Y.; Sakamoto, T.; Kinoshita, K.; Nakatani, Y.; Yamaguchi, Y.; Kataoka, N.; Nishida, K.; Kinugawa, K. Edoxaban suppresses the progression of atrial fibrosis and atrial fibrillation in a canine congestive heart failure model. Heart Vessels 2019, 34, 1381–1388. [Google Scholar] [CrossRef] [PubMed]
  296. Sabbah, H.N.; Gupta, R.C.; Singh-Gupta, V.; Zhang, K. Effects of elamipretide on skeletal muscle in dogs with experimentally induced heart failure. ESC Heart Fail. 2019, 6, 328–335. [Google Scholar] [CrossRef]
  297. Mondritzki, T.; Mai, T.; Vogel, J.; Pook, E.; Wasnaire, P.; Schmeck, C.; Hüser, J.; Dinh, W.; Truebel, H.; Kolkhof, P. Cardiac output improvement by pecavaptan: A novel dual-acting vasopressin V1a/V2 receptor antagonist in experimental heart failure. Eur. J. Heart Fail. 2021, 23, 743–750. [Google Scholar] [CrossRef]
  298. Sabbah, H.N.; Zhang, K.; Gupta, R.C.; Martin, E. Effects of Intravenous Infusion of Vepoloxamer on Left Ventricular Function in Dogs with Advanced Heart Failure. Cardiovasc. Drugs Ther. 2020, 34, 153–164. [Google Scholar] [CrossRef]
  299. Guyonnet, J.; Elliott, J.; Kaltsatos, V. A preclinical pharmacokinetic and pharmacodynamic approach to determine a dose of spironolactone for treatment of congestive heart failure in dog. J. Vet. Pharmacol. Ther. 2010, 33, 260–267. [Google Scholar] [CrossRef]
  300. Ishikawa, T.; Tanaka, R.; Suzuki, S.; Miyaishi, Y.; Akagi, H.; Iino, Y.; Fukushima, R.; Yamane, Y. The Effect of Angiotensin-Converting Enzyme Inhibitors of Left Atrial Pressure in Dogs with Mitral Valve Regurgitation. J. Vet. Intern. Med. 2010, 24, 342–347. [Google Scholar] [CrossRef]
  301. Lantis, A.C.; Atkins, C.E.; Defrancesco, T.C.; Keene, B.W.; Werre, S.R. Effects of furosemide and the combination of furosemide and the labeled dosage of pimobendan on the circulating renin-angiotensin-aldosterone system in clinically normal dogs. Am. J. Vet. Res. 2011, 72, 1646–1651. [Google Scholar] [CrossRef] [PubMed]
  302. Suzuki, S.; Ishikawa, T.; Hamabe, L.; Aytemiz, D.; Huai-Che, H.; Fukushima, R.; Machida, N.; Tanaka, R. The Effect of Furosemide on Left Atrial Pressure in Dogs with Mitral Valve Regurgitation. J. Vet. Intern. Med. 2011, 25, 244–250. [Google Scholar] [CrossRef] [PubMed]
  303. Suzuki, S.; Fukushima, R.; Ishikawa, T.; Hamabe, L.; Aytemiz, D.; Huahi-Che, H.; Nakao, S.; Machida, N.; Tanaka, R. The Effect of Pimobendan on Left Atrial Pressure in Dogs with Mitral Valve Regurgitation. J. Vet. Intern. Med. 2011, 25, 1328–1333. [Google Scholar] [CrossRef]
  304. Suzuki, S.; Fukushima, R.; Ishikawa, T.; Yamamoto, Y.; Hamabe, L.; Kim, S.; Yoshiyuki, R.; Machida, N.; Tanaka, R. Comparative effects of amlodipine and benazepril on Left Atrial Pressure in Dogs with experimentally-induced Mitral Valve Regurgitation. BMC Vet. Res. 2012, 8, 166. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  305. Mochel, J.P.; Peyrou, M.; Fink, M.; Strehlau, G.; Mohamed, R.; Giraudel, J.M.; Ploeger, B.; Danhof, M. Capturing the dynamics of systemic Renin-Angiotensin-Aldosterone System (RAAS) peptides heightens the understanding of the effect of benazepril in dogs. J. Vet. Pharmacol. Ther. 2013, 36, 174–180. [Google Scholar] [CrossRef] [PubMed]
  306. Ames, M.K.; Atkins, C.E.; Lantis, A.C.; Were, S.R. Effect of furosemide and high-dosage pimobendan administration on the renin-angiotensin-aldosterone system in dogs. Am. J. Vet. Res. 2013, 74, 1084–1090. [Google Scholar] [CrossRef] [PubMed]
  307. Suzuki, S.; Fukushima, R.; Yamamoto, Y.; Ishikawa, T.; Hamabe, L.; Kim, S.; Yoshiyuki, R.; Fukuyama, T.; Machida, N.; Tanaka, R. Comparative Effect of Carperitide and Furosemide on Left Atrial Pressure in Dogs with Experimentally Induced Mitral Valve Regurgitation. J. Vet. Intern. Med. 2013, 27, 1097–1104. [Google Scholar] [CrossRef]
  308. Lantis, A.C.; Ames, M.K.; Atkins, C.E.; Defrancesco, T.C.; Keene, B.W.; Werre, S.R. Aldosterone breakthrough with benazepril in furosemide-activated renin-angiotensin-aldosterone system in normal dogs. J. Vet. Pharmacol. Ther. 2015, 38, 65–73. [Google Scholar] [CrossRef]
  309. Mochel, J.P.; Fink, M.; Peyrou, M.; Soubret, A.; Giraudel, J.M.; Danhof, M. Pharmacokinetic/Pharmacodynamic Modeling of Renin-Angiotensin Aldosterone Biomarkers Following Angiotensin-Converting Enzyme (ACE) Inhibition Therapy with Benazepril in Dogs. Pharm. Res. 2015, 32, 1931–1946. [Google Scholar] [CrossRef]
  310. Lantis, A.C.; Ames, M.K.; Werre, S.; Atkins, C.E. The effect of enalapril on furosemide-activated renin–angiotensin– aldosterone system in healthy dogs. J. Vet. Pharmacol. Ther. 2015, 38, 513–517. [Google Scholar] [CrossRef]
  311. Ames, M.K.; Atkins, C.E.; Lee, S.; Lantis, A.C.; zum Brunnen, J.R. Effects of high doses of enalapril and benazepril on the pharmacologically activated renin-angiotensin-aldosterone system in clinically normal dogs. Am. J. Vet. Res. 2015, 76, 1041–1050. [Google Scholar] [CrossRef] [PubMed]
  312. Harada, K.; Ukai, Y.; Kanakubo, K.; Yamano, S.; Lee, J.; Kurosawa, T.A.; Uechi, M. Comparison of the diuretic effect of furosemide by different methods of administration in healthy dogs. J. Vet. Emerg. Crit. Care 2015, 25, 364–371. [Google Scholar] [CrossRef]
  313. Yata, M.; McLachlan, A.J.; Foster, D.J.R.; Page, S.W.; Beijerink, N.J. Pharmacokinetics and cardiovascular effects following a single oral administration of a nonaqueous pimobendan solution in healthy dogs. J. Vet. Pharmacol. Ther. 2016, 39, 45–53. [Google Scholar] [CrossRef] [PubMed]
  314. Bell, E.T.; Devi, J.L.; Chiu, S.; Zahra, P.; Whittem, T. The pharmacokinetics of pimobendan enantiomers after oral and intravenous administration of racemate pimobendan formulations in healthy dogs. J. Vet. Pharmacol. Ther. 2016, 39, 54–61. [Google Scholar] [CrossRef]
  315. Bieth, B.; Bornkamp, B.; Toutain, C.; Garcia, R.; Mochel, J.P. Multiple comparison procedure and modeling: A versatile tool for evaluating dose–response relationships in veterinary pharmacology—A case study with furosemide. J. Vet. Pharmacol. Ther. 2016, 39, 539–546. [Google Scholar] [CrossRef] [PubMed]
  316. Paulin, A.; Schneider, M.; Dron, F.; Woehrlé, F. A pharmacokinetic/pharmacodynamic model capturing the time course of torasemide-induced diuresis in the dog. J. Vet. Pharmacol. Ther. 2016, 39, 547–559. [Google Scholar] [CrossRef] [Green Version]
  317. Qian, M.; Chen, T.; Zhou, D.; Chang, Z.; Zhang, Q.; Tang, S.; Xiao, X. Development of a new benazepril hydrochloride chewable tablet and evaluation of its bioequivalence for treatment of heart failure in dogs. J. Vet. Pharmacol. Ther. 2016, 39, 98–101. [Google Scholar] [CrossRef]
  318. Sakatani, A.; Miyagawa, Y.; Takemura, N. Evaluation of the effect of an angiotensin-converting enzyme inhibitor, alacepril, on drug-induced renineangiotensinealdosterone system activation in normal dogs. J. Vet. Cardiol. 2016, 18, 248–254. [Google Scholar] [CrossRef]
  319. Adin, D.; Atkins, C.; Papich, M.; Defrancesco, T.C.; Griffiths, E.; Penteado, M.; Kurtz, K.; Klein, A. Furosemide continuous rate infusion diluted with 5% dextrose in water or hypertonic saline in normal adult dogs: A pilot study. J. Vet. Cardiol. 2017, 19, 44–56. [Google Scholar] [CrossRef]
  320. Konta, M.; Nagakawa, M.; Sakatani, A.; Akabane, R.; Miyagawa, Y.; Takemura, N. Evaluation of the inhibitory effects of telmisartan on drug-induced reninangiotensin- aldosterone system activation in normal dogs. J. Vet. Cardiol. 2018, 20, 376–383. [Google Scholar] [CrossRef] [PubMed]
  321. Goya, S.; Wada, T.; Shimada, Z.; Hirao, D.; Tanaka, R. Effects of high-dose alacepril on left atrial pressure and central aortic pressure in awake dogs with mitral valve regurgitation. Vet. J. 2019, 245, 7–11. [Google Scholar] [CrossRef]
  322. Hori, Y.; Taira, H.; Nakajima, Y.; Ishikawa, Y.; Yumoto, Y.; Maekawa, Y.; Oshiro, A. Inotropic effects of a single intravenous recommended dose of pimobendan in healthy dogs. J. Vet. Med. Sci. 2019, 81, 22–25. [Google Scholar] [CrossRef] [Green Version]
  323. Potter, B.M.; Ames, M.K.; Hess, A.; Poglitsch, M. Comparison between the effects of torsemide and furosemide on the reninangiotensin- aldosterone system of normal dogs. J. Vet. Cardiol. 2019, 26, 51–62. [Google Scholar] [CrossRef]
  324. Treseder, J.R.; LeBlanc, N.L.; Scollan, K.F. Inotropic and chronotropic effects of sotalol in healthy dogs. J. Vet. Cardiol. 2019, 25, 14–24. [Google Scholar] [CrossRef] [PubMed]
  325. Ovaert, P.; Elliott, J.; Bernay, F.; Guillot, E.; Bardon, T. Aldosterone receptor antagonists—How cardiovascular actions may explain their beneficial effects in heart failure. J. Vet. Pharmacol. Ther. 2010, 33, 109–117. [Google Scholar] [CrossRef]
  326. Boswood, A. Current use of pimobendan in canine patients with heart disease. Vet. Clin. N. Am. Small Anim. Pract. 2010, 40, 571–580. [Google Scholar] [CrossRef]
  327. Disatian, S. Myxomatous Degenerative Mitral Valve Disease: An Update. Thai Vet. Med. 2010, 40, 151–157. [Google Scholar]
  328. Kellihan, H.B.; Stepien, R.L. Pulmonary hypertension in dogs: Diagnosis and therapy. Vet. Clin. N. Am. Small Anim. Pract. 2010, 40, 623–641. [Google Scholar] [CrossRef]
  329. Borgarelli, M.; Häggström, J. Canine degenerative myxomatous mitral valve disease: Natural history, clinical presentation and therapy. Vet. Clin. N. Am. Small Anim. Prac. 2010, 40, 651–663. [Google Scholar] [CrossRef]
  330. Bowles, D.; Fry, D. Pimobendan and its use in treating canine congestive heart failure. Compendium 2011, 33, E1. [Google Scholar]
  331. Oyama, M.A. Canine heart failure—early diagnosis, prompt treatment. NAVC Clin. Brief 2011, 9. [Google Scholar]
  332. Jenkins, H.; Pace, C. Nursing approach: Clinical nutrition of the canine with cardiac disease. Vet. Nurse 2012, 3, 148–153. [Google Scholar] [CrossRef]
  333. Kellihan, H.B.; Stepien, R.L. Pulmonary hypertension in canine degenerative mitral valve disease. J. Vet. Cardiol. 2012, 14, 149–164. [Google Scholar] [CrossRef] [PubMed]
  334. Atkins, C.E.; Häggström, J. Pharmacologic management of myxomatous mitral valve disease in dogs. J. Vet. Cardiol. 2012, 14, 165–184. [Google Scholar] [CrossRef]
  335. Boyle, K.L.; Leech, E. A review of the pharmacology and clinical uses of pimobendan. J. Vet. Emerg. Crit. Care 2012, 22, 398–408. [Google Scholar] [CrossRef] [PubMed]
  336. Omamegbe, J.O.; Nwoha, R.I.O. Heart failure in small animals—Advances in clinical case management. Niger. Vet. J. 2013, 34. [Google Scholar]
  337. Burchell, R.K.; Schoeman, J. Medical management of myxomatous mitral valve disease: An evidence-based veterinary medicine approach. J. S. Afr. Vet. Assoc. 2014, 85, 1–7. [Google Scholar] [CrossRef] [Green Version]
  338. Andréjak, J. Management of chronic heart failure dog caused by mitral valve disease. Point Vétérinaire 2015, 46, 62–66. [Google Scholar]
  339. Petrič, A.D. Myxomatous Mitral Valve Disease in Dogs—An Update and Perspectives. Maced. Vet. Rev. 2015, 38, 13–20. [Google Scholar] [CrossRef] [Green Version]
  340. Ames, M.K.; Atkins, C.E. Beyond furosemide: The role of diuretics in congestive heart failure part 2: Spironolactone. Today’s Vet. Pract. 2016, 6, 87–92. [Google Scholar]
  341. Poser, H.; Guglielmini, G. Pulmonary hypertension in the dog. Acta Vet.-Beogr. 2016, 66, 1–25. [Google Scholar] [CrossRef] [Green Version]
  342. Menciotti, G.; Borgarelli, M. Review of Diagnostic and Therapeutic Approach to Canine Myxomatous Mitral Valve Disease. Vet. Sci. 2017, 4, 47. [Google Scholar] [CrossRef] [Green Version]
  343. Sewell, D. Myxomatous mitral valve disease in dogs part 2: Management. Companion Anim. 2017, 22, 60–70. [Google Scholar] [CrossRef]
  344. Turgut, K.; Süleymanoğlu, H.; Ertan, M.; Ince, M. Geriatric Cardiology in Dogs—Part 1: Classification and Treatment of Heart Failure in Geriatrics. Kafkas Üniversitesi Vet. Fakültesi Derg. 2018, 24, 159–167. [Google Scholar] [CrossRef]
  345. Ames, M.K.; Atkins, C.E.; Pitt, B. The renin-angiotensin-aldosterone system and its suppression. J. Vet. Intern. Med. 2019, 33, 363–382. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  346. Hoque, M.; Saxena, A.C.; Gugjoo, M.B.; Bodh, D. Cardiac diseases in dogs. Indian J. Anim. Health 2019, 58, 1–20. [Google Scholar] [CrossRef]
  347. Mochel, J. A Review of Relevant Therapeutic Targets for the Management of Congestive Heart Failure in Dogs: Present and Future Directions. Preprints 2019. [Google Scholar]
  348. Packham, L. In dogs with congestive heart failure, is torasemide superior to furosemide as a first line diuretic treatment? Vet. Evid. 2020, 5, 4. [Google Scholar] [CrossRef]
  349. Pedro, B.; Fontes-Sousa, A.P.; Gelzer, A.R. Diagnosis and management of canine atrial fibrillation. Vet. J. 2020, 265, 105549. [Google Scholar] [CrossRef]
  350. Brown, A.J.; Davison, E.; Sleeper, M.M. Clinical Efficacy of Sildenafil in Treatment of Pulmonary Arterial Hypertension in Dogs. J. Vet. Intern. Med. 2010, 24, 850–854. [Google Scholar] [CrossRef]
  351. Jaffey, J.A.; Leach, S.B.; Kong, L.R.; Wiggen, K.E.; Bender, S.B.; Reinero, C.R. Clinical efficacy of tadalafil compared to sildenafil in treatment of moderate to severe canine pulmonary hypertension: A pilot study. J. Vet. Cardiol. 2019, 24, 7–19. [Google Scholar] [CrossRef]
  352. Ueda, Y.; Johnson, L.R.; Ontiveros, E.S.; Visser, L.C.; Gunther-Harrington, C.T.; Stern, J.A. Effect of a phosphodiesterase-5A (PDE5A) gene polymorphism on response to sildenafil therapy in canine pulmonary hypertension. Sci. Rep. 2019, 9, 6899. [Google Scholar] [CrossRef]
  353. Saetang, K.; Disatian, S. Short-term effects of sildenafil in the treatment of dogs with pulmonary hypertension secondary to degenerative mitral valve disease. Vet. World 2020, 13, 2260–2268. [Google Scholar] [CrossRef] [PubMed]
  354. Arita, S.; Arita, N.; Hikasa, Y. Therapeutic effect of low-dose imatinib on pulmonary arterial hypertension in dogs. Can Vet. J. 2013, 54, 255–261. [Google Scholar] [PubMed]
  355. Cunningham, S.M.; Rush, J.E.; Freeman, L.M. Short-Term Effects of Atorvastatin in Normal Dogs and Dogs with Congestive Heart Failure Due to Myxomatous Mitral Valve Disease. J. Vet. Intern. Med. 2013, 27, 985–989. [Google Scholar] [CrossRef]
  356. Thassakorn, P.; Patchanee, P.; Pongkan, W.; Chattipakorn, N.; Boonyapakorn, C. Effect of atorvastatin on oxidative stress and inflammation markers in myxomatous mitral valve disease in dogs: A comparison of subclinical and clinical stages. J. Vet. Pharmacol. Ther. 2019, 42, 258–267. [Google Scholar] [CrossRef]
  357. Tachampa, K.; Lertwanakarn, T.; Atchariyasakchai, P.; Pumpitakkul, V.; Kireewan, S.; Buranakarl, C. Effects of coenzyme Q10 supplementation on cardiac troponin i level, heart rate vari-ability, and echocardiographic profiles in canine with myxomatous degenerative mitral valve disease: A pilot study. Thai J. Vet. Med. 2018, 48, 443–452. [Google Scholar]
  358. Christiansen, L.B.; Morsing, M.K.; Reimann, M.J.; Martinussen, T.; Birlie, Z.; Schou-Pedersen, A.M.V.; Lykkesfeldt, J.; Olsen, L.H. Pharmacokinetics of Repeated Oral Dosing with Coenzyme Q10 in Cavalier King Charles Spaniels with Myxomatous Mitral Valve Disease. Antioxidants 2020, 9, 827. [Google Scholar] [CrossRef]
  359. Duarte, C.N.; Larsson, M.H.M.A. Adverse Effects of amlodipine on the treatment of heart failure in dogs with myxomatous mitral valve disease: Preliminary results. J. Vet. Intern. Med. 2019, 33, 1073–1074. [Google Scholar]
  360. Yata, M.; Kooistra, H.S.; Beijerink, N. Cardiorenal and endocrine effects of synthetic canine BNP1-32 in dogs with compensated con-gestive heart failure caused by myxomatous mitral valve disease. J. Vet. Intern. Med. 2019, 33, 462–470. [Google Scholar] [CrossRef]
  361. Ibarrola, J.; Garcia-Peña, A.; Matilla, L.; Bonnard, B.; Sádaba, R.; Arrieta, V.; Alvarez, V.; Fernández-Celis, A.; Gainza, A.; Navarro, A.; et al. A New Role for the Aldosterone/Mineralocorticoid Receptor Pathway in the Development of Mitral Valve Prolapse. Circ. Res. 2020, 127, e80–e93. [Google Scholar] [CrossRef]
  362. Chetboul, V.; Pouchelon, J.L.; Menard, J.; Blanc, J.; Desquilibet, L.; Petit, A.; Rougier, S.; Lucats, L.; Woehrlé, F.; The TEST Study Investigators. Short-Term Efficacy and Safety of Torasemide and Furosemide in 366 Dogs with Degen-erative Mitral Valve Disease: The TEST Study. J. Vet. Intern. Med. 2017, 31, 1629–1642. [Google Scholar] [CrossRef]
  363. Besche, B.; Blondel, T.; Guillot, E.; Garelli-Paar, C.; Oyama, M.A. Efficacy of oral torasemide in dogs with degenerative mitral valve disease and new onset con-gestive heart failure: The CARPODIEM study. J. Vet. Intern. Med. 2020, 34, 1746–1758. [Google Scholar] [CrossRef] [PubMed]
  364. Bernay, F.; Bland, J.M.; Häggström, J.; Baduel, L.; Combes, B.; Lopez, A.; Kaltsatos, V. Efficacy of Spironolactone on Survival in Dogs with Naturally Occurring Mitral Regurgitation Caused by Myxomatous Mitral Valve Disease. J. Vet. Intern. Med. 2010, 24, 331–341. [Google Scholar] [CrossRef]
  365. Schuller, S.; Van Israël, N.; Vanbelle, S.; Clercx, C.; McEntee, K. Lack of efficacy of low-dose spironolactone as adjunct treatment to conventional congestive heart failure treatment in dogs. J. Vet. Pharmacol. Ther. 2011, 34, 322–331. [Google Scholar] [CrossRef]
  366. Oyama, M.A.; Peddle, G.D.; Reynolds, C.A.; Singletary, G.E. Use of the loop diuretic torsemide in three dogs with advanced heart failure. J. Vet. Cardiol. 2011, 13, 287–292. [Google Scholar] [CrossRef] [PubMed]
  367. Peddle, G.D.; Singletary, G.E.; Reynolds, C.A.; Trafny, D.J.; Machen, M.C.; Oyama, M.A. Effect of torsemide and furosemide on clinical, laboratory, radiographic and quality of life variables in dogs with heart failure secondary to mitral valve disease. J. Vet. Cardiol. 2012, 14, 253–259. [Google Scholar] [CrossRef] [PubMed]
  368. Lefebvre, H.P.; Ollivier, E.; Atkins, C.E.; Combes, B.; Concodet, D.; Katlsatos, V.; Baduel, L. Safety of Spironolactone in Dogs with Chronic Heart Failure because of Degenerative Valvular Disease: A Population-Based, Longitudinal Study. J. Vet. Intern. Med. 2013, 27, 1083–1091. [Google Scholar] [CrossRef]
  369. Loughran, K.A.; Larouche-Lebel, E.; Huh, T.; Testani, J.M.; Rao, V.S.; Oyama, M.A. Prediction and measurement of diuretic responsiveness after oral administration of furosemide to healthy dogs and dogs with congestive heart failure. J. Vet. Intern. Med. 2020, 34, 2253–2264. [Google Scholar] [CrossRef] [PubMed]
  370. Häggström, J.; Boswood, A.; O’Grady, M.; Jöns, O.; Smith, S.; Swift, S.; Borgarelli, M.; Gavaghan, B.; Kresken, J.G.; Patteson, M.; et al. Longitudinal Analysis of Quality of Life, Clinical, Radiographic, Echocardiographic, and Laboratory Variables in Dogs with Myxomatous Mitral Valve Disease Receiving Pimobendan or Benazepril: The QUEST Study. J. Vet. Intern. Med. 2013, 27, 1441–1451. [Google Scholar] [CrossRef] [Green Version]
  371. Boswood, A.; Häggström, J.; Gordon, S.G.; Wess, G.; Stepien, R.L.; Oyama, M.A.; Keene, B.E.; Bonagura, J.; MacDonald, K.A.; Patteson, M.; et al. Effect of Pimobendan in Dogs with Preclinical Myxomatous Mitral Valve Disease and Cardiomegaly: The EPIC Study-A Randomized Clinical Trial. J. Vet. Intern. Med. 2016, 6, 1765–1779. [Google Scholar] [CrossRef]
  372. Häggström, J.; Lord, P.F.; Höglund, K.; Ljungvall, I.; Jöns, O.; Kvart, C.; Hansson, K. Short-Term Hemodynamic and Neuroendocrine Effects of Pimobendan and Benazapril in Dogs with Myxomatous Mitral Valve Disease and Congestive Heart Failure. J. Vet. Intern. Med. 2013, 27, 1452–1462. [Google Scholar] [CrossRef]
  373. Kim, W.; Park, H. Clinical efficacy and safety of imidapril in dogs with congestive heart failure. J. Vet. Intern. Med. 2015, 29, 1151. [Google Scholar]
  374. Marcondes-Santos, M.; Mansur, A.P.; Fragata, F.S.; Strunz, C.M.C. Short-term follow-up of exercise training program and beta-blocker treatment on quality of life in dogs with naturally acquired chronic mitral valve disease. Braz. J. Med. Biol. Res. 2015, 48, 886–894. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  375. Mocanu, D.; Baisan, A.; Stanciu, G.; Armasu, M.; Musteata, M.; Solcan, G. Assessment of the therapeutically efficiency of benazepril-furosemide bimedication from a clinical and echocardiographic point of view in dogs with mitral valve endocardiosis. Lucr. Ştiinţifice Med. Vet. 2015, 48, 95–106. [Google Scholar]
  376. Lake-Bakaar, G.A.; Singh, M.K.; Kass, P.H.; Griffiths, L.G. Effect of pimobendan on the incidence of arrhythmias in small breed dogs with myxomatous mitral valve degeneration. J. Vet. Cardiol. 2015, 17, 120–128. [Google Scholar] [CrossRef] [PubMed]
  377. Jung, S.W.; Sun, W.; Griffiths, L.G.; Kittleson, M.D. Atrial Fibrillation as a Prognostic Indicator in Medium to Large- Sized Dogs with Myxomatous Mitral Valvular Degeneration and Congestive Heart Failure. J. Vet. Intern. Med. 2016, 30, 51–57. [Google Scholar] [CrossRef]
  378. Disatian, S.; Boonlue, N.; Pupa, P.; Boonsathitanan, W.; Rakthaidee, S.; Mangklabruks, T.; Sakarin, S. Electrocardiographic Changes in Dogs with Degenerative Mitral Valve Disease Treated with Pimobendan: A Retrospective Study of 29 Cases. Thai J. Vet. Med. 2016, 46, 243–249. [Google Scholar]
  379. Mizuno, M.; Yamano, S.; Chimura, S.; Hirakawa, A.; Takusagawa, Y.; Sawada, T.; Maetani, S.; Takahashi, A.; Mizuno, T.; Harada, K.; et al. Efficacy of pimobendan on survival and reoccurrence of pulmonary edema in canine congestive heart failure. J. Vet. Med. Sci. 2017, 79, 29–34. [Google Scholar] [CrossRef] [Green Version]
  380. King, J.N.; Hirakawa, A.; Sonobe, J.; Otaki, H.; Sakakibara, N.; Seewald, W.; Forster, S. Evaluation of a fixed-dose combination of benazepril and pimobendan in dogs with congestive heart failure: A randomized non-inferiority clinical trial. J. Vet. Sci. 2018, 19, 117–128. [Google Scholar] [CrossRef]
  381. Uemura, A.; Hamabe, L.; Shimada, K.; Shimizu, M.; Tanaka, R. Evaluation of symptomatic improvements observed by switching to alacepril from other ACE-Inhibitors in dogs with mitral valve regurgitation. Thai J. Vet. Med. 2018, 48, 29–36. [Google Scholar]
  382. Varshney, J.P.; Huma, Z.I.; Sharma, N. Evaluation of cardiac troponin-i and vitamin D3 in dogs with left heart failure and its management using pimobendan. Vet. Pract. 2019, 20, 74–77. [Google Scholar]
  383. Lee, J.; Ahn, H. The misuse (overdose) of pimobendan may potentially induce myocardial fatigue in dogs with myxomatous mitral valve disease. J. Vet. Intern. Med. 2019, 33, 1038–1039. [Google Scholar]
  384. Wess, G.; Kresken, J.; Wendt, R.; Gaugele, J.; Killich, M.; Keller, L.; Simak, J.; Holler, P.; Bauer, A.; Küchenhof, H.; et al. Efficacy of adding ramipril (VAsotop) to the combination of furosemide (Lasix) and pimobendan (VEtmedin) in dogs with mitral valve degeneration: The VALVE trial. J. Vet. Intern. Med. 2020, 34, 2232–2241. [Google Scholar] [CrossRef]
  385. Beaumier, A.; Rush, J.E.; Yang, V.K.; Freeman, L.M. Clinical findings and survival time in dogs with advanced heart failure. J. Vet. Intern. Med. 2018, 32, 944–950. [Google Scholar] [CrossRef] [PubMed]
  386. Mohammadyar, L.; Molazem, M. Follow up the Treatment Process of Mitral Valve Diseases by Radiography and Echocardiography in Dogs. Iran J. Vet. Med. 2019, 13, 123–130. [Google Scholar]
  387. Ames, M.K.; Atkins, C.E.; Eriksson, A.; Hess, A.M. Aldosterone breakthrough in dogs with naturally occurring myxomatous mitral valve disease. J. Vet. Cardiol. 2017, 19, 218–227. [Google Scholar] [CrossRef]
  388. Freeman, L.M.; Rush, J.E.; Cunningham, S.M.; Yang, V.K.; Bulmer, B.J. Pilot study of a myostatin antagonist in dogs with cardiac cachexia. J. Vet. Cardiol. 2015, 17, 210–215. [Google Scholar] [CrossRef] [PubMed]
  389. Wolf, J.; Gerlach, N.; Weber, K.; Klima, A.; Wess, G. Lowered N-terminal pro-B-type natriuretic peptide levels in response to treatment predict survival in dogs with symptomatic mitral valve disease. J. Vet. Cardiol. 2012, 14, 399–408. [Google Scholar] [CrossRef]
  390. Hezzell, M.J.; Block, C.L.; Laughlin, D.S.; Oyama, M.A. Effect of prespecified therapy escalation on plasma NT-proBNP concentrations in dogs with stable congestive heart failure due to myxomatous mitral valve disease. J. Vet. Intern. Med. 2018, 32, 1509–1516. [Google Scholar] [CrossRef]
  391. Schober, K.E.; Hart, T.M.; Stern, J.A.; Li, X.; Samii, V.F.; Zekas, L.J.; Scansen, B.A.; Bonagura, J.D. Effects of treatment on respiratory rate, serum natriuretic peptide concentration, and doppler echocardiographic indices of left ventricular filling pressure in dogs with congestive heart failure secondary to degenerative mitral valve disease and dilated cardiomyopathy. J. Am. Vet. Med. Assoc. 2011, 239, 468–479. [Google Scholar]
  392. Lee, J.; Kim, W. Potential renoprotective effect of angiotensin-receptor antagonists in dogs with myxomatous mitral valve disease. J. Vet. Intern. Med. 2020, 34, 393. [Google Scholar]
  393. Davies, T.; Everitt, S.; Cobb, M. Variation in the management of congestive cardiac failure in dogs. Vet. Rec. 2015, 176, 435. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  394. Coffman, M.; Guillot, E.; Blondel, T.; Garelli-Paar, C.; Feng, S.; Heartsill, S.; Atkins, C.E. Clinical efficacy of a benazepril and spironolactone combination in dogs with congestive heart failure due to myxomatous mitral valve disease: The BEnazepril Spironolactone STudy (BESST). J. Vet. Intern. Med. 2021, 35, 1673–1687. [Google Scholar] [CrossRef] [PubMed]
Animals 12 00209 g001 550
Figure 1. Flow chart of the literature selection process for the present article.
Figure 1. Flow chart of the literature selection process for the present article.
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Figure 2. Number of studies identified in the three databases and allocated into three categories.
Figure 2. Number of studies identified in the three databases and allocated into three categories.
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Animals 12 00209 g003 550
Figure 3. Numerousness of studies on CHF in dogs found in each database and in all decades.
Figure 3. Numerousness of studies on CHF in dogs found in each database and in all decades.
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Animals 12 00209 g004 550
Figure 4. Subdivision of the studies published in veterinary medicine journals (DMD and DNAD) according to the type of study in the five decades taken into consideration. It is interesting to note that in the last decades the typologies of veterinary medicine studies were more diversified than in the last century.
Figure 4. Subdivision of the studies published in veterinary medicine journals (DMD and DNAD) according to the type of study in the five decades taken into consideration. It is interesting to note that in the last decades the typologies of veterinary medicine studies were more diversified than in the last century.
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Animals 12 00209 g005 550
Figure 5. Comparison of numerous studies published in veterinary medicine journals.
Figure 5. Comparison of numerous studies published in veterinary medicine journals.
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Animals 12 00209 g006 550
Figure 6. Studies found in each database, allocated into three categories, and distributed in the considered decades. It is interesting to note the increased number of studies carried out on dogs with a spontaneous disease in the last decades compared to studies in which the dog was a model for testing drugs potentially useful for the treatment of human CHF.
Figure 6. Studies found in each database, allocated into three categories, and distributed in the considered decades. It is interesting to note the increased number of studies carried out on dogs with a spontaneous disease in the last decades compared to studies in which the dog was a model for testing drugs potentially useful for the treatment of human CHF.
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Figure 7. Timeline representing the main categories of drugs used for canine CHF therapy over the past fifty years.
Figure 7. Timeline representing the main categories of drugs used for canine CHF therapy over the past fifty years.
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Table
Table 1. Subclassification of the studies into three categories.
Table 1. Subclassification of the studies into three categories.
DMHDMDDNAD
Journal Human medicine journal Veterinary medicine journalVeterinary medicine journal
Aim of the studyTo test efficacy of medication of CHF in humans To test efficacy of medication of CHF in dogs To test the therapy of CHF in dogs
Population Healthy dogsAffected or healthy dogs Affected dogs
MMVDInduced Natural or induced Natural
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Bagardi, M.; Zamboni, V.; Locatelli, C.; Galizzi, A.; Ghilardi, S.; Brambilla, P.G. Management of Chronic Congestive Heart Failure Caused by Myxomatous Mitral Valve Disease in Dogs: A Narrative Review from 1970 to 2020. Animals 2022, 12, 209. https://doi.org/10.3390/ani12020209

AMA Style

Bagardi M, Zamboni V, Locatelli C, Galizzi A, Ghilardi S, Brambilla PG. Management of Chronic Congestive Heart Failure Caused by Myxomatous Mitral Valve Disease in Dogs: A Narrative Review from 1970 to 2020. Animals. 2022; 12(2):209. https://doi.org/10.3390/ani12020209

Chicago/Turabian Style

Bagardi, Mara, Viola Zamboni, Chiara Locatelli, Alberto Galizzi, Sara Ghilardi, and Paola G. Brambilla. 2022. "Management of Chronic Congestive Heart Failure Caused by Myxomatous Mitral Valve Disease in Dogs: A Narrative Review from 1970 to 2020" Animals 12, no. 2: 209. https://doi.org/10.3390/ani12020209

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