Publications by authors named "Zlatko Fras"

62 Publications

Exercise capacity improvement after cardiac rehabilitation following myocardial infarction and its association with long-term cardiovascular events.

Eur J Cardiovasc Nurs 2021 Apr 17. Epub 2021 Apr 17.

Department of Vascular Diseases, Centre for Preventive Cardiology, University Medical Centre Ljubljana, Zaloška cesta 7/VI, Ljubljana SI-1000, Slovenia.

Aims : Cardiovascular rehabilitation (CR) improves aerobic capacity and quality of life in patients after myocardial infarction (MI). The aim was to examine the associations between exercise capacity improvement and different clinically relevant cardiovascular events.

Methods And Results : This was a registry-based study of post-MI patients, referred to CR. All patients were submitted to exercise testing before and after CR (36 sessions, 2-3 times/week, and combined exercise). Patients were divided into two groups, based on the difference in exercise capacity before and after the CR programme with the cut-off of two metabolic equivalents (METs) improvement. We assessed the correlation between the extent of exercise capacity improvement and the following cardiovascular events: major adverse cardiac events (MACE), cardiovascular-related hospitalizations, and unplanned coronary angiography. A total of 499 patients were included (mean age 56 ± 10 years, 20% women). Both groups significantly improved in terms of exercise capacity, natriuretic peptide levels, resting heart rate, and resting diastolic pressure; however, lipid status significantly improved only in patients with ≥2 METs difference in exercise capacity. A total of 13.4% patients suffered MACE (median follow-up 858 days); 21.8% were hospitalized for cardiovascular reasons (median follow-up 791 days); and 19.8% had at least one unplanned coronary angiography (median follow-up 791 days). Exercise capacity improvement of ≥2 METs was associated with lower rates of MACE, cardiovascular hospitalizations, and unplanned coronary angiography in all examined univariate and multivariate models.

Conclusion : This study has shown that exercise improvement of ≥2 METs is associated with a significant decrease in MACE, cardiac hospitalizations, and unplanned coronary angiography.
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http://dx.doi.org/10.1093/eurjcn/zvab015DOI Listing
April 2021

Current Choice for LDL-C Lowering in High-Risk CVD Patients Intolerant to Statins.

Authors:
Zlatko Fras

Curr Vasc Pharmacol 2021 ;19(4):398-402

Centre for Preventive Cardiology, Department of Vascular Medicine, Division of Medicine, University Medical Centre Ljubljana, Ljubljana, Slovenia.

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http://dx.doi.org/10.2174/157016111904210216104403DOI Listing
January 2021

Prognostic Impact of Nonobstructive Coronary Artery Disease Detected by Coronary Computed Tomographic Angiography.

Angiology 2021 Mar 19:3319721999494. Epub 2021 Mar 19.

Department of Vascular Diseases, 364687Division of Internal Medicine, University Medical Centre of Ljubljana, Slovenia.

Coronary computed tomographic angiography (CCTA) is a promising technique for ruling out coronary artery disease (CAD) in patients with chest pain. We aimed to investigate the prognostic impact of nonobstructive CAD on CCTA. We retrospectively reviewed patients who underwent CCTA between 2010 and 2016 at our institution. We divided them into 3 groups: (1) patients with no CAD, (2) patients with nonobstructive CAD, and (3) patients with obstructive CAD. We investigated the incidence of the primary outcome (combination of death, nonfatal myocardial infarction, unstable angina, and late revascularization). A total of 989 patients were included: 540 patients had CAD, which was obstructive (≥50% stenosis) in 256 cases. During the follow-up period, 99 events occurred (32 [7%] in patients without CAD, 26 [9%] in patients with nonobstructive CAD, and 41 [16%] in patients with obstructive CAD; < .001). The presence of nonobstructive and obstructive CAD was an independent predictor of events (HR: 2.33 [1.15-4.69], < .001; and 4.02 [1.98-8.13], = .019, respectively) compared with no CAD. Nonobstructive CAD on CCTA is associated with a 2-fold increase in risk of coronary events compared with patients with no CAD.
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http://dx.doi.org/10.1177/0003319721999494DOI Listing
March 2021

Do we have a unified consensus on antithrombotic management of PAD?

Int Angiol 2021 Mar 19. Epub 2021 Mar 19.

Department of Angiology and Vascular Surgery of CUF Porto Hospital, Porto, Portugal.

Peripheral artery disease (PAD) is one of the most frequent manifestations of atherosclerosis with high rates of morbidity and mortality. Platelets and coagulation are involved in the progression of atherosclerosis and thromboembolic complications. PAD patients have increased pro-thrombotic potential, which includes platelet hyperaggregability and increased pro-coagulant state. Therefore, antithrombotic treatment is of utmost importance for the prevention of cardiovascular events in this group of patients. Aspirin is the basic antiplatelet drug, but with limited efficacy in PAD. In contrast to coronary artery disease, its effect on the prevention of cardiovascular events in PAD has been limited proven. Particularly in asymptomatic PAD, there is no evidence for risk reduction with aspirin. Clopidogrel and ticagrelor are more effective than aspirin. Clopidogrel is thus an effective alternative to aspirin for prevention of cardiovascular events in symptomatic PAD. In patients who are non-responders to clopidogrel, ticagrelor is indicated. Dual antiplatelet treatment (DAPT) with aspirin and ticagrelor in patients with coronary artery disease and concomitant PAD significantly decreased the rate of major adverse cardiovascular events, including adverse limb events. However, in the CHARISMA trial, aspirin and clopidogrel were not more effective than aspirin alone and increased bleeding complications. Therefore, DAPT seems effective only in PAD accompanied by coronary artery disease. Anticoagulant treatment for symptomatic PAD with vitamin K antagonists alone or in combination with aspirin is not more effective than single antiplatelet treatment but increases the rate of major bleeding. Low dose rivaroxaban combined with aspirin in PAD patients significantly reduces cardiovascular events, including limb-threatening ischemia and limb amputations. Anticoagulation and antiplatelet treatment after percutaneous or surgical revascularization of PAD improve the patency of treated vessels. Aspirin with or without dipyridamole improved patency of infra-inguinal by-pass grafts at one year. The combination of clopidogrel with aspirin was more effective than aspirin alone in the prevention of prosthetic graft occlusions in patients undergoing below-knee by-pass-grafting. Oral vitamin K antagonists were not more effective than aspirin in the prevention of infra-inguinal by-pass occlusion. The combination of low dose rivaroxaban and aspirin was effective in preventing major adverse cardiovascular events and adverse limb events after infrainguinal endovascular or surgical revascularization in patients with intermittent claudication. However, the data on antithrombotic treatment after revascularization for limb-threatening ischemia is scanty and inconclusive. In conclusion: Antithrombotic treatment of PAD is a cornerstone for the management of these patients. Antiplatelet drugs prevent the initiation and progression of atherosclerosis and are effective also in the prevention of thromboembolic events. Simultaneous use of antiplatelet and anticoagulation drugs is accompanied by an increased risk of bleeding. However, combined treatment with aspirin and low-dose rivaroxaban is more effective than single antithrombotic treatment and safer than full-dose combined treatment.
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http://dx.doi.org/10.23736/S0392-9590.21.04597-1DOI Listing
March 2021

Prediction of recurrent event in patients with coronary heart disease: the EUROASPIRE Risk Model.

Eur J Prev Cardiol 2020 Dec 29. Epub 2020 Dec 29.

Department of Public Health and Primary Care, Ghent University, C. Heymanslaan 10, 9000 Gent, Belgium.

Aims: Most patients with established atherosclerotic cardiovascular disease (CVD) are at very high risk for developing recurrent events. Since this risk varies a lot between patients there is a need to identify those in whom an even more intensive secondary prevention strategy should be envisaged. Using data from the EUROASPIRE IV and V cohorts of coronary heart disease (CHD) patients from 27 European countries, we aimed at developing and internally and externally validating a risk model predicting recurrent CVD events in patients aged < 75 years.

Methods And Results: Prospective data were available for 12 484 patients after a median follow-up time of 1.7 years. The primary endpoint, a composite of fatal CVD or new hospitalizations for non-fatal myocardial infarction (MI), stroke, heart failure, coronary artery bypass graft, or percutaneous coronary intervention (PCI), occurred in 1424 patients. The model was developed based on data from 8000 randomly selected patients in whom the association between potential risk factors and the incidence of the primary endpoint was investigated. This model was then validated in the remaining 4484 patients. The final multivariate model revealed a higher risk for the primary endpoint with increasing age, a previous hospitalization for stroke, heart failure or PCI, a previous diagnosis of peripheral artery disease, self-reported diabetes and its glycaemic control, higher non-high-density lipoprotein cholesterol, reduced renal function, symptoms of depression and anxiety and living in a higher risk country. The model demonstrated excellent internal validity and proved very adequate in the validation cohort. Regarding external validity, the model demonstrated good discriminative ability in 20 148 MI patients participating in the SWEDEHEART register. Finally, we developed a risk calculator to estimate risks at 1 and 2 years for patients with stable CHD.

Conclusion: In patients with CHD, fatal and non-fatal rates of recurrent CVD events are high. However, there are still opportunities to optimize their management in order to prevent further disease or death. The EUROASPIRE Risk Calculator may be of help to reach this goal.
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http://dx.doi.org/10.1093/eurjpc/zwaa128DOI Listing
December 2020

Optimal use of lipid-lowering therapy after acute coronary syndromes: A Position Paper endorsed by the International Lipid Expert Panel (ILEP).

Pharmacol Res 2021 Apr 17;166:105499. Epub 2021 Feb 17.

Department of Internal Medicine, University Hospital Center Zagreb, School of Medicine, University of Zagreb, Zagreb, Croatia. Electronic address:

Atherosclerotic cardiovascular disease (ASCVD) and consequent acute coronary syndromes (ACS) are substantial contributors to morbidity and mortality across Europe. Much of these diseases burden is modifiable, in particular by lipid-lowering therapy (LLT). Current guidelines are based on the sound premise that with respect to low density lipoprotein cholesterol (LDL-C), "lower is better for longer", and the recent data have strongly emphasized the need of also "the earlier the better". In addition to statins, which have been available for several decades, the availability of ezetimibe and inhibitors of proprotein convertase subtilisin/kexin type 9 (PCSK9) are additional very effective approach to LLT, especially for those at very high and extremely high cardiovascular risk. LLT is initiated as a response to an individual's calculated risk of future ASCVD and is intensified over time in order to meet treatment goals. However, in real-life clinical practice goals are not met in a substantial proportion of patients. This Position Paper complements existing guidelines on the management of lipids in patients following ACS. Bearing in mind the very high risk of further events in ACS, we propose practical solutions focusing on immediate combination therapy in strict clinical scenarios, to improve access and adherence to LLT in these patients. We also define an 'Extremely High Risk' group of individuals following ACS, completing the attempt made in the recent European guidelines, and suggest mechanisms to urgently address lipid-medicated cardiovascular risk in these patients.
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http://dx.doi.org/10.1016/j.phrs.2021.105499DOI Listing
April 2021

HDL and cancer - causality still needs to be confirmed? Update 2020.

Semin Cancer Biol 2020 Oct 28. Epub 2020 Oct 28.

Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran; Neurogenic Inflammation Research Center, Mashhad University of Medical Sciences, Mashhad, Iran; Halal Research Center of IRI, FDA, Tehran, Iran. Electronic address:

An inverse correlation between high-density lipoprotein cholesterol (HDL-C) and cancer risk has been shown by several epidemiological studies. Some studies have even suggested that HDL-C can be used as a prognostic marker in patients with certain types of cancer. However, whether reduced HDL-C level is a consequential or causal factor in the development and progression of cancer remains a controversial issue. In this review, we update and summarize recent advances that highlight the role of HDL and some of its components in prognosis, diagnosis and treatment of cancer.
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http://dx.doi.org/10.1016/j.semcancer.2020.10.007DOI Listing
October 2020

Socioeconomic characteristics of patients with coronary heart disease in relation to their cardiovascular risk profile.

Heart 2020 Oct 16. Epub 2020 Oct 16.

Department of Public Health and Primary Care, Ghent University, Ghent, Belgium.

Objective: People's socioeconomic status (SES) has a major impact on the risk of atherosclerotic cardiovascular disease (ASCVD) in primary prevention. In patients with existing ASCVD these associations are less documented. Here, we evaluate to what extent SES is still associated with patients' risk profile in secondary prevention.

Methods: Based on results from a large sample of patients with coronary heart disease from the European Action on Secondary and Primary Prevention through Intervention to Reduce Events study, the relationship between SES and cardiovascular risk was examined. A SES summary score was empirically constructed from the patients' educational level, self-perceived income, living situation and perception of loneliness.

Results: Analyses are based on observations in 8261 patients with coronary heart disease from 27 countries. Multivariate logistic regression analyses demonstrate that a low SES is associated (OR, 95% CI) with lifestyles such as smoking in men (1.63, 1.37 to 1.95), physical activity in men (1.51, 1.28 to 1.78) and women (1.77, 1.32 to 2.37) and obesity in men 1.28 (1.11 to 1.49) and women 1.65 (1.30 to 2.10). Patients with a low SES have more raised blood pressure in men (1.24, 1.07 to 1.43) and women (1.31, 1.03 to 1.67), used less statins and were less adherent to them. Cardiac rehabilitation programmes were less advised and attended by patients with a low SES. Access to statins in middle-income countries was suboptimal leaving about 80% of patients not reaching the low-density lipoprotein cholesterol target of <1.8 mmol/L. Patients' socioeconomic level was also strongly associated with markers of well-being.

Conclusion: These results illustrate the complexity of the associations between SES, well-being and secondary prevention in patients with ASCVD. They emphasise the need for integrating innovative policies in programmes of cardiac rehabilitation and secondary prevention.
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http://dx.doi.org/10.1136/heartjnl-2020-317549DOI Listing
October 2020

Lipoprotein(a) lowering by alirocumab reduces the total burden of cardiovascular events independent of low-density lipoprotein cholesterol lowering: ODYSSEY OUTCOMES trial.

Eur Heart J 2020 11;41(44):4245-4255

Division of Cardiology, University of Colorado School of Medicine, Box B130, Aurora, CO 80045, USA.

Aims: Lipoprotein(a) concentration is associated with first cardiovascular events in clinical trials. It is unknown if this relationship holds for total (first and subsequent) events. In the ODYSSEY OUTCOMES trial in patients with recent acute coronary syndrome (ACS), the proprotein convertase subtilisin/kexin type 9 inhibitor alirocumab reduced lipoprotein(a), low-density lipoprotein cholesterol (LDL-C), and cardiovascular events compared with placebo. This post hoc analysis determined whether baseline levels and alirocumab-induced changes in lipoprotein(a) and LDL-C [corrected for lipoprotein(a) cholesterol] independently predicted total cardiovascular events.

Methods And Results: Cardiovascular events included cardiovascular death, non-fatal myocardial infarction, stroke, hospitalization for unstable angina or heart failure, ischaemia-driven coronary revascularization, peripheral artery disease events, and venous thromboembolism. Proportional hazards models estimated relationships between baseline lipoprotein(a) and total cardiovascular events in the placebo group, effects of alirocumab treatment on total cardiovascular events by baseline lipoprotein(a), and relationships between lipoprotein(a) reduction with alirocumab and subsequent risk of total cardiovascular events. Baseline lipoprotein(a) predicted total cardiovascular events with placebo, while higher baseline lipoprotein(a) levels were associated with greater reduction in total cardiovascular events with alirocumab (hazard ratio Ptrend = 0.045). Alirocumab-induced reductions in lipoprotein(a) (median -5.0 [-13.6, 0] mg/dL) and corrected LDL-C (median -51.3 [-67.1, -34.0] mg/dL) independently predicted lower risk of total cardiovascular events. Each 5-mg/dL reduction in lipoprotein(a) predicted a 2.5% relative reduction in cardiovascular events.

Conclusion: Baseline lipoprotein(a) predicted the risk of total cardiovascular events and risk reduction by alirocumab. Lipoprotein(a) lowering contributed independently to cardiovascular event reduction, supporting the concept of lipoprotein(a) as a treatment target after ACS.
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http://dx.doi.org/10.1093/eurheartj/ehaa649DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7724642PMC
November 2020

Peripheral arterial disease and intermittent claudication in coronary heart disease patients.

Int J Cardiol 2021 Jan 9;322:227-232. Epub 2020 Sep 9.

Department of Public Health and Primary Care, Ghent University, Belgium. Electronic address:

Background And Aim: Peripheral artery disease (PAD) is associated with an increased risk of fatal and non-fatal coronary heart disease (CHD). The aims of the this study were 1) to investigate the prevalence of PAD and suspected PAD in a large population of established CHD patients, and 2) to assess the prevalence and control of risk factors in these patients as well health-related quality of life.

Material And Methods: In the EUROASPIRE V survey, 8243 patients with documented CHD were recruited from 27 ESC member countries and were invited to attend a study visit. Patients were investigated using questionnaires, in-depth interviews and a clinical examination. Intermittent claudication (IC) was assessed using the Edinburgh Claudication Questionnaire. Patients without previously diagnosed PAD were suspected of having PAD if they were found to have IC.

Results: Overall, 6.4% of the patients had already a confirmed diagnosis of PAD and another 6.3% were suspected of having PAD. Independent of age and gender, patients with previously diagnosed PAD were significantly more frequently current smokers, had the lowest smoking cessation rates, were less physically active, reported more often previously diagnosed diabetes and had significantly higher blood pressure levels, compared to patients without PAD. They had also significantly higher levels of serum triglycerides, lower HDL-C levels, and had more often renal insufficiency. In comparison with patients without PAD, those with suspected PAD demonstrated significantly higher smoking cessation rates but their obesity rates were significantly higher. In CHD patients with a history of PAD, the use of calcium channel blockers and diuretics was significantly higher than in patients without PAD. Compared to the latter group, the use of diuretics, anti-arrhythmics and anti-depressants in patients with suspected PAD was significantly higher. Moreover, patients with previously diagnosed PAD had significantly higher levels of anxiety and depression and reported a significantly worse health-related quality of life (HRQoL), in comparison with those without PAD. HRQoL levels were significantly reduced in patients with suspected PAD as well.

Conclusion: In CHD patients without a previous diagnosis of PAD, IC is not infrequent. Diagnosed PAD was significantly associated with a worse CHD risk factor profile. Patients with known PAD as well as those with suspected PAD had a considerable loss of health-related quality of life. Therefore, physicians should consider to screen for IC in all their CHD patients.
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http://dx.doi.org/10.1016/j.ijcard.2020.09.004DOI Listing
January 2021

Five-Year Outcomes and Prognostic Value of Feature-Tracking Cardiovascular Magnetic Resonance in Patients Receiving Early Prereperfusion Metoprolol in Acute Myocardial Infarction.

Am J Cardiol 2020 10 28;133:39-47. Epub 2020 Jul 28.

Department of Cardiology, Heart Lung Center, Leiden University Medical Center, Leiden, The Netherlands. Electronic address:

The aim of the present study was to investigate the long-term impact of early intravenous metoprolol in ST-segment elevation myocardial infarction (STEMI) patients in terms of left ventricular (LV) strain with feature-tracking cardiovascular magnetic resonance (CMR) and its association with prognosis. A total of 270 patients with first anterior STEMI enrolled in the randomized METOCARD-CNIC clinical trial, assigned to receive up to 15 mg intravenous metoprolol before primary percutaneous coronary intervention versus conventional STEMI therapy, were included. LV global circumferential (GCS) and longitudinal (GLS) strain were assessed with feature-tracking CMR at 1 week after STEMI in 215 patients. The occurrence of major adverse cardiac events (MACE) at 5-year follow-up was the primary end point. Among 270 patients enrolled, 17 of 139 patients assigned to metoprolol arm and 31 of 131 patients assigned to control arm experienced MACE (hazard ratio [HR] 0.500, 95% confidence interval [CI] 0.277 to 0.903; p = 0.022). Impaired LV GCS and GLS strain were significantly associated with increased occurrence of MACE (GCS: HR 1.208, 95% CI 1.076 to 1.356, p =0.001; GLS: HR 1.362, 95% CI 1.180 to 1.573, p < 0.001). On multivariable analysis, LV GLS provided incremental prognostic value over late gadolinium enhancement (LGE) and LV ejection fraction (LVEF) (LGE + LVEF chi-square = 12.865, LGE + LVEF + GLS chi-square = 18.459; p =0.012). Patients with GLS ≥-11.5% (above median value) who received early intravenous metoprolol were 64% less likely to experience MACE than their counterparts with same degree of GLS impairment (HR 0.356, 95% CI 0.129 to 0.979; p = 0.045). In conclusion, early intravenous metoprolol has a long-term beneficial prognostic effect, particularly in patients with severely impaired LV systolic function. LV GLS with feature-tracking CMR early after percutaneous coronary intervention offers incremental prognostic value over conventional CMR parameters in risk stratification of STEMI patients.
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http://dx.doi.org/10.1016/j.amjcard.2020.07.037DOI Listing
October 2020

The Use of Aspirin in Contemporary Primary Prevention of Atherosclerotic Cardiovascular Diseases Revisited: The Increasing Need and Call for a Personalized Therapeutic Approach.

Am J Cardiovasc Drugs 2021 Mar;21(2):139-151

Cardiovascular Research Centre, University of Zielona-Gora, Zielona Gora, Poland.

The use of aspirin has been widely accepted for the secondary prevention of atherosclerotic cardiovascular disease (ASCVD) in all patient populations, as the benefits linked to the reduction of clinical events outweigh the risk of major bleeding. However, despite the undisputable, though modest, potential of aspirin to reduce atherothrombotic events, its overall efficacy and safety in primary ASCVD prevention remains debatable, despite being used for this purpose for decades. The net clinical benefit of aspirin was brought into question by three recent large contemporary randomized controlled trials evaluating its role in various primary prevention populations (individuals with diabetes [ASCEND], an elderly population [ASPREE], and middle-aged adults at high estimated cardiovascular risk [ARRIVE]) and numerous large meta-analyses published during the past year. As a result, the usual generalized recommendations for the use of aspirin in patients with estimated intermediate to high ASCVD risk but without overt ASCVD have already been removed from most international guidelines. Since the primary prevention framework encompasses heterogenous groups of subjects with variable absolute ASCVD risk, a more individualized approach based on the best possible estimated ratio between the potential health benefits from fewer atherothrombotic events and harms because of potential increases in major bleeding is warranted in clinical practice. With this compromise, clinicians can better decide on the personalized use of aspirin in patients at high risk of major adverse cardiovascular events.
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http://dx.doi.org/10.1007/s40256-020-00424-yDOI Listing
March 2021

Have we learnt all from IMPROVE-IT? Part II. Subanalyses on the effects of ezetimibe added to statin therapy on selected clinical and laboratory outcomes, cost effectiveness, guideline and clinical implications.

Curr Vasc Pharmacol 2020 07 27. Epub 2020 Jul 27.

Department of Clinical Biochemistry, Royal Free Hospital Campus, University College Medical School, University College London, London. United Kingdom.

In this second part of a review of the IMProved Reduction of Outcomes: Vytorin Efficacy International Trial (IMPROVE-IT), we discuss the findings in relation to patients with stroke, the ACS phenotype, history of coronary artery bypass graft surgery, heart failure, concurrent polyvascular atherosclerotic cardiovascular disease (ASCVD) and diabetes mellitus, and different levels of expression of selected cardiovascular biomarkers. The combination therapy was proven safe, and drug discontinuation rates were not increased by adding ezetimibe. Since both statins and ezetimibe are now almost globally generically available, we can conclude that for secondary prevention of ASCVD, adding ezetimibe to high-intensity statin therapy further reduces low-density lipoprotein cholesterol (LDL-C) and cardiovascular risk cost-effectively.
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http://dx.doi.org/10.2174/1570161118999200727230120DOI Listing
July 2020

Have we learnt all from IMPROVE-IT? Part I. Core results and subanalyses on the effects of ezetimibe added to statin therapy related to age, gender and selected chronic diseases (kidney disease, diabetes mellitus and non-alcoholic fatty liver disease)

Curr Vasc Pharmacol 2020 07 27. Epub 2020 Jul 27.

Department of Clinical Biochemistry, Royal Free Hospital Campus, University College Medical School, University College London, London. United Kingdom.

IMPROVE-IT (IMProved Reduction of Outcomes: Vytorin Efficacy International Trial) was a randomized clini- cal trial (18,144 patients) that evaluated the efficacy of the combination of ezetimibe with simvastatin vs simvastatin mono- therapy in patients with acute coronary syndrome (ACS) and moderately increased low-density lipoprotein cholesterol (LDL-C) levels (of up to 2.6-3.2 mmol/L; 100-120 mg/dL). After 7 years of follow-up, combination therapy resulted in an additional LDL-C decrease [1.8 mmol/L, or 70 mg/dL, within the simvastatin (40 mg/day) monotherapy arm and 1.4 mmol/L, or 53 mg/dL for simvastatin (40 mg/day) + ezetimibe (10 mg/day)] and showed an incremental clinical benefit (composite of cardiovascular death, nonfatal myocardial infarction, unstable angina requiring rehospitalization, coronary re- vascularization (≥30 days after randomization), or nonfatal stroke; hazard ratio (HR) of 0.936, and 95% CI 0.887-0.996, p=0.016). Therefore, for very high cardiovascular risk patients "even lower is even better" regarding LDL-C, independently of the LDL-C reducing strategy. These findings confirm ezetimibe as an option to treat very-high-risk patients who cannot achieve LDL-C targets with statin monotherapy. Additional analyses of the IMPROVE-IT (both prespecified and post-hoc) include specific very-high-risk subgroups of patients (those with previous acute events and/or coronary revascularization, older than 75 years, as well as patients with diabetes mellitus, chronic kidney disease or non-alcoholic fatty liver disease). The data from IMPROVE-IT also provide reassurance regarding longer-term safety and efficacy of the intensification of li- pid-lowering therapy in very-high-risk patients resulting in very low LDL-C levels. We comment on the results of several (sub) analyses of IMPROVE-IT.
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http://dx.doi.org/10.2174/1570161118999200727224946DOI Listing
July 2020

Left ventricular functional recovery of infarcted and remote myocardium after ST-segment elevation myocardial infarction (METOCARD-CNIC randomized clinical trial substudy).

J Cardiovasc Magn Reson 2020 06 11;22(1):44. Epub 2020 Jun 11.

Department of Cardiology, Heart Lung Center, Leiden University Medical Center, Albinusdreef 2, 2333, ZA, Leiden, The Netherlands.

Background: We aimed to evaluate the effect of early intravenous metoprolol treatment, microvascular obstruction (MVO), intramyocardial hemorrhage (IMH) and adverse left ventricular (LV) remodeling on the evolution of infarct and remote zone circumferential strain after acute anterior ST-segment elevation myocardial infarction (STEMI) with feature-tracking cardiovascular magnetic resonance (CMR).

Methods: A total of 191 patients with acute anterior STEMI enrolled in the METOCARD-CNIC randomized clinical trial were evaluated. LV infarct zone and remote zone circumferential strain were measured with feature-tracking CMR at 1 week and 6 months after STEMI.

Results: In the overall population, the infarct zone circumferential strain significantly improved from 1 week to 6 months after STEMI (- 8.6 ± 9.0% to - 14.5 ± 8.0%; P < 0.001), while no changes in the remote zone strain were observed (- 19.5 ± 5.9% to - 19.2 ± 3.9%; P = 0.466). Patients who received early intravenous metoprolol had significantly more preserved infarct zone circumferential strain compared to the controls at 1 week (P = 0.038) and at 6 months (P = 0.033) after STEMI, while no differences in remote zone strain were observed. The infarct zone circumferential strain was significantly impaired in patients with MVO and IMH compared to those without (P < 0.001 at 1 week and 6 months), however it improved between both time points regardless of the presence of MVO or IMH (P < 0.001). In patients who developed adverse LV remodeling (defined as ≥ 20% increase in LV end-diastolic volume) remote zone circumferential strain worsened between 1 week and 6 months after STEMI (P = 0.036), while in the absence of adverse LV remodeling no significant changes in remote zone strain were observed.

Conclusions: Regional LV circumferential strain with feature-tracking CMR allowed comprehensive evaluation of the sequelae of an acute STEMI treated with primary percutaneous coronary intervention and demonstrated long-lasting cardioprotective effects of early intravenous metoprolol.

Trial Registration: ClinicalTrials.gov, NCT01311700. Registered 8 March 2011 - Retrospectively registered.
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http://dx.doi.org/10.1186/s12968-020-00638-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7288440PMC
June 2020

Brief recommendations on the management of adult patients with familial hypercholesterolemia during the COVID-19 pandemic.

Pharmacol Res 2020 08 7;158:104891. Epub 2020 May 7.

FH Europe, Europe. Electronic address:

Individuals with Familial Hypercholesterolaemia (FH) are at very high risk of cardiovascular disease, which is associated with poor outcomes from coronavirus infections. COVID-19 puts strain on healthcare systems and may impair access to routine FH services. On behalf of the International Lipid Expert Panel (ILEP) and the European FH Patient Network (FH Europe), we present brief recommendations on the management of adult patients with FH during the COVID-19 pandemic. We discuss the implications of COVID-19 infections for FH patients, the importance of continuing lipid-lowering therapy where possible, issues relating to safety monitoring and service delivery. We summarise the evidence for additional benefits of statins and other lipid-lowering drugs during viral infections. The recommendations do not override in any way the individual responsibility of physicians to make appropriate and accurate decisions taking into account the condition of a given patient and the doses, rules, and regulations applicable to drugs and devices at the time of their prescription/use.
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http://dx.doi.org/10.1016/j.phrs.2020.104891DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7204727PMC
August 2020

Association between rs2107595 HDAC9 gene polymorphism and advanced carotid atherosclerosis in the Slovenian cohort.

Lipids Health Dis 2020 Apr 13;19(1):71. Epub 2020 Apr 13.

Department of Cardiology, Division of Medicine, University Medical Centre of Ljubljana, Ljubljana, Slovenia.

Background: Histone deacetylase 9 (HDAC9) plays an important role in transcriptional regulation, cell cycle progression and developmental events; moreover, it has been investigated as a candidate gene in a number of conditions, including the onset and progression of atherosclerosis. We hypothesized that the rs2107595 HDAC9 gene polymorphism may be associated with advanced carotid artery disease in a Slovenian cohort. We also investigated the effect of this polymorphism on HDAC9 receptor expression in the internal carotid artery (ICA) specimens obtained by endarterectomy.

Methods: This case-control study enrolled 619 unrelated Slovenian patients: 311 patients with ICA stenosis > 75% as the study group and 308 patients with ICA stenosis < 50% as the control group. Patient laboratory and clinical data were obtained from the medical records. The rs2107595 polymorphisms were genotyped using TaqMan SNP Genotyping assay. HDAC9 expression was assessed by immunohistochemistry in 30 ICA specimens from patients with ICA atherosclerosis > 75%, and the numerical areal density of HDAC9 positive cells was calculated.

Results: The occurrence of advanced ICA atherosclerosis in the Slovenian cohort was 3.81 times higher in the codominant genetic model (OR = 3.81, 95%CI = 1.06-13.77, p = 0.04), and 3.10 times higher in the recessive genetic model (OR = 3.10, 95%CI = 1.16-8.27, p = 0.02). In addition, the A allele of rs2107595 was associated with increased HDAC9 expression in the ICA specimens obtained by endarterectomy.

Conclusions: We observed a significant association between the AA genotype of rs2107595 with the advanced carotid artery disease in our Slovenian cohort, indicating that this polymorphism may be a genetic risk factor for ICA atherosclerosis.
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http://dx.doi.org/10.1186/s12944-020-01255-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7155263PMC
April 2020

Increased cardiovascular risk associated with hyperlipoproteinemia (a) and the challenges of current and future therapeutic possibilities.

Authors:
Zlatko Fras

Anatol J Cardiol 2020 Jan;23(2):60-69

Division of Medicine, Centre for Preventive Cardiology, University Medical Centre Ljubljana; Medical Faculty, University of Ljubljana; Ljubljana-Slovenia.

Population, genetic, and clinical studies demonstrated a causative and continuous, from other plasma lipoproteins independent relationship between elevated plasma lipoprotein (a) [Lp(a)] concentration and the development of cardiovascular disease (CVD), mainly those related to athe-rosclerotic CVD, and calcific aortic stenosis. Currently, a strong international consensus is still lacking regarding the single value which would be commonly used to define hyperlipoproteinemia (a). Its prevalence in the general population is estimated to be in the range of 10%-35% in accordance with the most commonly used threshold levels (>30 or >50 mg/dL). Since elevated Lp(a) can be of special importance in patients with some genetic disorders, as well as in individuals with otherwise controlled major risk factors, the identification and establishment of the proper therapeutic interventions that would lower Lp(a) levels and lead to CVD risk reduction could be very important. The majority of the classical lipid-lowering agents (statins, ezetimibe, and fibrates), as well as nutraceuticals (CoQ10 and garlic), appear to have no significant effect on its plasma levels, whereas for the drugs with the demonstrated Lp(a)-lowering effects (aspirin, niacin, and estrogens), their clinical efficacy in reducing cardiovascular (CV) events has not been unequivocally proven yet. Both Lp(a) apheresis and proprotein convertase subtilisin/kexin type 9 inhibitors can reduce the plasma Lp(a) by approximately 20%-30% on average, in parallel with much larger reduction of low-density lipoprotein cholesterol (up to 70%), what puts us in a difficulty to conclude about the true contribution of lowered Lp(a) to the reduction of CV events. The most recent advancement in the field is the introduction of the novel apolipoprotein (a) [apo(a)] antisense oligonucleotide therapy targeting apo(a), which has already proven itself as being very effective in decreasing plasma Lp(a) (by even >90%), but should be further tested in clinical trials. The aim of this review was to present some of the most important accessible scientific data, as well as dilemmas related to the currently and potentially in the near future more widely available therapeutic options for the management of hyperlipoproteinemia (a).
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http://dx.doi.org/10.14744/AnatolJCardiol.2019.56068DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7040869PMC
January 2020

Effect of Alirocumab on Lipoprotein(a) and Cardiovascular Risk After Acute Coronary Syndrome.

J Am Coll Cardiol 2020 01;75(2):133-144

Division of Cardiology, University of Colorado School of Medicine, Aurora, Colorado.

Background: Lipoprotein(a) concentration is associated with cardiovascular events. Alirocumab, a proprotein convertase subtilisin/kexin type 9 inhibitor, lowers lipoprotein(a) and low-density lipoprotein cholesterol (LDL-C).

Objectives: A pre-specified analysis of the placebo-controlled ODYSSEY Outcomes trial in patients with recent acute coronary syndrome (ACS) determined whether alirocumab-induced changes in lipoprotein(a) and LDL-C independently predicted major adverse cardiovascular events (MACE).

Methods: One to 12 months after ACS, 18,924 patients on high-intensity statin therapy were randomized to alirocumab or placebo and followed for 2.8 years (median). Lipoprotein(a) was measured at randomization and 4 and 12 months thereafter. The primary MACE outcome was coronary heart disease death, nonfatal myocardial infarction, ischemic stroke, or hospitalization for unstable angina.

Results: Baseline lipoprotein(a) levels (median: 21.2 mg/dl; interquartile range [IQR]: 6.7 to 59.6 mg/dl) and LDL-C [corrected for cholesterol content in lipoprotein(a)] predicted MACE. Alirocumab reduced lipoprotein(a) by 5.0 mg/dl (IQR: 0 to 13.5 mg/dl), corrected LDL-C by 51.1 mg/dl (IQR: 33.7 to 67.2 mg/dl), and reduced the risk of MACE (hazard ratio [HR]: 0.85; 95% confidence interval [CI]: 0.78 to 0.93). Alirocumab-induced reductions of lipoprotein(a) and corrected LDL-C independently predicted lower risk of MACE, after adjustment for baseline concentrations of both lipoproteins and demographic and clinical characteristics. A 1-mg/dl reduction in lipoprotein(a) with alirocumab was associated with a HR of 0.994 (95% CI: 0.990 to 0.999; p = 0.0081).

Conclusions: Baseline lipoprotein(a) and corrected LDL-C levels and their reductions by alirocumab predicted the risk of MACE after recent ACS. Lipoprotein(a) lowering by alirocumab is an independent contributor to MACE reduction, which suggests that lipoprotein(a) should be an independent treatment target after ACS. (ODYSSEY Outcomes: Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab; NCT01663402).
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http://dx.doi.org/10.1016/j.jacc.2019.10.057DOI Listing
January 2020

Authorship: From credit to accountability - Reflections from the Editors' network.

Arch Cardiol Mex 2019 ;89(1):93-99

Editor in Chief Ukrainian Journal of Cardiology.

The Editors' Network of the European Society of Cardiology (ESC) provides a dynamic forum for editorial discussions and endorses the recommendations of the International Committee of Medical Journal Editors (ICMJE) to improve the scientific quality of biomedical journals. Authorship confers credit and important academic rewards. Recently, however, the ICMJE emphasized that authorship also requires responsibility and accountability. These issues are now covered by the new -(fourth) criterion for authorship. Authors should agree to be accountable and ensure that questions regarding the accuracy and integrity of the entire work will be appropriately addressed. This review discusses the implications of this paradigm shift on authorship requirements with the aim of increasing awareness on good scientific and editorial practices.
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http://dx.doi.org/10.24875/ACME.M19000030DOI Listing
June 2020

New European Society of Cardiology Guidelines on diabetes; prediabetes, and cardiovascular diseases - a truly strong base for the major paradigm shift in clinical practice?

Authors:
Zlatko Fras

Anatol J Cardiol 2019 11;22(5):214-218

Division of Medicine, Centre for Preventive Cardiology, University Medical Centre Ljubljana; Division of Medicine, Centre for Preventive Cardiology, University Medical Centre Ljubljana; Ljubljana-Slovenia.

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http://dx.doi.org/10.14744/AnatolJCardiol.2019.90232DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6955060PMC
November 2019

Authorship: From credit to accountability. Reflections from the Editors' Network.

Rev Port Cardiol 2019 07 3;38(7):519-525. Epub 2019 Sep 3.

Editor in Chief Ukrainian Journal of Cardiology.

The Editors' Network of the European Society of Cardiology (ESC) provides a dynamic forum for editorial discussions and endorses the recommendations of the International Committee of Medical Journal Editors (ICMJE) to improve the scientific quality of biomedical journals. Authorship confers credit and important academic rewards. Recently, however, the ICMJE emphasized that authorship also requires responsibility and accountability. These issues are now covered by the new (fourth) criterion for authorship. Authors should agree to be accountable and ensure that questions regarding the accuracy and integrity of the entire work will be appropriately addressed. This review discusses the implications of this paradigm shift on authorship requirements with the aim of increasing awareness on good scientific and editorial practices.
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http://dx.doi.org/10.1016/j.repc.2019.07.005DOI Listing
July 2019

Authorship: From credit to accountability - Reflections from the Editors' network.

Arch Cardiol Mex 2019 ;89(2):105-111

Editor in Chief Ukrainian Journal of Cardiology.

The Editors' Network of the European Society of Cardiology (ESC) provides a dynamic forum for editorial discussions and endorses the recommendations of the International Committee of Medical Journal Editors (ICMJE) to improve the scientific quality of biomedical journals. Authorship confers credit and important academic rewards. Recently, however, the ICMJE emphasized that authorship also requires responsibility and accountability. These issues are now covered by the new -(fourth) criterion for authorship. Authors should agree to be accountable and ensure that questions regarding the accuracy and integrity of the entire work will be appropriately addressed. This review discusses the implications of this paradigm shift on authorship requirements with the aim of increasing awareness on good scientific and editorial practices.
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http://dx.doi.org/10.24875/ACM.M19000044DOI Listing
January 2019

Blood pressure distribution and control in coronary patients from 24 European countries in the European Society of Cardiology EURoObservational Research Programme European survey of cardiovascular disease prevention and diabetes. EUROASPIRE IV Registry.

J Hypertens 2019 10;37(10):2015-2023

Department of Public Health and Primary Care, Ghent University, Ghent, Belgium.

Background: Hypertension is the most prevalent major independent risk factor for developing coronary heart disease (CHD). The present analysis aimed to assess blood pressure (BP) distribution and factors associated with insufficient BP control in coronary patients from 24 countries participating in the European Society of Cardiology (ESC) EURoObservational Research Programme (EORP) EUROASPIRE IV survey.

Methods: EUROASPIRE IV is a cross-sectional study conducted in 2012-2013 in patients aged 80 years or less hospitalized for CHD with a follow-up visit at a median of 16 months later. Logistic regression analysis was applied to confirm factors associated with BP control defined as less than 140/90 mmHg for nondiabetic patients and less than 140/85 mmHg for diabetic patients.

Results: A total of 7998 patients (response rate, 48.7%) attended the follow-up visit. Complete data were available in 7653 participants (mean age 62.5 ± 9.6 years). The BP goal was achieved in 57.6%. Patients failing to achieve the BP goal were older, had higher BMI, had more often a history of coronary artery bypass grafting (CABG) and reported diabetes more frequently. Logistic regression confirmed the following independent significant predictors of not achieving the BP goal: a history of diabetes [odds ratio (OR) 1.75], obesity (OR 1.70 vs. normal BMI), overweight (OR 1.28 vs. normal BMI), age at least 65 years (OR 1.53) and CABG as the index event (OR 1.26 vs. acute MI).

Conclusion: EUROASPIRE IV found insufficient BP control in a large proportion of patients with stable CHD, with diabetes, increased BMI, older age and CABG as the index event being independent predictors of poor BP control.
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http://dx.doi.org/10.1097/HJH.0000000000002130DOI Listing
October 2019

Prioritizing research challenges and funding for allergy and asthma and the need for translational research-The European Strategic Forum on Allergic Diseases.

Allergy 2019 11 2;74(11):2064-2076. Epub 2019 Jun 2.

Institute of Translational Pharmacology, Italian National Research Council, Rome, Italy.

The European Academy of Allergy and Clinical Immunology (EAACI) organized the first European Strategic Forum on Allergic Diseases and Asthma. The main aim was to bring together all relevant stakeholders and decision-makers in the field of allergy, asthma and clinical Immunology around an open debate on contemporary challenges and potential solutions for the next decade. The Strategic Forum was an upscaling of the EAACI White Paper aiming to integrate the Academy's output with the perspective offered by EAACI's partners. This collaboration is fundamental for adapting and integrating allergy and asthma care into the context of real-world problems. The Strategic Forum on Allergic Diseases brought together all partners who have the drive and the influence to make positive change: national and international societies, patients' organizations, regulatory bodies and industry representatives. An open debate with a special focus on drug development and biomedical engineering, big data and information technology and allergic diseases and asthma in the context of environmental health concluded that connecting science with the transformation of care and a joint agreement between all partners on priorities and needs are essential to ensure a better management of allergic diseases and asthma in the advent of precision medicine together with global access to innovative and affordable diagnostics and therapeutics.
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http://dx.doi.org/10.1111/all.13856DOI Listing
November 2019

Authorship: From Credit to Accountability Reflections From the Editors´ Network.

Anatol J Cardiol 2019 Apr;21(5):281-286

Editor in Chief Ukrainian Journal of Cardiology.

The Editors´ Network of the European Society of Cardiology (ESC) provides a dynamic forum for editorial discussions and endorses the recommendations of the International Committee of Medical Journal Editors (ICMJE) to improve the scientific quality of biomedical journals. Authorship confers credit and important academic rewards. Recently, however, the ICMJE emphasized that authorship also requires responsibility and accountability. These issues are now covered by the new (fourth) criterion for authorship. Authors should agree to be accountable and ensure that questions regarding the accuracy and integrity of the entire work will be appropriately addressed. This review discusses the implications of this paradigm shift on authorship requirements with the aim of increasing awareness on good scientific and editorial practices.
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http://dx.doi.org/10.14744/AnatolJCardiol.2019.18124DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6528517PMC
April 2019

Authorship: from credit to accountability. Reflections from the Editors' Network.

Clin Res Cardiol 2019 Jul 1;108(7):723-729. Epub 2019 May 1.

Cardiology Department, Hospital Universitario de La Princesa, Instituto de Investigación Sanitaria IIS-IP, Universidad Autónoma de Madrid, C/Diego de León 62, 28006, Madrid, Spain.

The Editors' Network of the European Society of Cardiology provides a dynamic forum for editorial discussions and endorses the recommendations of the International Committee of Medical Journal Editors (ICMJE) to improve the scientific quality of biomedical journals. Authorship confers credit and important academic rewards. Recently, however, the ICMJE emphasized that authorship also requires responsibility and accountability. These issues are now covered by the new (fourth) criterion for authorship. Authors should agree to be accountable and ensure that questions regarding the accuracy and integrity of the entire work will be appropriately addressed. This review discusses the implications of this paradigm shift on authorship requirements with the aim of increasing awareness on good scientific and editorial practices.
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http://dx.doi.org/10.1007/s00392-019-01436-8DOI Listing
July 2019

Authorship: from credit to accountability. Reflections from the Editors' Network.

Basic Res Cardiol 2019 04 8;114(3):23. Epub 2019 Apr 8.

Cardiology Department, Hospital Universitario de La Princesa, Instituto de Investigación Sanitaria IIS-IP, Universidad Autónoma de Madrid, C/Diego de León 62, 28006, Madrid, Spain.

The Editors' Network of the European Society of Cardiology provides a dynamic forum for editorial discussions and endorses the recommendations of the International Committee of Medical Journal Editors (ICMJE) to improve the scientific quality of biomedical journals. Authorship confers credit and important academic rewards. Recently, however, the ICMJE emphasized that authorship also requires responsibility and accountability. These issues are now covered by the new (fourth) criterion for authorship. Authors should agree to be accountable and ensure that questions regarding the accuracy and integrity of the entire work will be appropriately addressed. This review discusses the implications of this paradigm shift on authorship requirements with the aim of increasing awareness on good scientific and editorial practices.
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http://dx.doi.org/10.1007/s00395-019-0729-yDOI Listing
April 2019

Moderate-pain versus pain-free exercise, walking capacity, and cardiovascular health in patients with peripheral artery disease.

J Vasc Surg 2019 07 25;70(1):148-156. Epub 2019 Mar 25.

Division of Internal Medicine, Department of Vascular Diseases, University Medical Centre Ljubljana, Ljubljana, Slovenia; Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia.

Objective: Supervised exercise training (walking) is recommended in patients with intermittent claudication, both as a means to improve symptoms (walking distance and quality of life [QoL]) and as a means to improve general cardiovascular health (including vascular function and heart rate variability [HRV]). Our aim was to compare two types of supervised training (moderate-pain and pain-free walking) with comparable intensity based on heart rate, in terms of walking capacity, QoL, vascular function, biomarkers, and HRV in patients with intermittent claudication.

Methods: Thirty-six adults with intermittent claudication were randomized to either moderate-pain or pain-free exercise training (36 sessions, two or three times a week) or usual care (no supervised exercise). Initial walking distance and absolute walking distance using treadmill testing, flow-mediated vasodilation and pulse wave velocity using ultrasound, N-terminal pro-B-type natriuretic peptide and fibrinogen levels, HRV, and QoL (36-Item Short Form Health Survey questionnaire) were determined at baseline and after the intervention period.

Results: Twenty-nine patients (mean age, 64 ± 9 years; 72% male) completed the study. Both training programs similarly improved walking capacity. Initial walking distance and absolute walking distance significantly increased with either moderate-pain walking (median, 50 m to 107 m [P = .005] and 85 m to 194 m [P = .005], respectively) or pain-free walking (median, 53 m to 128 m [P = .003] and 92 m to 163 m [P = .003], respectively). QoL also similarly improved with both training modalities, whereas only moderate-pain walking was also associated with a statistically significant improvement in the vascular parameters flow-mediated vasodilation (4.4% to 8.0%; P = .002) and pulse wave velocity (6.6 m/s to 6.1 m/s; P = .013). Neither training program was associated with changes in biomarker levels and HRV.

Conclusions: Both moderate-pain and pain-free training modalities were safe and similarly improved walking capacity and health-related QoL. Conversely, vascular function improvements were associated with only moderate-pain walking.
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http://dx.doi.org/10.1016/j.jvs.2018.10.109DOI Listing
July 2019