Search Results (575)

Background/Objectives: Transthyretin cardiomyopathy (ATTR-CM) is frequently associated with conduction disease requiring pacing. Conventional right ventricular pacing may worsen cardiac function, whereas left bundle branch area pacing (LBBAP) aims to preserve physiological activation. Evidence for LBBAP in ATTR-CM remains limited. Methods: A structured narrative review of PubMed and Google Scholar was performed through November 2025 using predefined terms related to LBBAP and ATTR-CM. Peer-reviewed articles, case reports, case series, and relevant abstracts were included. Studies exclusively on light-chain cardiac amyloidosis were excluded. Results: Ten publications met inclusion criteria, comprising three case reports, five case series, one retrospective cohort without a comparator, and one cohort comparing LBBAP with cardiac resynchronization therapy (CRT). In total, 56 patients with ATTR-CM underwent LBBAP. Implantation success was high, with stable acute and mid-term electrical parameters. Follow-up (typically 3–12 months) showed stable electrical parameters with narrow paced QRS complexes and preserved or improved left ventricular ejection fraction in most reports. Symptomatic improvement and reductions in natriuretic peptides were variably described. No major lead-related complications were reported. Comparative data remain sparse and inconclusive. Conclusions: This review suggests that LBBAP is a feasible and safe pacing approach in patients with ATTR-CM and may help to stabilize or improve heart failure symptoms. Further prospective studies are needed to confirm its clinical effectiveness. Full article

Background: Heart failure (HF) patients with a ‘reduced’ ejection fraction (HFrEF) have several proven treatment options, but for those with a ‘preserved’ ejection fraction (HFpEF) there are very few. However, recent trials such as the EMPEROR-Preserved and DELIVER have shown that sodium-glucose cotransporter 2 (SGLT2) inhibitors significantly reduce HF hospitalization in HFpEF patients, and these are now supported by both Australian and international guidelines. Methods: We undertook a narrative review using a structured multi-database search (MEDLINE, Embase, CINAHL, Scopus) and key Australian sources (AIHW, ABS, Department of Health and Aged Care) without geographic or publication-year restrictions. Results: In Australia there were approximately 179,000 hospitalizations in 2020–2021 due to HF equating to a rate of 697 per 100,000 population. The age-standardized hospitalization rate for HF in remote and very remote areas was 1.8 times higher than in major cities. Likewise, since 2000 the prevalence of diabetes has nearly tripled, from 460,000 to 1.3 million. In remote areas, there were 47,600 diabetes hospitalizations in 2021–2022, with residents being 2.5 times more likely to be hospitalized for diabetes compared to those in major cities. Conclusions: In rural Australia, reducing preventable hospitalizations and premature mortality from heart failure and type 2 diabetes requires a stronger rural generalist and general practitioner workforce, improved access to essential medicines and telehealth, and equity-focused evaluation. Full article

Sodium–glucose cotransporter 2 (SGLT2) inhibitors have substantially reshaped the management of type 2 diabetes mellitus (T2DM), owing not only to their glucose-lowering properties but also to their consistent cardiovascular and renal protective effects. Beyond their initial metabolic indication, these agents have emerged as disease-modifying therapies across a broad spectrum of cardiometabolic and renal conditions. Building on the clinical success of first-generation SGLT2 inhibitors, such as empagliflozin and dapagliflozin, next-generation SGLT2-based therapies have been developed with the aim of refining pharmacological selectivity, optimizing pharmacokinetic profiles, and expanding therapeutic applicability beyond diabetes. These innovations include dual SGLT1/SGLT2 inhibition, alternative dosing strategies, and molecular designs tailored to specific clinical phenotypes, such as heart failure with preserved ejection fraction (HFpEF) and chronic kidney disease (CKD). This narrative review critically evaluates the evolving landscape of next-generation SGLT2 inhibitors, with a focus on structural and pharmacokinetic innovations, transporter selectivity, glucose-independent mechanisms, and emerging clinical implications. A comprehensive literature search was conducted using PubMed/MEDLINE, Scopus, and Web of Science, encompassing publications from inception to March 2025. Eligible sources included randomized clinical trials, observational studies, meta-analyses, and authoritative reviews published in English. Available evidence indicates that, while conventional SGLT2 inhibitors confer robust and reproducible cardiorenal benefits, newer agents may further extend therapeutic potential through incretin-related effects, modulation of extra-renal pathways, and disease-specific cardiac and renal mechanisms. Nevertheless, evidence supporting incremental clinical benefit beyond established SGLT2 inhibitors remains limited and heterogeneous, particularly for recently developed compounds. Overall safety profiles appear broadly consistent within the class, although long-term data for next-generation agents are still evolving. Key limitations of the current evidence base include reliance on emerging or indirect mechanistic data, heterogeneity in study populations and clinical endpoints, and the relative scarcity of large, outcome-driven trials for newer SGLT2-based therapies. Future research should prioritize mechanism-driven clinical trials, precision-oriented patient stratification, and head-to-head comparative studies to more clearly define the role of next-generation SGLT2 inhibitors in cardiovascular, renal, and metabolic disease management. Full article

Background: The aim of this study is to assess the safety of sodium channel blocker (SCB) therapy in patients with atrial fibrillation (AF). Methods: The REGUEIFA registry is a prospective, observational, multicenter registry from a Community Health Area in Spain that recruited patients with AF, whom it followed for 2 years. Results: From the 997 patients, 632 were assigned to a rhythm control strategy and analyzed. Patients exposed to SCBs demonstrated a risk ratio (RR) of 0.38 (95% CI: 0.18–0.79; p = 0.007) for worsening heart failure (HF), and 0.40 (95% CI: 0.21–0.78; p = 0.005) for the composite endpoint (death, ischemic stroke, or worsening HF), with no significant differences in all-cause mortality, cardiovascular (CV) mortality, ischemic stroke, or bleeding compared with patients not exposed to SCBs. In the subgroup of patients with structural heart disease, no differences were observed between those exposed and those not exposed to SCBs across all the clinical outcomes analyzed (all-cause mortality, CV mortality, ischemic stroke, bleeding and composite event). However, a lower event trend was observed across all these variables. The rate of sinus rhythm at 2 years follow-up was significantly higher in the SCB group (81.8% vs. 63.9%; p < 0.001). During Cox regression analysis for all-cause mortality, SCB exposure was not identified as an independent factor (HR: 0.82; 95% CI 0.17–3.87; p = 0.802). Age (HR: 1.10; 95% CI: 1.04–1.17; p < 0.001) and HF (HR: 4.23; 95% CI: 1.63–11.00; p = 0.003) were the only predictors of mortality. Conclusions: SCB therapy appears to be safe and effective, both in the overall cohort and in the patient subgroup with AF and structural heart disease. These agents may play a role in AF management in patients with revascularized coronary heart disease, left ventricular hypertrophy, and HF with preserved left ventricular ejection fraction. Full article

Heart failure with preserved ejection fraction (HFpEF) represents a growing clinical challenge, accounting for more than half of all cases of heart failure, for which there are currently no effective treatments. Emerging evidence identifies mitochondrial dysfunction as a central mechanism linking metabolic comorbidities, systemic inflammation, and energy failure in HFpEF. This review provides a comprehensive overview of the metabolic–mitochondrial mechanisms underlying the pathophysiology of HFpEF. Loss of metabolic flexibility, characterized by reduced fatty acid and glucose oxidation, leads to energy inefficiency, lipid accumulation, and oxidative stress. Structural and functional mitochondrial abnormalities, including damaged cristae, altered fission-fusion dynamics, and impaired oxidative phosphorylation, contribute to diastolic dysfunction and ventricular remodeling. In parallel, chronic inflammation and redox imbalance amplify mitochondrial damage through cytokine- and ROS-mediated pathways, creating a cycle of bioenergetic failure. From a therapeutic perspective, strategies aimed at restoring mitochondrial homeostasis, such as physical training, metabolic modulation, SGLT2 inhibition, ketone supplementation, and mitochondria-targeted antioxidants, show promising preclinical results. However, clinical translation remains limited. Deepening the understanding of mitochondrial metabolism could enable the development of personalized treatments capable of improving outcomes for HFpEF patients. Full article

Objective: This study examined the clinical characteristics, management strategies, and outcomes of heart failure (HF) patients in the Lebanese population to address knowledge gaps regarding comorbidities, adherence to guideline-directed medical therapy, and mortality. Methods: The study included 835 patients aged 18 years or older who were hospitalized for HF at a tertiary center between January 2020 and December 2023. Data encompassed demographics, medical history, treatments, and all-cause mortality. Results: The median age was 70.0 years (IQR: 62.0–79.0), with males comprising 60.8%. The most common comorbidities were hypertension (84.2%), coronary artery disease (74.6%), diabetes mellitus (55.2%), and atrial fibrillation (33.4%). Males had more ICD (17.1% vs. 8.6%, p < 0.001) and CRT-D implants (8.9% vs. 3.7%, p = 0.004), and higher coronary artery disease frequency (78.3% vs. 68.8%; p = 0.002), whereas females had higher rates of atrial fibrillation (39.4% vs. 29.5%; p = 0.003). HF patients with reduced ejection fraction were the most common (56.4%), followed by HF with preserved ejection fraction (30.1%). HF with preserved ejection fraction had the highest rates of hypertension (89.6%) and atrial fibrillation (39.4%). Utilization of ARNI (β = −0.423, HR = 0.655, p = 0.041, 95% CI: 0.437–0.983) and SGLT2i (β = −0.432, HR = 0.649, p = 0.035, 95% CI: 0.435–0.969) were linked to 34.5% and 35.1% reductions in mortality risk, respectively. Conclusions: These results highlight the substantial burden of HF in Lebanon. Distinct demographic and clinical patterns were identified by gender and left ventricular ejection fraction groups. The findings underscore the need for population-specific screening, management strategies, and targeted interventions to improve HF outcomes. Full article

Cardiovascular disease (CVD) remains the leading cause of morbidity and mortality worldwide, with heart failure (HF) representing a major contributor to hospitalizations, healthcare costs, and death. Effective management of HF is hindered by the limitations of current biomarkers and diagnostic tools. Conventional biomarkers, such as natriuretic peptides, primarily reflect downstream hemodynamic stress and often lack specificity, particularly in HF with preserved ejection fraction or multiple comorbidities. While imaging provides valuable structural and functional information, it is resource-intensive, costly, and unsuitable for frequent longitudinal monitoring. As a result, these conventional approaches are inadequate to capture the dynamic and heterogeneous nature of HF pathophysiology. Circulating cell-free nucleic acids (cfNAs), including cell-free DNA (cfDNA) and RNA (cfRNA), have emerged as promising noninvasive liquid biopsy biomarkers capable of providing real-time insight into upstream pathological events, such as cardiomyocyte injury, immune activation, inflammation, and maladaptive remodeling. Importantly, cfNAs also act as active mediators of CVD pathology. When released under stress or injury, cfNAs interact with pattern recognition receptors (PRRs) that trigger sterile inflammation, cardiovascular cell dysfunction, and adverse cardiac remodeling. This review summarizes the origins, mechanistic roles, and clinical significance of cfNAs in HF and related CVD, highlighting their dual roles as diagnostic biomarkers and mechanistic effectors of disease. Finally, we discuss emerging cfNA-targeted therapeutic strategies, challenges, and future opportunities for precision medicine in HF and HF-associated CVD. Full article

Heart failure (HF) is a condition with a high clinical and healthcare burden. In Europe, the current incidence is approximately 5 per 1000 persons per year in the adult population, with a prevalence of 1–2%. Prognosis remains poor, with persistently high rates of mortality and hospitalization. The period immediately following hospital discharge is known as the “vulnerable phase,” marked by a heightened incidence of clinical events, including a 30% chance of rehospitalization and a 10% mortality risk. Effective patient management during this time is crucial and should incorporate a risk stratification process, which is vital for designing a personalized follow-up plan and ensuring optimal resource utilization. This review aims to outline the available tools for prognostic risk stratification and propose a structured follow-up model applicable at discharge from an HF hospitalization in patients with HF with reduced ejection fraction and in patients with mildly reduced/preserved ejection fraction. Full article

Heart failure (HF) remains a leading cause of morbidity and mortality worldwide, affecting over 30 million individuals, with its prevalence steadily increasing due to population aging. Among its forms, heart failure with preserved ejection fraction (HFpEF) has emerged as a major clinical and public health concern, now accounting for more than half of all HF cases and closely associated with comorbidities such as hypertension, obesity, and diabetes. MicroRNAs (miRNAs) have gained recognition as key regulators of the molecular mechanisms underlying HF, particularly HFpEF, where they modulate interconnected pathways of inflammation, fibrosis, and endothelial dysfunction. This review discusses the mechanisms by which miRNAs contribute to the pathogenesis of HF and examines their potential as both biomarkers and therapeutic targets. By integrating current evidence, it aims to clarify the prognostic significance and clinical applicability of these molecular markers, highlighting their role in advancing personalized strategies for the diagnosis and management of HF. Full article

Heart failure (HF) remains a prevalent, high-risk condition particularly common among the elderly population. The impairment of systolic function, secondary dysregulation of maladaptive neurohormonal systems and HF therapies lead to electrolyte disturbances. Hyponatremia is a well-studied, robust marker of adverse prognosis in HF. Serum chloride has emerged as a promising prognostic marker, accurately predicting adverse outcomes in both acute and chronic settings. Hypochloremia reflects a compound of maladaptive neurohormonal, renal and acid–base mechanisms, frequently worsened by diuretic therapy. In the context of HF, low chloride levels are independently associated with increased cardiovascular mortality, HF hospitalization and diuretic resistance. Urinary chloride (uCl⁻) has recently been shown to serve as a dynamic biomarker of HF severity, Renin–Angiotensin–Aldosterone-system (RAAS) activation, and poor outcomes, offering incremental prognostic value. Our review synthesizes the latest evidence on serum and urinary chloride disturbances in HF, framing key distinctions between acute versus persistent electrolyte disturbances. We also explore the interrelationship between chloride and sodium, the differential impact of hypochloremia in Heart Failure with Preserved Ejection Fraction (HFpEF) versus Heart Failure with Reduced Ejection Fraction (HFrEF), and clinical outcomes stratified by the temporary vs. persistent nature of chloride imbalance. We have also included visual flowcharts for classifying and managing hypochloremia based on the underlying etiology. Full article

Background: Aging elevates reactive oxygen species (ROS) and weakens antioxidant defenses, contributing to cardiac dysfunction. The objective of this study was to determine whether sustained activation of skeletal muscle (SkM) Nrf2 preserves cardiac function during aging and to explore the underlying mechanisms, focusing on myocardial antioxidant pathways. Methods: Tamoxifen-induced SkM-specific Keap1 knockout male mice (iMS-Keap1^flox/flox; SkM-Nrf2 overexpression) were divided into young wild-type (Y-WT), aged wild-type (A-WT), and aged knockout (A-KO) groups. Cardiac performance was evaluated by echocardiography and invasive hemodynamics. Myocardial proteomics identified differentially expressed proteins (DEPs) and enriched biological pathways. Results: Compared with Y-WT, A-WT mice showed impaired left ventricular function, including reduced ejection fraction, prolonged isovolumic relaxation time, blunted inotropic response to dobutamine, and elevated Tau index. These age-related deficits were partially reversed in A-KO mice. Proteomic analysis revealed 561 DEPs between A-WT and Y-WT, and 741 DEPs between A-KO and A-WT, enriched in calcium signaling, Nrf2-mediated oxidative stress response, oxidative phosphorylation, ROS detoxification, and cardiac-specific processes, such as hypertrophy, conduction, and dilated cardiomyopathy. Conclusions: Lifelong SkM-Nrf2 activation strengthens myocardial antioxidant capacity and alleviates age-related cardiac dysfunction. These data support an antioxidant crosstalk between skeletal muscle and the heart, highlighting a potential therapeutic target for aging-associated heart failure. Full article

Background/Objectives: Heart failure with preserved ejection fraction (HFpEF) accounts for nearly half of all heart failure cases and remains challenging to diagnose and manage due to its complex, multifactorial nature. Increasing evidence highlights the significance of arterial stiffness, assessed by pulse wave velocity (PWV), and autonomic dysfunction, reflected by impaired heart rate recovery (HRR) after exercise, as relevant markers in HFpEF. This review aims to synthesize current knowledge on the diagnostic and prognostic value of PWV and HRR in HFpEF. Methods: A narrative literature review was conducted using PubMed to identify studies published between 2009 and 2025 that investigated PWV and HRR in patients with HFpEF or populations at risk. Included studies ranged from invasive hemodynamic measurements and cardiopulmonary exercise tests to large cohort analyses such as IDENTIFY-HF and MESA. Key findings were summarized in comparative tables. Results: Patients with HFpEF consistently show higher PWV than age-matched controls, supporting the concept of HFpEF as a systemic vascular disorder. Elevated PWV has been linked to increased risk of HFpEF onset and poorer outcomes. Likewise, blunted HRR indicates autonomic imbalance and is strongly associated with higher morbidity and mortality. Interventions including structured exercise training and optimized risk factor management may help improve PWV and HRR. Conclusions: PWV and HRR offer valuable, complementary insights for risk stratification and individualized care in HFpEF. Further research should focus on integrating these parameters into diagnostic algorithms and evaluating targeted therapies that address vascular stiffness and autonomic dysfunction. Full article

Heart Failure with Preserved Ejection Fraction (HFpEF) is an increasingly prevalent clinical syndrome that poses a significant public health challenge due to its complex pathophysiology, diagnostic limitations, and lack of effective therapies. Central to its development are multifactorial and interrelated mechanisms, including left ventricular diastolic dysfunction, myocardial fibrosis, inflammation, endothelial dysfunction, and cardiomyocyte hypertrophy. In recent years, noncoding RNAs (ncRNAs)—particularly microRNAs (miRNAs) and long noncoding RNAs (LncRNAs)—have emerged as critical regulators of these cellular and molecular pathways. This review outlines the major pathophysiological mechanisms underlying HFpEF and highlights the noncoding RNAs most extensively studied in this context. Several ncRNAs have shown promise as biomarkers for the diagnosis and prognosis of HFpEF, owing to their tissue specificity, stability in circulation, and involvement in disease-relevant pathways. However, their integration into routine clinical practice remains limited. Importantly, the regulatory functions of ncRNAs in HFpEF pathophysiology also position them as potential therapeutic targets. Early experimental studies demonstrate encouraging results, suggesting that ncRNA-targeted interventions may support the development of personalized treatment strategies tailored to the diverse clinical phenotypes observed in HFpEF. Full article

Cellular senescence and oxidative stress constitute an interdependent axis that underlies cardiac pathophysiology. Cellular senescence, defined as durable proliferative arrest, is initiated and sustained by redox imbalance, whereas mitochondrial reactive oxygen species function as signaling molecules or mediators of injury. In the heart, cellular senescence and oxidative stress influence remodeling and dysfunction across diseases, including ischemia–reperfusion injury, heart failure with preserved ejection fraction, dilated cardiomyopathy, and cardiac hypertrophy. Accordingly, delineating stress adaptation in cellular senescence is essential for elucidating oxidative stress-related pathogenesis. In this review, we attempt to provide an overview of the fundamental mechanisms and functions of cellular senescence in response to oxidative stress and redox signaling in disease. In addition, we integrate experimental and clinical evidence and delineate implications for mechanism-informed prevention and therapy. Full article

(1) Background: The systemic right ventricular (SRV) dysfunction and severe tricuspid regurgitation (TR) remain significant challenges in patients with congenitally corrected transposition of the great arteries (ccTGA) or following atrial switch procedures. Currently, there is no established, evidence-based medical therapy specifically designed for SRV failure, and treatment approaches are largely extrapolated from left ventricular heart failure (HF) guidelines. This therapeutic gap highlights the need for tailored pharmacologic strategies and optimized perioperative management in this unique population. The optimal timing of surgical intervention and the role of modern HF therapy are still under active investigation. (2) Methods: We present a case series of four patients (three adults and one child) with SRV dysfunction and severe TR, who underwent staged treatment consisting of optimized medical therapy followed by surgical tricuspid valve (TV) replacement. Medical therapy included positive inotropes, sacubitril/valsartan, sodium-glucose co-transporter 2 inhibitors (iSGLT2), beta-blockers, mineralocorticoid receptor antagonists (MRAs), and loop diuretics. (3) Results: All patients demonstrated clinical and hemodynamic improvement prior to surgery, with an increase in systemic ventricular ejection fraction (SVEF > 40%) and cardiac index. TV replacement was performed with favorable early postoperative outcomes and preserved ventricular function at mid-term follow-up. No mortality or major adverse events occurred during follow-up. One case of acute cystitis was associated with dapagliflozin. In all patients, postoperative SVEF remained >40%, and no recurrence of significant TR was observed. (4) Conclusions: A stepwise approach combining modern heart failure therapy and elective TV replacement in patients with SRV dysfunction and TR is safe and effective. Preoperative optimization leads to improved ventricular function and may enhance surgical outcomes. These findings support the integration of contemporary pharmacotherapy in the management strategy for SRV failure. Full article