Exercise Training in Patients with Heart Failure: From Pathophysiology to Exercise Prescription.

Heart failure (HF) is a chronic, progressive, and inexorable syndrome affecting worldwide billion of patients (equally distributed among men and women), with prevalence estimate of 1-3% in developed countries. HF leads to enormous direct and indirect costs, and because of ageing population, the total number of HF patients keep rising, approximately 10% in patients > 65 years old. Exercise training (ET) is widely recognized as an evidence-based adjunct treatment modality for patients with HF, and growing evidence is emerging among elderly patients with HF. We used relevant data from literature search (PubMed, Medline, EMBASE) highlighting the epidemiology of HF; focusing on central and peripheral mechanisms underlying the beneficial effect of ET in HF patients; and on frail HF elderly patients undergoing ET. Since many Countries ordered a lockdown in early stages pandemic trying to limit infections, COVID-19 pandemic, and its limitation to exercise-based cardiac rehabilitation operativity was also discussed. ET exerts both central and peripheral adaptations that clinically translate into anti-remodeling effects, increased functional capacity and reduced morbidity and mortality. Ideally, ET programs should be prescribed in a patient-tailored approach, particularly in frail elderly patients with HF. In conclusion, given the complexity of HF syndrome, combining, and tailoring different ET modalities is mandatory. A procedural algorithm according to patient's baseline clinical characteristics [i.e., functional capacity, comorbidity, frailty status (muscle strength, balance, usual daily activities, hearing and vision impairment, sarcopenia, and inability to actively exercise), logistics, individual preferences and goals] has been proposed. Increasing long-term adherence and reaching the frailest patients are challenging goals for future initiatives in the field.

Exercise Training in Elderly Cancer Patients: A Systematic Review.

Due to the aging of the population, in 70% of cases, a new cancer diagnosis equals a cancer diagnosis in a geriatric patient. In this population, beyond the concept of mortality and morbidity, functional capacity, disability, and quality of life remain crucial. In fact, when the functional status is preserved, the pathogenetic curve towards disability will stop or even regress. The present systematic review investigated the effectiveness of physical exercise, as part of a holistic assessment of the patient, for preventing disability and improving the patient's quality of life, and partially reducing all-cause mortality. This evidence must point towards decentralization of care by implementing the development of rehabilitation programs for elderly cancer patients either before or after anti-cancer therapy.

Potential Role of Global Longitudinal Strain in Cardiac and Oncological Patients Undergoing Cardio-Oncology Rehabilitation (CORE).

Although shown to be effective in improving survival and quality of life in patients with cancer, some treatments are well-known causes of cardiotoxicity, such as anthracyclines, monoclonal antibodies against human epidermal growth factor receptor 2 (HER2) and radiotherapy. To prevent cardiovascular disease (CVD) in patients living with cancer, cardiologists and oncologists promoted the development of cardio-oncology, an interdisciplinary field which aims to further improving life expectancy in these patients. Cardio-oncology rehabilitation (CORE), through correction of risk factors, prescription of drug therapies and structured exercise programs, tries to improve symptoms, quality of life, cardiorespiratory fitness (CRF) and survival in patients with cancer. Different imaging modalities can be used to evaluate the real effectiveness of exercise training on cardiac function. Among these, the global longitudinal strain (GLS) has recently aroused interest, thanks to its high sensitivity and specificity for cardiac dysfunction detection due to advanced ultrasound programs. This review summarizes the evidence on the usefulness of GLS in patients with cancer undergoing cardiac rehabilitation programs.

Short-term treatment of iron deficiency anemia after cardiac surgery.

Iron deficiency anemia (IDA) is frequent after cardiac surgery and is associated with increased morbidity and mortality. In a retrospective study, we analyzed 106 patients with IDA (hemoglobin [Hb] ≤ 12 g/dl in women and ≤ 13 g/dl in men, transferrin saturation [TSAT] ≤ 20%) on admission to a Cardiac Rehabilitation Unit after cardiac surgery. The patients were divided into two groups, one was treated with oral sucrosomial iron (SI) and the other with intravenous ferric carboxymaltose (FCM). Patients received a single 1000 mg dose of FCM from the day after admission to rehabilitation (T1), or a 120 mg/day dose of SI from T1 until discharge (T2); after discharge, SI was reduced to 30 mg/day until the end of follow-up (T3). Hb was evaluated at T1, T2 and T3; the other hematological parameters at T1 and T3; natriuretic peptides at T1, T2 and T3; 6-minute walk test (6MWT) at T1 and T2. Folate, vitamin B12 and reticulocytes were sampled on admission. Folate deficiency was documented in 60.4% of patients. Hb increased in both groups with no significant differences between the two treatments (p = 0.397). The other iron metabolism parameters (sideremia, transferrin, TSAT) displayed similar behavior, showing a significant increase at T3 (p < 0.001) with both therapies, although the increase was faster with FCM. Ferritin - high on admission - decreased at T3 in the SI group and rose significantly in the FCM group (SI 219.5 vs. FCM 689 ng/ml p < 0.0001). The 6MWT increased significantly at T2, with an overlap between SI and FCM. In conclusion, the results of this study show that SI and FCM exhibit the same effectiveness on IDA; the response time to therapy of both treatments is also equally fast. SI and FCM induce a similar increase in functional capacity. The study shows that SI can be a viable alternative to FCM after cardiac surgery in terms of effectiveness and tolerability.

Dyslipidemia in Transplant Patients: Which Therapy?

Cardiovascular disease is the most important cause of death worldwide in recent years; an increasing trend is also shown in organ transplant patients subjected to immunosuppressive therapies, in which cardiovascular diseases represent one of the most frequent causes of long-term mortality. This is also linked to immunosuppressant-induced dyslipidemia, which occurs in 27 to 71% of organ transplant recipients. The aim of this review is to clarify the pathophysiological mechanisms underlying dyslipidemia in patients treated with immunosuppressants to identify immunosuppressive therapies which do not cause dyslipidemia or therapeutic pathways effective in reducing hypercholesterolemia, hypertriglyceridemia, or both, without further adverse events.

Proprotein Convertase Subtilisin/Kexin Type 9 Inhibitors Use for Atherogenic Dyslipidemia in Solid Organ Transplant Patients.

Dyslipidemia is a widespread risk factor in solid organ transplant patients, due to many reasons, such as the use of immunosuppressive drugs, with a consequent increase in cardiovascular diseases in this population. PCSK9 is an enzyme mainly known for its role in altering LDL levels, consequently increasing cardiovascular risk. Monoclonal antibody PCSK9 inhibitors demonstrated remarkable efficacy in the general population in reducing LDL cholesterol levels and preventing cardiovascular disease. In transplant patients, these drugs are still poorly used, despite having comparable efficacy to the general population and giving fewer drug interactions with immunosuppressants. Furthermore, there is enough evidence that PCSK9 also plays a role in other pathways, such as inflammation, which is particularly dangerous for graft survival. In this review, the current evidence on the function of PCSK9 and the use of its inhibitors will be discussed, particularly in transplant patients, in which they may provide additional benefits.

Inhibitors of Protein Convertase Subtilisin/Kexin 9 (PCSK9) and Acute Coronary Syndrome (ACS): The State-of-the-Art.

Acute Coronary Syndrome (ACS) remains one of the most frequent causes of morbidity and mortality in the world. Although the age- and gender-adjusted incidence of ACS is decreasing, the mortality associated with this condition remains high, especially 1-year after the acute event. Several studies demonstrated that PCSK9 inhibitors therapy determine a significant reduction of major adverse cardiovascular events (MACE) in post-ACS patients, through a process of plaque modification, by intervening in lipid metabolism and platelet aggregation and finally determining an improvement in endothelial function. In the EVACS (Evolocumab in Acute Coronary Syndrome) study, evolocumab allows >90% of patients to achieve LDL-C < 55 mg/dL according to ESC/EAS guidelines compared to 11% of patients who only receive statins. In the EVOPACS (EVOlocumab for Early Reduction of low-density lipoprotein (LDL)-cholesterol Levels in Patients With Acute Coronary Syndromes) study, evolocumab determined LDL levels reduction of 40.7% (95% CI: 45.2 to 36.2; p < 0.001) and allowed 95.7% of patients to achieve LDL levels <55 mg/dL. In ODYSSEY Outcome trial, alirocumab reduced the overall risk of MACE by 15% (HR = 0.85; CI: 0.78-0.93; p = 0.0003), with a reduced risk of all-cause mortality (HR = 0.85; CI: 0.73-0.98: nominal p = 0026), and fewer deaths for coronary heart disease (CHD) compared to the control group (HR = 0.92; CI: 0.76-1.11; p = 0.38). The present review aimed at describing the beneficial effect of PCSK9 inhibitors therapy early after ACS in reducing LDL circulating levels (LDL-C) and the risk of major adverse cardiovascular events, which was very high in the first year and persists higher later after the acute event.

Carotid Atherosclerosis, Ultrasound and Lipoproteins.

Carotid artery plaques are considered a measure of atherosclerosis and are associated with an increased risk of atherosclerotic cardiovascular disease, particularly ischemic strokes. Monitoring of patients with an elevated risk of stroke is critical in developing better prevention strategies. Non-invasive imaging allows us to directly see atherosclerosis in vessels and many features that are related to plaque vulnerability. A large body of evidence has demonstrated a strong correlation between some lipid parameters and carotid atherosclerosis. In this article, we review the relationship between lipids and atherosclerosis with a focus on carotid ultrasound, the most common method to estimate atherosclerotic load.

Exercise Training: The Holistic Approach in Cardiovascular Prevention.

Nowadays, there are robust clinical and pathophysiological evidence supporting the beneficial effects of physical activity on cardiovascular (CV) system. Thus, the physical activity is considered a key strategy for CV prevention. In fact, exercise training exerts favourable effects on all risk factors for CV diseases (i.e. essential hypertension, type 2 diabetes mellitus, hypercholesterolemia, obesity, metabolic syndrome, etc…). In addition, all training modalities such as the aerobic (continuous walking, jogging, cycling, etc.) or resistance exercise (weights), as well as the leisure-time physical activity (recreational walking, gardening, etc) prevent the development of the major CV risk factors, or delay the progression of target organ damage improving cardio-metabolic risk. Exercise training is also the core component of all cardiac rehabilitation programs that have demonstrated to improve the quality of life and to reduce morbidity in patients with CV diseases, mostly in patients with coronary artery diseases. Finally, it is still debated whether or not exercise training can influence the occurrence of atrial and ventricular arrhythmias. In this regard, there is some evidence that exercise training is protective predominantly for atrial arrhythmias, reducing the incidence of atrial fibrillation. In conclusion, the salutary effects evoked by physical acitvity are useful in primary and secondary CV prevention.

The core components of cardio-oncology rehabilitation.

The increased efficacy of cancer therapy has resulted in greater cancer survival and increasing number of people with cancer and cardiovascular diseases. The sharing of risk factors, the bidirectional relationship between cancer and cardiovascular diseases and the cardiotoxic effect of chemotherapy and radiotherapy, are the cause of the rapid expansion of cardio-oncology. All strategies to preserve cardiovascular health and mitigate the negative effect of cancer therapy, by reducing the cardiovascular risk, must be pursued to enable the timely and complete delivery of anticancer therapy and to achieve the longest remission of the disease. Comprehensive cardiac rehabilitation is an easy-to-use model, even in cancer care, and is the basis of Cardio-Oncology REhabilitation (CORE), an exercise-based multi-component intervention. In addition, CORE, besides using the rationale and knowledge of cardiac rehabilitation, can leverage the network of cardiac rehabilitation services to offer to cancer patients exercise programs, control of risk factors, psychological support, and nutrition counseling. The core components of CORE will be discussed, describing the beneficial effect on cardiorespiratory fitness, quality of life, psychological and physical well-being, and weight management. Furthermore, particular attention will be paid to how CORE can counterbalance the negative effect of therapies in those at heightened cardiovascular risk after a cancer diagnosis. Barriers for implementation, including personal, family, social and of the health care system barriers for a widespread diffusion of the CORE will also be discussed. Finally, there will be a call-to-action, for randomized clinical trials that can test the impact of CORE, on morbidity and mortality.

Frailty in Acute and Chronic Coronary Syndrome Patients Entering Cardiac Rehabilitation.

Worldwide population ageing is partly due to advanced standard of care, leading to increased incidence and prevalence of geriatric syndromes such as frailty and disability. Hence, the age at the onset of acute coronary syndromes (ACS) keeps growing as well. Moreover, ageing is a risk factor for both frailty and cardiovascular disease (CVD). Frailty and CVD in the elderly share pathophysiological mechanisms and associated conditions, such as malnutrition, sarcopenia, anemia, polypharmacy and both increased bleeding/thrombotic risk, leading to a negative impact on outcomes. In geriatric populations ACS is associated with an increased frailty degree that has a negative effect on re-hospitalization and mortality outcomes. Frail elderly patients are increasingly referred to cardiac rehabilitation (CR) programs after ACS; however, plans of care must be tailored on individual's clinical complexity in terms of functional capacity, nutritional status and comorbidities, cognitive status, socio-economic support. Completing rehabilitative intervention with a reduced frailty degree, disability prevention, improvement in functional state and quality of life and reduction of re-hospitalization are the goals of CR program. Tools for detecting frailty and guidelines for management of frail elderly patients post-ACS are still debated. This review focused on the need of an early identification of frail patients in elderly with ACS and at elaborating personalized plans of care and secondary prevention in CR setting.

A comprehensive individual patient data meta-analysis of the effects of cardiac contractility modulation on functional capacity and heart failure-related quality of life.

AIMS: Cardiac contractility modulation, also referred to as CCM™, has emerged as a promising device treatment for heart failure (HF) in patients not indicated for cardiac resynchronization therapy. We performed a comprehensive individual patient data meta-analysis of all non-confounded prospective randomized controlled trials of CCM vs. control that have measured functional capacity and/or quality of life questionnaires in patients with HF. METHODS AND RESULTS: The Cochrane Central Register of Controlled Trials, MEDLINE, and EMBASE were searched in January 2020 to identify eligible randomized controlled trials. We also asked the sole manufacturer of the device for their list of known trials. Primary outcomes of interest were peak oxygen consumption (peak VO2 ), 6 min walk test distance, and quality of life measured by Minnesota Living with Heart Failure Questionnaire (MLWHFQ), and all data were received as individual patient and individual time point data-points. Mean differences and 95% confidence intervals (CIs) were calculated for continuous data using a fixed-effects model. Five trials were identified, four randomized studies enrolling 801 participants for all endpoints of interest, and for peak VO2 alone (n = 60), there was an additional single arm non-randomized trial (FIX-HF-5C2) with a prospective comparison of its 24 week peak VO2 data compared with the control group of the FIX-HF-5C control patients. Pooled analysis showed that, compared with control, CCM significantly improved peak VO2 (mean difference +0.93, 95% CI 0.56 to 1.30 mL/kg/min, P < 0.00001), 6 min walk test distance (mean difference +17.97, 95% CI 5.48 to 30.46 m, P = 0.005), and quality of life measured by MLWHFQ (mean difference -7.85, 95% CI -10.76 to -4.94, P < 0.00001). As a sensitivity analysis, we excluded the FIX-HF-5C2 trial (only relevant for peak VO2 ), and the result was similar, mean difference +0.65, 95% CI 0.21 to 1.08 mL/kg/min, P = 0.004. CONCLUSIONS: This comprehensive meta-analysis of individual patient data from all known randomized trials has shown that CCM provides statistically significant and clinically meaningful benefits in measures of functional capacity and HF-related quality of life.

Clinical Evidence for Q10 Coenzyme Supplementation in Heart Failure: From Energetics to Functional Improvement.

Oxidative stress and mitochondrial dysfunction are hallmarks of heart failure (HF). Coenzyme Q10 (CoQ10) is a vitamin-like organic compound widely expressed in humans as ubiquinol (reduced form) and ubiquinone (oxidized form). CoQ10 plays a key role in electron transport in oxidative phosphorylation of mitochondria. CoQ10 acts as a potent antioxidant, membrane stabilizer and cofactor in the production of adenosine triphosphate by oxidative phosphorylation, inhibiting the oxidation of proteins and DNA. Patients with HF showed CoQ10 deficiency; therefore, a number of clinical trials investigating the effects of CoQ10 supplementation in HF have been conducted. CoQ10 supplementation may confer potential prognostic advantages in HF patients with no adverse hemodynamic profile or safety issues. The latest evidence on the clinical effects of CoQ10 supplementation in HF was reviewed.