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Article

The Association between Major Adverse Cardiovascular Events and Peripheral Artery Disease Burden

by
Oskari Niiranen
1,
Juha Virtanen
2,
Ville Rantasalo
1,
Amer Ibrahim
3,
Maarit Venermo
2 and
Harri Hakovirta
1,2,4,*
1
Department of Surgery, University of Turku, 20520 Turku, Finland
2
Department of Vascular Surgery, University of Helsinki and Helsinki University Hospital, 00100 Helsinki, Finland
3
Department of Surgery, KFSHRC, King Faisal Specialist Hospital and Research Centre, Madinah 11211, Saudi Arabia
4
Department of Surgery, Satasairaala, 28500 Pori, Finland
*
Author to whom correspondence should be addressed.
J. Cardiovasc. Dev. Dis. 2024, 11(6), 157; https://doi.org/10.3390/jcdd11060157
Submission received: 16 April 2024 / Revised: 19 May 2024 / Accepted: 20 May 2024 / Published: 21 May 2024
(This article belongs to the Special Issue Clinical Burden of Comorbidities on Cardiovascular System and Beyond)

Abstract

:
Objective: The aim of the present study was to investigate the possible relationship between the segmental burden of lower limb atherosclerosis and Major Adverse Cardiovascular Events (MACEs). Methods: All the consecutive symptomatic peripheral artery disease (PAD) patients admitted for digital subtraction angiography (DSA) at Turku University Hospital department of Vascular Surgery between 1 January 2009 and 30 July 2011 were retrospectively analyzed. Angiography due to symptomatic PAD was used as the index date for the inclusion in the study. The segmental burden of atherosclerosis based on DSA was divided into three categories according to the highest disease burden of the defined artery segment: aorto-iliac, femoropopliteal, or tibial segments. The major association for the study was MACEs (defined as a cerebrovascular event, heart failure (HF) and myocardial infarction requiring hospital admission). Demographic data and MACEs were obtained from the hospital electronic medical records system. Results. The lower limb atherosclerosis burden of tibial vessels was related to an increased probability for HF (OR 3.9; 95%CI 2.4–6.5) and for MACEs overall (OR 2.3; 95%CI 1.4–3.6). The probability of both HF and MACEs overall rose with the increasing severity of the atherosclerosis burden. Moreover, the more severe the tibial vessel atherosclerosis, the higher the risk of HF and MACEs. The most extensive tibial atherosclerosis patients had an OR 4.5; 95%CI 2.6–8.0 for HF and an OR 3.1; and 95%CI 1.7–5.6 for MACEs overall. The femoropopliteal disease burden was also associated with an increased risk of HF (OR 2.3; 95%CI 1.6–3.2) and MACE (OR 1.9; 95%CI 1.3–2.7). However, the increasing extent of atherosclerosis of the femoropopliteal segment solely increased the risk of MACEs. Conclusions: PAD patients with severe tibial atherosclerosis are likely to present with MACEs. The risk is further enhanced as the extent of tibial vessel atherosclerosis is increased. An association between MACE and severe atherosclerosis on the aortoiliac segment was not detected. However, when the femoropopliteal segment was the most affected artery segment, the risk of MACEs was increased.

1. Introduction

Peripheral artery disease (PAD) is a major risk factor for a poor cardiovascular outcome. It affects more than 200 million people worldwide [1] and in addition to mortality, it has a significant impact on patients’ daily functioning. There is a strong body of evidence in the present literature that supports the use of non-invasive pressure measurements for predicting the overall and cardiovascular mortality [2,3,4,5,6,7]. Both the non-invasive measures of the ankle brachial index (ABI) and the less utilized toe brachial pressure index (TBI) indirectly reflect the severity of atherosclerotic lesions between the descending aorta and the ankle or toe arteries. The possible significance of the extent of atherosclerosis on the lower limb vessels and patient outcome is poorly understood, however.
Peripheral arteries can be divided into three distinct segments and in each segment, the development of atherosclerosis is associated with distinctive risk factors [8]. For example, smoking, male sex and younger age are associated with aortoiliac lesions [9], whereas male sex and smoking are associated with both internal and external iliac calcification [10]. Both smoking and COPD are risk factors [11] associated with atherosclerosis of the femoropopliteal segment. Diabetes, hypertension, heart failure (HF) and CKD are associated with the tibial and pedal vessel disease [12].
Multiple studies have investigated the clinical significance of atherosclerosis in one or more of these artery segments. Abdominal aortic calcification is associated with cardiovascular mortality, and coronary and cerebrovascular events. The risks for coronary and cerebrovascular events therefore increase along with the extent of abdominal aortic atherosclerosis [13,14]. A retrospective study of infrainguinal atherosclerosis assessed Bollinger scores and demonstrated that the Bollinger score is an independent predictor of mortality. Furthermore, the authors concluded that both the femoropopliteal and tibial Bollinger scores predicted mortality [15]. Recent studies compared the extent of tibial atherosclerosis (crural index (CXi)) and observed an association between the extent of tibial atherosclerosis and several poor outcomes such as cardiovascular mortality, overall mortality amputation free survival, ischemic degenerative brain changes and poor outcome after thrombolysis [16,17,18,19]. However, the cardiovascular outcome in relation to the burden of atherosclerosis on each lower limb artery segment still requires further investigation.
Since the association between extensive atherosclerosis and cardiovascular morbidity is still controversial, the aim of the present study was to investigate whether the extent of aortoiliac, femoropopliteal or tibial disease has an impact on the major adverse cardiovascular events (MACEs) in PAD patients with major adverse limb events (MALEs).

2. Materials and Methods

2.1. Patient Characteristics

The present study was a retrospective study of 732 symptomatic peripheral artery disease (PAD) patients at Turku University Hospital’s department of vascular surgery admitted for digital subtraction angiography either for diagnostic digital subtraction angiography (DSA) or for endovascular treatment of lower limb atherosclerosis between 1 January 2009 and 30 July 2011. The angiography date was used as the index date for MALEs and an index date for inclusion in the study. Data were collected from hospital electronic databases. The study was approved by the Hospital District of South-Western Finland Ethics Committee (decision ID TK-53-1266-15). Patient consent was not required due to the retrospective nature of the study. This study conformed to the ethics guidelines of the 1975 Declaration of Helsinki.

2.2. DSA Analysis and Description of the Crural Index (CXi)

All analyses of segment-specific atherosclerosis were based on DSA images. The index classification was as described in TASC II for aortoiliac and femoropopliteal segments (TASC A–D converted to indices I–IV). All three tibial vessels were analyzed separately for the CXi. Each crural vessel was coded as follows: no detectable occlusive disease or minor stenosis: 0; total occlusion of less than 5 cm: 1; total occlusion of less than 10 cm: 2; total occlusion of less than 15 cm: 3; total occlusion of more than 15 cm: 4. Only total occlusions were measured; other atherosclerotic lesions were not considered. The CXi was created by a sum of the three values that had been obtained from each individual tibial vessel. If the sum was 0, the index was 0, if the sum was between 1 and 3 the index was I, if the sum was 4–6 the index was II, if the sum was 7–9 the index was III and if the sum was 10–12 the index was IV.
Each patient was assigned to a specific group of disease burden (1) aortoiliac, (2) femoropopliteal or (3) crural, based on which 0-IV rating gave the highest number [16,17]. The method is further described in our earlier publications [16,17,20].

2.3. Base Line Characteristics and MACEs

The baseline characteristics were collected from the hospital’s patient electronic medical records, retrospectively. Comorbidities were recorded according to ICD-10 codes: coronary artery disease (CAD) (I20.0–I25.9), hypertension (I10.0–I10.9), (I48.0–I48.9), diabetes mellitus (E10.0–E11.9), chronic obstructive pulmonary disease (COPD) (J44.8), hypercholesterolemia (E78.0) and chronic kidney disease (CKD) (N18.1–N18.9). In addition, a smoking history and Rutherford class were recorded at the index date. The last values of the ABI and TBI before the index date for the study were obtained, and the value of the leg with the lower index was used for analyses. All non-invasive pressures were analyzed in a certified Angio laboratory as described earlier by Wickström and colleagues [21].
A MACE was defined as stroke, HF or another acute coronary syndrome. MACE data for the study cohort of 732 patients with a MACE were obtained from hospital digital patient files before and after the study index date.

2.4. Statistical Analyses

Statistical analyses were performed using the IBM SPSS® version 29 statistics program. The Shapiro–Wilk test was used to test the normality of the study data. Continuous variables were expressed as mean ± standard deviation (SD) and the Kruskal–Wallis test was used for comparisons. Categorical variables were expressed as frequency and percentage and comparisons were performed using the Chi-square test. Age-adjusted logistic regression analyses were performed on MACE overall data and all selected MACEs separately as the outcome. Significant burdens were selected for the multilogistic regression analyses based on age-adjusted regression analyses. The following confounding variables were added to the model: Age, CAD, Diabetes, CKD. All authors had full access to all the study data. The corresponding author takes the responsibility for the integrity of the data analyses. Data cannot be shared publicly because of patient identification. However, data are available from the corresponding author for researchers who meet the criteria for access to confidential data.

3. Results

3.1. Demography and MACEs

The patients’ demographic data are presented on Table 1, Table 2, Table 3 and Table 4. Altogether, 489 (66.8% of the cohort) patients presented with one or more MACEs. Myocardial infarct (MI) was the most abundant (n = 303 patients; 41.4%), followed by HF (n = 268 patients; 36.6%) and cerebrovascular incidents (n = 209 patients; 28.6%). Both HF and MI were diagnosed in 160 patients (21.9%), with MI and cerebrovascular incidents in 87 patients (11.9%), and HF and cerebrovascular incidents in 83 patients (11.3%).

3.2. The Risk of a MACE and Atherosclerosis Burden

An age-adjusted logistic regression analysis was performed to analyze the possible association between the atherosclerosis burden group and risk of defined outcomes. The aortoiliac or femoropopliteal segment did not present an increased OR (odds ratio) for any MACEs (Table 5 and Table 6). Extensive tibial artery atherosclerosis was associated with MACEs (Table 7). When analyzed against the segment-specific burden of atherosclerosis, the infrainguinal disease femoropopliteal and tibial burden was associated with an increased risk compared to severe aortoiliac segment disease (Table 8).
Based on the age-adjusted regression analyses, the CXi and lower limb artery disease burden was further analyzed via multilogistic regression analyses. The model contained significant comorbidities in regard to CAD, CKD and diabetes; see Table 9.

4. Discussion

The present study suggests that extensive tibial vessel atherosclerosis is associated with an increased risk of HF and MACE overall. In addition, both infrainguinal lower limb atherosclerosis burdens, i.e., of the femoropopliteal segment and the tibial segment, are associated with an increased risk of either HF or MACEs in general. In contrast, the aortoiliac burden could not be demonstrated to be associated with any consistent risk of any of the selected outcomes. Our earlier studies on the overall and cardiovascular mortality based on this cohort are in line with the present observations that the highest cardiovascular disease burden is associated with extensive and severe tibial vessel disease [16,17].
The inclusion criteria for this cohort were MALEs. Therefore, every patient in this cohort had significant PAD. The present study did not demonstrate an association between aortoiliac segment disease and MACEs. However, compared to the normal population, the cardiovascular burden of these patients was increased [22,23], and this was further borne out by the logistic regression analyses. The classification utilized for aortoiliac and femoropopliteal segments is based on the TASC A-D criteria. These criteria might not best present the extent of atherosclerosis on the aortoiliac segment of patients for all categories, but rather present the complicity of revascularization in that TASC class. Therefore, AI III and IV might especially comprise patients that had lesions that were technically difficult to treat but who did not have extensive atherosclerosis at that particular segment [24].
Even one in seven CAD or PAD patients present with a new MACE or MALE within 2 years of follow-up [25]. Therefore, these patients have a large economic burden, and targeted efficient secondary preventive actions for patients with the highest MACE risk is therefore essential [25]. Some general health-related predictors for MACEs and MALEs among patients with CAD and/or MALEs have previously been identified [25]. Based on the present observations, the analyses of the segment-specific burden of atherosclerosis among MALE patients enable the identification of those with the highest risk of HF and MACEs overall. In accordance with the present observations, HF has been shown to be associated with low ABI indices [26]. In that study, which was an Atherosclerosis Risk in Communities (ARIC) study, Gupta et al., 2014 also demonstrated a threshold value of 1.0 [26] for the increased risk of MACEs. In addition, borderline ABI values of 0.9–1.0 were shown to be associated with an increased risk of HF. However, the present observations are, to our knowledge, the first observations that suggest that the extent and anatomic distribution of atherosclerosis of the lower limb arteries can have a significant effect on the burden of HF among patients with symptomatic PAD. The mean ABI for patients at the highest risk of HF for CXi category IV was 0.57 and that for the segment-specific tibial vessel atherosclerosis burden was 0.97, which suggests that the ABI alone cannot distinguish patients with the highest risk.
The utilized parameters for disease extent and severity are based on the clinician’s evaluation of DSA images. The categories and grading of atherosclerosis severity based on the TASC II classification was originally created to serve as a guide to select the strategy for revascularization. The CXi is based on the length of the occlusions of three tibial arteries. For example, a patient with the CXi IV disease has extensive severe lesions in all tibial arteries, and mild lesions are not taken into consideration when the index is calculated. All these aspects should be considered when interpreting the present observations. However, the present observations strongly suggest that the localization, extent and severity of atherosclerosis of three lower limb artery segments has a significant input on the patient’s outcome. Therefore, the development of algorithms that can automatically sequence the lower limb arteries and objectively analyze the disease burden [27] is needed. Such algorithms will provide a quick tool for angiography-based risk analyses. The algorithms could predict not only selected MACEs, but also predict cardiovascular death and even overall death.
The present study further emphasizes the need for new means for the risk analyses for peripheral artery disease. The most utilized non-invasive lower limb pressure measurement ABI has many advantages. However, the present results suggest that the ABI together with other parameters such as the extent or severity of the disease burden would further enhance the risk analyses. In the presence of tibial disease, the ABI is especially pseudohypertensive in many patients; thus, it may not distinguish all patients with a significant tibial atherosclerotic burden. Whether the ABI or TBI is more sensitive for risk analyses together with automated artificially intelligent produced data on disease burden will be an interesting topic for further studies as well as the possibility to utilize cytokines and chemokines as biomarkers for the progression and risk of the acute onset of vascular disease in various organ systems [28,29,30].

5. Conclusions

According to the present study data, severe tibial vessel PAD is associated with high overall MACE risk and especially the risk of HF. Further studies are essential for creating artificial intelligence-assisted analyses of lower limb atherosclerosis in order to provide a rapid and effective tool for both risk analyses for individual patients and possibly helping the planning of the optimal revascularization for the affected limb.

Author Contributions

Conceptualization, H.H., O.N. and J.V.; methodology, H.H., O.N. and J.V.; software, H.H.; validation, H.H.; formal analysis, H.H.; investigation, H.H., O.N. and J.V.; resources, H.H.; data curation, H.H., O.N. and J.V.; writing—original draft preparation, O.N., J.V., V.R., M.V., A.I. and H.H.; writing–review and editing, O.N., J.V., V.R., M.V., A.I. and H.H.; visualization, H.H.; supervision, H.H.; project administration, H.H.; funding acquisition, H.H. All authors have read and agreed to the published version of the manuscript.

Funding

Finnish culture foundation, Satakunta fund under grant numbers 75212239, 75221501; Federal grant Satasairaala under grant number 960100020_00004.

Institutional Review Board Statement

The study was a retrospective registry-based cohort study. It was approved by the University of Turku and reviewed and accepted by the Institutional Review Board (IRB number T344/2017). Due to the nature of the study, the informed consent of the patients was not required.

Informed Consent Statement

Due to the nature of the study, the informed consent of the patients was not required.

Data Availability Statement

The data are unavailable due patient identification privacy as decided by the Ethics Committee. However, anonymized data can be accessed on demand by contacting the Research Center VARHA (Varsinais-Suomen hyvinvointialue).

Conflicts of Interest

The authors declare no conflicts of interest.

References

  1. Fowkes, F.G.R.; Rudan, D.; Rudan, I.; Aboyans, V.; Denenberg, J.O.; McDermott, M.M.; Norman, P.E.; Sampson, U.K.A.; Williams, L.J.; Mensah, G.A.; et al. Comparison of global estimates of prevalence and risk factors for peripheral artery disease in 2000 and 2010: A systematic review and analysis. Lancet 2013, 382, 1329–1340. [Google Scholar] [CrossRef] [PubMed]
  2. Hyun, S.; Forbang, N.I.; Allison, M.A.; Denenberg, J.O.; Criqui, M.H.; Ix, J.H. Ankle-brachial index, toe-brachial index, and cardiovascular mortality in persons with and without diabetes mellitus. J. Vasc. Surg. 2014, 60, 390–395. [Google Scholar] [CrossRef] [PubMed]
  3. Vogt, M.T.; McKenna, M.; Wolfson, S.K.; Kuller, L.H. The relationship between ankle brachial index, other atherosclerotic disease, diabetes, smoking and mortality in older men and women. Atherosclerosis 1993, 101, 191–202. [Google Scholar] [CrossRef] [PubMed]
  4. Samba, H.; Guerchet, M.; Ndamba-Bandzouzi, B.; Kehoua, G.; Mbelesso, P.; Desormais, I.; Aboyans, V.; Preux, P.-M.; Lacroix, P. Ankle Brachial Index (ABI) predicts 2-year mortality risk among older adults in the Republic of Congo: The EPIDEMCA-FU study. Atherosclerosis 2019, 286, 121–127. [Google Scholar] [CrossRef] [PubMed]
  5. Criqui, M.H.; McClelland, R.L.; McDermott, M.M.; Allison, M.A.; Blumenthal, R.S.; Aboyans, V.; Ix, J.H.; Burke, G.L.; Liu, K.; Shea, S. The Ankle-Brachial Index and Incident Cardiovascular Events in the MESA (Multi-Ethnic Study of Atherosclerosis). J. Am. Coll. Cardiol. 2010, 56, 1506–1512. [Google Scholar] [CrossRef] [PubMed]
  6. Aboyans, V.; Lacroix, P.; Postil, A.; Guilloux, J.; Rollé, F.; Cornu, E.; Laskar, M. Subclinical Peripheral Arterial Disease and Incompressible Ankle Arteries Are Both Long-Term Prognostic Factors in Patients Undergoing Coronary Artery Bypass Grafting. J. Am. Coll. Cardiol. 2005, 46, 815–820. [Google Scholar] [CrossRef] [PubMed]
  7. Aboyans, V.; Criqui, M.H.; Abraham, P.; Allison, M.A.; Creager, M.A.; Diehm, C.; Fowkes, F.G.R.; Hiatt, W.R.; Jönsson, B.; Lacroix, P.; et al. Measurement and interpretation of the ankle-brachial index: A scientific statement from the American Heart Association. Circulation 2012, 126, 2890–2909. [Google Scholar] [CrossRef]
  8. Diehm, N.; Shang, A.; Silvestro, A.; Do, D.-D.; Dick, F.; Schmidli, J.; Mahler, F.; Baumgartner, I. Association of Cardiovascular Risk Factors with Pattern of Lower Limb Atherosclerosis in 2659 Patients Undergoing Angioplasty. Eur. J. Vasc. Endovasc. Surg. 2006, 31, 59–63. [Google Scholar] [CrossRef]
  9. Chen, Q.; Smith, C.Y.; Bailey, K.R.; Wennberg, P.W.; Kullo, I.J. Disease Location Is Associated With Survival in Patients With Peripheral Arterial Disease. J. Am. Hear. Assoc. 2013, 2, e000304. [Google Scholar] [CrossRef]
  10. Hendriks, E.J.; Beulens, J.W.; de Jong, P.A.; van der Schouw, Y.T.; Sun, W.-N.; Wright, C.M.; Criqui, M.H.; Allison, M.A.; Ix, J.H. Calcification of the splenic, iliac, and breast arteries and risk of all-cause and cardiovascular mortality. Atherosclerosis 2017, 259, 120–127. [Google Scholar] [CrossRef]
  11. Gray, B.H.; Grant, A.A.; Kalbaugh, C.A.; Blackhurst, D.W.; Langan, E.M., III; Taylor, S.A.; Cull, D.L. The impact of isolated tibial disease on outcomes in the critical limb ischemic population. Ann. Vasc. Surg. 2010, 24, 349–359. [Google Scholar] [CrossRef]
  12. Aboyans, V.; Desormais, I.; Lacroix, P.; Salazar, J.; Criqui, M.H.; Laskar, M. The General Prognosis of Patients With Peripheral Arterial Disease Differs According to the Disease Localization. J. Am. Coll. Cardiol. 2010, 55, 898–903. [Google Scholar] [CrossRef]
  13. Bastos Goncalves, F.; Voute, M.T.; Hoeks, S.E.; Chonchol, M.B.; Boersma, E.E.; Stolker, R.J.; Verhagen, H.J.M. Calcification of the abdominal aorta as an independent predictor of cardiovascular events: A meta-analysis. Heart 2012, 98, 988–994. [Google Scholar] [CrossRef]
  14. Rantasalo, V.; Laukka, D.; Nikulainen, V.; Jalkanen, J.; Gunn, J.; Hakovirta, H. Aortic calcification index predicts mortality and cardiovascular events in operatively treated patients with peripheral artery disease: A prospective PURE ASO cohort follow-up study. J. Vasc. Surg. 2022, 76, 1657–1666.e2. [Google Scholar] [CrossRef]
  15. Tern, P.J.; Kujawiak, I.; Saha, P.; Berrett, T.B.; Chowdhury, M.M.; Coughlin, P.A. Site and Burden of Lower Limb Atherosclerosis Predicts Long-term Mortality in a Cohort of Patients With Peripheral Arterial Disease. Eur. J. Vasc. Endovasc. Surg. 2018, 56, 849–856. [Google Scholar] [CrossRef]
  16. Wickström, J.-E.; Jalkanen, J.M.; Venermo, M.; Hakovirta, H.H. Crural Index and extensive atherosclerosis of crural vessels are associated with long-term cardiovascular mortality in patients with symptomatic peripheral artery disease. Atherosclerosis 2017, 264, 44–50. [Google Scholar] [CrossRef]
  17. Jalkanen, J.M.; Wickström, J.-E.; Venermo, M.; Hakovirta, H.H. The extent of atherosclerotic lesions in crural arteries predicts survival of patients with lower limb peripheral artery disease: A new classification of crural atherosclerosis. Atherosclerosis 2016, 251, 328–333. [Google Scholar] [CrossRef]
  18. Virtanen, J.; Varpela, M.; Biancari, F.; Jalkanen, J.; Hakovirta, H. Association between anatomical distribution of symptomatic peripheral artery disease and cerebrovascular disease. Vascular 2020, 28, 295–300. [Google Scholar] [CrossRef]
  19. Vakhitov, D.; Hakovirta, H.; Saarinen, E.; Oksala, N.; Suominen, V. Prognostic risk factors for recurrent acute lower limb ischemia in patients treated with intra-arterial thrombolysis. J. Vasc. Surg. 2020, 71, 1268–1275. [Google Scholar] [CrossRef]
  20. Koivunen, V.; Juonala, M.; Venermo, M.; Laivuori, M.; Jalkanen, J.M.; Hakovirta, H.H. Toe pressure and toe brachial index are predictive of cardiovascular mortality regardless of the most diseased arterial segment in symptomatic lower-extremity artery disease—A retrospective cohort study. PLoS ONE 2021, 16, e0259122. [Google Scholar] [CrossRef]
  21. Wickström, J.-E.; Laivuori, M.; Aro, E.; Sund, R.; Hautero, O.; Venermo, M.; Jalkanen, J.; Hakovirta, H. Toe Pressure and Toe Brachial Index are Predictive of Cardiovascular Mortality, Overall Mortality, and Amputation Free Survival in Patients with Peripheral Artery Disease. Eur. J. Vasc. Endovasc. Surg. 2017, 53, 696–703. [Google Scholar] [CrossRef] [PubMed]
  22. Criqui, M.H.; Langer, R.D.; Fronek, A.; Feigelson, H.S.; Klauber, M.R.; McCann, T.J.; Browner, D. Mortality over a Period of 10 Years in Patients with Peripheral Arterial Disease. N. Engl. J. Med. 1992, 326, 381–386. [Google Scholar] [CrossRef] [PubMed]
  23. Steg, P.G.; Bhatt, D.L.; Wilson, P.W.F.; D’agostino, R.; Ohman, E.M.; Röther, J.; Liau, C.-S.; Hirsch, A.T.; Mas, J.-L.; Ikeda, Y.; et al. One-Year Cardiovascular Event Rates in Outpatients with Atherothrombosis. JAMA 2007, 297, 1197–1206. [Google Scholar] [CrossRef] [PubMed]
  24. Norgren, L.; Hiatt, W.R.; Dormandy, J.A.; Nehler, M.R.; Harris, K.A.; Fowkes, F.G. Inter-Society Consensus for the Management of Peripheral Arterial Disease (TASC II). Eur. J. Vasc Endovasc. Surg. 2007, 33, S1–S75. [Google Scholar] [CrossRef] [PubMed]
  25. Berger, A.; Simpson, A.; Bhagnani, T.; Leeper, N.J.; Murphy, B.; Nordstrom, B.; Ting, W.; Zhao, Q.; Berger, J.S. Incidence and Cost of Major Adverse Cardiovascular Events and Major Adverse Limb Events in Patients with Chronic Coronary Artery Disease or Peripheral Artery Disease. Am. J. Cardiol. 2019, 123, 1893–1899. [Google Scholar] [CrossRef] [PubMed]
  26. Gupta, D.K.; Skali, H.; Claggett, B.; Kasabov, R.; Cheng, S.; Shah, A.M.; Loehr, L.R.; Heiss, G.; Nambi, V.; Aguilar, D.; et al. Heart failure risk across the spectrum of ankle-brachial index: The ARIC study (Atherosclerosis Risk In Communities). JACC Heart Fail. 2014, 2, 447–454. [Google Scholar] [CrossRef] [PubMed]
  27. Halkoaho, J.; Niiranen, O.; Salli, E.; Kaseva, T.; Savolainen, S.; Kangasniemi, M.; Hakovirta, H. Quantifying the calcification of abdominal aorta and major side branches with deep learning. Clin. Radiol. 2024. [Google Scholar] [CrossRef] [PubMed]
  28. Quagliariello, V.; Passariello, M.; Rea, D.; Barbieri, A.; Iovine, M.; Bonelli, A.; Caronna, A.; Botti, G.; De Lorenzo, C.; Maurea, N. Evidences of CTLA-4 and PD-1 Blocking Agents-Induced Cardiotoxicity in Cellular and Preclinical Models. J. Pers. Med. 2020, 10, 179. [Google Scholar] [CrossRef] [PubMed]
  29. Quagliariello, V.; Bisceglia, I.; Berretta, M.; Iovine, M.; Canale, M.L.; Maurea, C.; Giordano, V.; Paccone, A.; Inno, A.; Maurea, N. PCSK9 Inhibitors in Cancer Patients Treated with Immune-Checkpoint Inhibitors to Reduce Cardiovascular Events: New Frontiers in Cardioncology. Cancers 2023, 15, 1397. [Google Scholar] [CrossRef]
  30. Jalkanen, J.; Maksimow, M.; Hollmén, M.; Jalkanen, S.; Hakovirta, H. Compared to Intermittant Claudication Critical Limb Ischemia Is Associated with Elevated Levels of Cytokines. PLoS ONE 2016, 11, e0162353. [Google Scholar] [CrossRef]
Table 1. The demography and diagnosed MACE conditions of the MALE patients for each aortoiliac (AI) burden group for categorical values n (%) and continuous variables mean (SD).
Table 1. The demography and diagnosed MACE conditions of the MALE patients for each aortoiliac (AI) burden group for categorical values n (%) and continuous variables mean (SD).
AI 0AI IAI IIAI IIIAI IVp Value
MI220 (43.1)26 (30.2)20 (39.2)12 (40.0)25 (45.5)0.227
HF204 (40.0)24 (27.9)14 (27.5)10 (33.3)16 (29.1)0.073
CeV149 (29.2)26 (30.2)13 (25.5)4 (13.3)17 (30.9)0.392
MACE overall350 (68.6)57 (66.3)30 (58.8)16 (53.3)36 (65.5)0.305
Age 75.4 ± 10.474.23 ± 10.875.4 ± 10.569.3 ± 10.873.7 ± 11.00.030
Male291 (57.1)54 (62.8)27 (52.9)19 (63.3)36 (65.5)0.552
CAD219 (42.9)36 (41.9)16 (31.4)14 (46.7)30 (54.5)0.198
CeVD86 (16.9)17 (19.8)4 (7.8)5 (16.7)11 (20.0)0.385
Hypertension359 (70.4)60 (69.8)30 (58.8)18 (60.0)42 (76.4)0.245
Diabetes234 (45.9)31 (36.0)14 (27.5)10 (33.3)11 (20.0)<0.001
COPD52 (10.2)13 (15.1)9 (18.0)11 (36.7)7 (12.7)0.002
CKD57 (11.2)5 (5.9)2 (3.9)2 (6.7)4 (7.3)0.320
Hyperlipidaemia186 (36.5)31 (36.0)14 (27.5)16 (53.3)26 (47.3)0.096
Smoking history112 (22.0)35 (40.7)27 (52.9)15 (50.0)23 (41.8)<0.001
Rf 210 (2.0)2 (36.1))0 (0.0)0 (0.0)0 (0.0)
Rf 3184 (36.1)54 (62.8)39 (76.5)15 (50.0)26 (47.3)
Rf 497 (19.9)17 (19.8)7 (13.7)4 (13.3)15 (27.3)
Rf 5105 (20.6)7 (8.1)3 (5.9)4 (13.3)8 (14.5)
Rf 6112 (22.0)6 (7.0)2 (3.9)7 (23.3)6 (10.9)<0.001
ABI0.809 ± 0.6710.630 ± 0.4670.670 ± 0.4920.501 ± 0.2050.448 ± 0.211<0.001
TBI0.294 ± 0.1740.339 ± 0.1800.329 ± 0.1350.309 ± 0.1890.251 ± 0.1700.029
ABI: ankle brachial index, AI; aortoiliac, CAD: coronary artery disease, CeV: cerebrovascular event, CeVD: cerebrovascular disease, CKD: chronic kidney dysfunction, COPD: chronic obstructive pulmonary disease, HF: heart failure, MACE: major adverse cardiovascular event, Rf: Rutherford category, TBI; toe brachial index.
Table 2. The demography and diagnosed MACE conditions of the MALE patients for each femoropopliteal (FP) burden group for categorical values n (%) and continuous variables mean (SD).
Table 2. The demography and diagnosed MACE conditions of the MALE patients for each femoropopliteal (FP) burden group for categorical values n (%) and continuous variables mean (SD).
FP 0FP IFP IIFP IIIFP IVp Value
MI63 (36.0)23 (33.3)63 (52.1)41 (43.2)113 (41.5)0.046
HF69 (39.4)17 (24.6)46 (38.0)34 (35.8)102 (37.5)0.268
CeV59 (33.7)18 (26.1)37 (30.6)21 (22.1)74 (27.2)0.303
MACE (overall)118 (67.4)41 (59.4)89 (73.6)64 (67.4)177 (65.1)0.329
Age75.5 ± 11.175.4 ± 9.6376.0 ± 9.5474.1 ± 10.274.2 ± 11.00.455
Male107 (61.1)42 (60.9)73 (60.3)55 (57.9)150 (55.1)0.724
CAD66 (37.7)24 (34.8)64 (52.9)40 (42.1)121 (44.5)0.063
CeVD27 (15.4)15 (21.7)20 (16.5)20 (21.1)41 (15.1)0.499
Hypertension112 (64.0)52 (75.4)90 (74.4)72 (75.8)183 (67.3)0.123
Diabetes71 (40.6)32 (46.4)53 (43.8)44 (46.3)100 (36.8)0.354
COPD13 (7.5)8 (11.6)9 (7.4)15 (16.0)47 (17.3)0.008
CKD29 (16.6)6 (8.7)8 (6.6)9 (9.5)18 (6.6)0.012
Hyperlipidaemia58 (33.1)28 (40.6)43 (35.5)39 (41.1)105 (38.6)0.633
Smoking history44 (25.1)23 (33.3)28 (23.1)33 (34.7)84 (30.9)0.202
Rf 21 (0.6)2 (2.9)6 (5.0)0 (0.0)3 (1.1)
Rf 371 (40.6)40 (58.0)59 (48.8)48 (50.5)100 (36.8)
Rf 425 (14.3)7 (10.1)15 (12.4)19 (20.0)74 (27.2)
Rf 536 (20.6)6 (8.7)18 (14.9)15 (15.8)52 (19.1)
Rf 642 (24.0)14 (20.3)23 (19.0)11 (11.6)43 (15.8)<0.001
ABI1.08 ± 0.7600.779 ± 0.6330.784 ± 0.5820.611 ± 0.4930.532 ± 0.420<0.001
TBI0.326 ± 0.1660.308 ± 0.1660.353 ± 0.1900.299 ± 0.1800.255 ± 0.161<0.001
ABI: ankle brachial index, CAD: coronary artery disease, CeV: cerebrovascular event, CeVD: cerebrovascular disease, CKD: chronic kidney dysfunction, COPD: chronic obstructive pulmonary disease, FP: femoropopliteal, HF: heart failure, MACE: major adverse cardiovascular event, Rf: Rutherford category, TBI: toe brachial index.
Table 3. The demography and diagnosed MACE conditions of the MALE patients at each tibial crural index (CXi) burden group for categorical values n (%) and continuous variables mean (SD).
Table 3. The demography and diagnosed MACE conditions of the MALE patients at each tibial crural index (CXi) burden group for categorical values n (%) and continuous variables mean (SD).
CXi OCXi ICXi IICxi IIICxi IVp Value
MI43 (36.8)26 (41.3)78 (37.5)103 (45.8)53 (44.5)0.332
HF22 (18.8)16 (25.4)69 (33.2)100 (44.4)61 (51.3)<0.001
CeV31 (26.5)17 (27.0)57 (27.4)61 (27.1)43 (36.1)0.419
MACE overall66 (56.4)40 (63.5)132 (63.5)156 (69.3)95 (79.8)0.002
Age70.9 ± 9.1672.4 ± 10.575.5 ± 9.8275.3 ± 10.678.3 ± 11.6<0.001
Male67 (57.3)47 (74.6)132 (63.5)116 (51.6)65 (54.6)0.006
CAD49 (41.9)23 (36.5)83 (39.9)107 (47.6)53 (44.5)0.414
CeVD17 (14.5)9 (14.3)37 (17.8)42 (18.7)18 (15.1)0.828
Hypertension77 (65.8)42 (66.7)140 (67.3)162 (72.0)88 (73.9)0.513
Diabetes37 (31.6)30 (47.6)86 (41.3)97 (43.1)50 (42.0)0.203
COPD19 (16.2)7 (11.1)36 (17.4)21 (9.4)9 (7.6)0.032
CKD6 (5.1)9 (14.3)21 (10.1)30 (13.3)4 (3.4)0.006
Hyperlipidaemia55 (47.0)28 (44.4)73 (35.1)86 (38.2)31 (26.1)0.010
Smoking history66 (56.4)25 (39.7)71 (34.1)36 (16.0)14 (11.8)<0.001
Rf 23 (2.6)1 (1.6)4 (1.9)0 (0.0)4 (3.4)
Rf 377 (65.8)40 (63.5)94 (45.2)84 (37.3)4 (3.4)
Rf 418 (15.4)7 (11.1)41 (19.7)47 (20.9)27 (22.7)
Rf 513 (11.1)5 (7.9)17 (8.2)51 (22.7)41 (34.5)
Rf 65 (4.3)9 (14.3)52 (25.0)43 (19.1)24 (20.2)<0.001
ABI0.643 ± 0.3970.898 ± 0.6430.774 ± 0.6320.811 ± 0.7040.570 ± 0.482<0.001
TBI0.335 ± 0.1780.386 ± 0.1560.321 ± 0.1630.273 ± 0.1740.222 ± 0.159<0.001
ABI: ankle brachial index, CAD: coronary artery disease, CeV: cerebrovascular event, CeVD: cerebrovascular disease, CKD: chronic kidney dysfunction, COPD: chronic obstructive pulmonary disease, CXi: crural index, HF: heart failure, MACE: major adverse cardiovascular event, Rf: Rutherford category, TBI: toe brachial index.
Table 4. The demography and diagnosed MACE conditions the MALE patients according to the lower limb segment specific atherosclerosis burden groups for categorical values n (%) and continuous variables mean (SD).
Table 4. The demography and diagnosed MACE conditions the MALE patients according to the lower limb segment specific atherosclerosis burden groups for categorical values n (%) and continuous variables mean (SD).
AIFPTibialp Value
MI50 (38.8)155 (42.2)98 (42.1)0.779
HF28 (21.7)118 (32.2)121 (51.9)<0.001
CeV35 (27.1)89 (24.3)82 (35.2)0.015
MACE overall76 (58.9)232 (63.2)178 (76.4)<0.001
Age72.8 ± 10.474.4 ± 10.076.8 ± 11.20.001
Male87 (67.4)152 (41.4)109 (46.8)0.031
CAD55 (42.6)161 (43.9)99 (42.5)0.939
CeVD20 (15.5)367 (17.4)38 (16.3)0.879
Hypertension88 (68.2)249 (67.8)169 (72.5)0.456
Diabetes30 (23.3)144 (39.2)124 (53.2)<0.001
COPD23 (17.8)57 (15.6)11 (4.7)<0.001
CKD8 (6.2)30 (8.2)30 (12.9)<0.001
Hyperlipidaemia52 (40.3)152 (41.4)69 (29.6)0.010
Smoking history68 (52.7)121 (33.0)23 (9.9)<0.001
Rf 21 (0.8)7 (1.9)4 (1.7)
Rf 387 (67.4)183 (49.9)48 (20.6)
Rf 423 (17.8)79 (21.5)36 (15.5)
Rf 511 (8.5)41 (11.2)74 (31.8)
Rf 67 (5.4)55 (15.0)71 (30.5)<0.001
ABI0.557 ± 0.2600.650 ± 0.2600.971 ± 0.782<0.001
TBI0.324 ± 0.1730.308 ± 0.1770.270 ± 0.1650.008
ABI: ankle brachial index, AI: aortoiliac, CAD: coronary artery disease, CeV: cerebrovascular event, CeVD: cerebrovascular disease, CKD: chronic kidney dysfunction, COPD: chronic obstructive pulmonary disease, FP: femoropopliteal, HF: heart failure, MACE: major adverse cardiovascular event, Rf: Rutherford category, TBI: toe brachial index.
Table 5. The age-adjusted hazard for the overall MACE and MACEs (heart failure, myocardial infarct, cerebrovascular event) in five aortoiliac (AI) burden groups (an OR with 95% confidence intervals and p values).
Table 5. The age-adjusted hazard for the overall MACE and MACEs (heart failure, myocardial infarct, cerebrovascular event) in five aortoiliac (AI) burden groups (an OR with 95% confidence intervals and p values).
HF
OR95% CIp Value
AI 0Reference
AI I0.5810.345–0.9490.034
AI II0.5680.290–1.050.083
AI III0.7500.331–1.600.469
AI IV0.6150.326–1.110.118
MI
OR95% CIp Value
AI 0Reference
AI I0.5710.344–0.9250.026
AI II0.8500.466–1.520.590
AI III0.8790.405–1.850.736
AI IV1.0980.624–1.920.742
CeV
OR95% CIp Value
AI 0Reference
AI I0.9520.584–1.590.848
AI II1.2060.640–2.410.576
AI III2.6831.02–9.210.071
AI IV0.9230.513–1.720.793
MACE
OR95% CIp Value
AI 0Reference
AI I0.8990.558–1.470.665
AI II0.6530.364–1.190.156
AI III0.5220.249–1.110.086
AI IV0.8660.487–1.580.631
AI: aortoiliac, CeV: cerebrovascular event, 95% CI: 95% confidence interval; HF: heart failure, MACE: major adverse cardiovascular event, MI: myocardial infarct, OR: odds ratio.
Table 6. The age-adjusted hazards for the overall MACE and MACEs (heart failure, myocardial infarct, cerebrovascular event) in the defined femoropopliteal (FP) burden groups are presented with 95% confidence intervals and p values.
Table 6. The age-adjusted hazards for the overall MACE and MACEs (heart failure, myocardial infarct, cerebrovascular event) in the defined femoropopliteal (FP) burden groups are presented with 95% confidence intervals and p values.
HF
OR95% CIp Value
FP 0Reference
FP I0.5020.263–0.9240.031
FP II0.9420.584–1.520.806
FP III0.8560.508–1.430.557
FP IV0.9220.624–1.360.682
MI
OR95% CIp Value
FP 0Reference
FP I0.8890.488–1.590.695
FP II1.9311.21–3.100.006
FP III1.3500.809–2.250.249
FP IV1.2630.855–1.870.242
CeV
OR95% CIp Value
FP 0Reference
FP I1.4410.784–2.740.250
FP II1.1550.704–1.910.571
FP III1.7921.02–3.240.048
FP IV1.3610.900–2.050.142
MACE
OR95% CIp Value
FP 0Reference
FP I0.7070.399–1.260.238
FP II1.3430.808–2.260.259
FP III0.9970.587–1.710.992
FP IV0.9000.600–1.340.608
CeV: cerebrovascular event, 95% CI: 95% confidence interval; FP: femoropopliteal, HF: heart failure, MACE: major adverse cardiovascular event, MI: myocardial infarct, OR: odds ratio.
Table 7. The age-adjusted hazards for the overall MACE and MACEs (heart failure, acute cardiac syndrome, cerebrovascular event) for the defined tibial burden groups (CXi) are presented with 95% confidence intervals and p values.
Table 7. The age-adjusted hazards for the overall MACE and MACEs (heart failure, acute cardiac syndrome, cerebrovascular event) for the defined tibial burden groups (CXi) are presented with 95% confidence intervals and p values.
HF
OR95% CIp Value
CXi 0Reference
CXi I3.0500.699–1.470.303
CXi II3.7651.26–2.140.006
CXi III5.9992.06–3.46<0.001
CXi IV8.2982.56–4.54<0.001
MI
OR95% CIp Value
CXi 0Reference
CXi I1.2090.643–2.260.552
CXi II1.0330.647–1.660.894
CXi III1.4530.922–2.310.110
CXi IV1.3820.821–2.340.224
CeV
OR95% CIp Value
CXi 0Reference
CXi I0.9750.492–1980.944
CXi II0.9550.568–1.590.860
CXi III0.9690.580–1.600.903
CXi IV0.6370.364–1.110.112
MACE
OR95% CIp Value
CXi 0Reference
CXi I1.3440.720–2.550.358
CXi II1.3420.845–2.130.212
CXi III1.7471.10–2.780.018
CXi IV3.0591.73–5.52<0.001
CeV: cerebrovascular event, 95% CI: 95% confidence interval; CXi: crural index, HF: heart failure, MACE: major adverse cardiovascular event, MI: myocardial infarct, OR: odds ratio.
Table 8. The age-adjusted hazards for the overall MACE and MACEs (heart failure, acute cardiac syndrome, cerebrovascular event) in the most severely affected lower limb segment burden groups are presented with 95% confidence intervals and p values.
Table 8. The age-adjusted hazards for the overall MACE and MACEs (heart failure, acute cardiac syndrome, cerebrovascular event) in the most severely affected lower limb segment burden groups are presented with 95% confidence intervals and p values.
HF
OR95% CIp Value
AIReference
FP2.7801.08–1.710.026
Tibial6.4552.41–3.90<0.001
MI
OR95% CIp Value
AIReference
FP1.1550.768–1.750.491
Tibial1.1470.740–1.790.541
CeV
OR95% CIp Value
AIReference
FP1.1630.731–1.820.516
Tibial0.6860.424–0.1090.117
MACE
OR95% CIp Value
AIReference
FP1.1980.793–1.800.387
Tibial2.2571.42–3.59<0.001
AI: aortoiliac, CeV: cerebrovascular, 95% CI: 95% confidence interval, FP: femoropopliteal, HF: heart failure, MACE: major adverse cardiovascular event, MI: myocardial infarct, OR: odds ratio.
Table 9. The multilogistic regression analyses. The most severely affected lower limb segment and CXi are presented with 95% confidence intervals and p values. Model with significant comorbidities in regard to CAD, CKD and diabetes.
Table 9. The multilogistic regression analyses. The most severely affected lower limb segment and CXi are presented with 95% confidence intervals and p values. Model with significant comorbidities in regard to CAD, CKD and diabetes.
HF
OR95% CIp Value
AIReference
FP2.2801.63–3.20<0.001
Tibial3.8972.41–6.46<0.001
MACE
OR95% CIp Value
AIReference
FP1.8831.31–2.74<0.001
Tibial2.2571.42–3.59<0.001
HF
OR95% CIp Value
CXi 0Reference
CXi I1.3150.842–2.060.229
CXi II2.1191.34–3.370.001
CXi III3.0891.60–6.18<0.001
CXi IV4.5422.56–8.30<0.001
MACE
OR95% CIp Value
CXi 0Reference
CXi I1.7511.04–3.020.038
CXi II2.2791.36–3.930.002
CXi III2.2761.15–4.520.018
CXi IV3.0591.73–5.62<0.001
AI: aortoiliac, 95% CI: 95% confidence interval; FP: femoropopliteal, HF: heart failure, MACE: major adverse cardiovascular event, OR: odds ratio.
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Niiranen, O.; Virtanen, J.; Rantasalo, V.; Ibrahim, A.; Venermo, M.; Hakovirta, H. The Association between Major Adverse Cardiovascular Events and Peripheral Artery Disease Burden. J. Cardiovasc. Dev. Dis. 2024, 11, 157. https://doi.org/10.3390/jcdd11060157

AMA Style

Niiranen O, Virtanen J, Rantasalo V, Ibrahim A, Venermo M, Hakovirta H. The Association between Major Adverse Cardiovascular Events and Peripheral Artery Disease Burden. Journal of Cardiovascular Development and Disease. 2024; 11(6):157. https://doi.org/10.3390/jcdd11060157

Chicago/Turabian Style

Niiranen, Oskari, Juha Virtanen, Ville Rantasalo, Amer Ibrahim, Maarit Venermo, and Harri Hakovirta. 2024. "The Association between Major Adverse Cardiovascular Events and Peripheral Artery Disease Burden" Journal of Cardiovascular Development and Disease 11, no. 6: 157. https://doi.org/10.3390/jcdd11060157

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