Research Gaps in Pediatric Heart Failure: Defining the Gaps and Then Closing Them Over the Next Decade.

Given the numerous opportunities and the wide knowledge gaps in pediatric heart failure, an international group of pediatric heart failure experts with diverse backgrounds were invited and tasked with identifying research gaps in each pediatric heart failure domain that scientists and funding agencies need to focus on over the next decade.

Use of disease-modifying drugs in diabetic patients with heart failure with reduced ejection fraction.

Type 2 diabetes mellitus and heart failure are closely related, patients with type 2 diabetes mellitus have a higher risk of developing heart failure, and those with heart failure are at increased risk of developing type 2 diabetes. Although no specific randomized clinical trials have been conducted to test the effect of cardiovascular therapies (drugs and/or devices) in diabetic patients with heart failure, a lot of evidence shows that all interventions effective in improving prognosis in patients with heart failure reduced ejection fraction are equally beneficial in patients with and without diabetes. However, the use of disease-modifying drugs in patients with diabetes and heart failure reduced ejection fraction is a clinical challenge due to the increased risk of adverse effects. For example, ß-blockers are underutilized in diabetic patients due to the theoretical unfavorable effects on glucose metabolism as well as the use of drugs that interact with the renin-angiotensin system can be challenged in patients with diabetic nephropathy because of the risk of hyperkalemia. This review outlines the current use of disease-modifying drugs in diabetic patients with heart failure reduced ejection fraction. In addition, the role of novel pharmacologic agents as type 2 sodium-glucose co-transporter inhibitors (SGLT2ii) is discussed.

Genome Editing and Heart Failure.

Heart failure is a leading and growing cause of morbidity and mortality worldwide and clinically is defined by the presence of typical symptoms and signs due structural or functional cardiac abnormalities. In addition to family history of heart failure, genetic predisposition to cardiomyopathies and exposure to cardiotoxic agents, risk factors for heart failure with reduced ejection fraction are the same as for chronic coronary syndrome. Genome editing technologies can provide the tools to correct genetic defects responsible for various diseases, including cardiomyopathies. These technologies aim to reverse specific mutations. The same methods can also be applied to modulate and improve heart function. This chapter will briefly explain the pathophysiological and genetic aspects of heart failure and then discuss the clinical applications of genome editing in patients with heart failure.

Progressive right ventricular dysfunction and exercise impairment in patients with heart failure and diabetes mellitus: insights from the T.O.S.CA. Registry.

BACKGROUND: Findings from the T.O.S.CA. Registry recently reported that patients with concomitant chronic heart failure (CHF) and impairment of insulin axis (either insulin resistance-IR or diabetes mellitus-T2D) display increased morbidity and mortality. However, little information is available on the relative impact of IR and T2D on cardiac structure and function, cardiopulmonary performance, and their longitudinal changes in CHF. METHODS: Patients enrolled in the T.O.S.CA. Registry performed echocardiography and cardiopulmonary exercise test at baseline and at a patient-average follow-up of 36 months. Patients were divided into three groups based on the degree of insulin impairment: euglycemic without IR (EU), euglycemic with IR (IR), and T2D. RESULTS: Compared with EU and IR, T2D was associated with increased filling pressures (E/e'ratio: 15.9 ± 8.9, 12.0 ± 6.5, and 14.5 ± 8.1 respectively, p < 0.01) and worse right ventricular(RV)-arterial uncoupling (RVAUC) (TAPSE/PASP ratio 0.52 ± 0.2, 0.6 ± 0.3, and 0.6 ± 0.3 in T2D, EU and IR, respectively, p < 0.05). Likewise, impairment in peak oxygen consumption (peak VO2) in TD2 vs EU and IR patients was recorded (respectively, 15.8 ± 3.8 ml/Kg/min, 18.4 ± 4.3 ml/Kg/min and 16.5 ± 4.3 ml/Kg/min, p < 0.003). Longitudinal data demonstrated higher deterioration of RVAUC, RV dimension, and peak VO2 in the T2D group (+ 13% increase in RV dimension, - 21% decline in TAPSE/PAPS ratio and - 20% decrease in peak VO2). CONCLUSION: The higher risk of death and CV hospitalizations exhibited by HF-T2D patients in the T.O.S.CA. Registry is associated with progressive RV ventricular dysfunction and exercise impairment when compared to euglycemic CHF patients, supporting the pivotal importance of hyperglycaemia and right chambers in HF prognosis. Trial registration ClinicalTrials.gov identifier: NCT023358017.

Advanced heart failure: state of the art and future directions.

Advanced heart failure is a clinical challenge that requires a pathophysiological-based approach. As the field has been the subject of multiple reviews, the objective of this paper is not to duplicate these publications but rather to offer practical tips for the clinical cardiologist to enable the optimal management of patients with advanced heart failure. Advanced heart failure is defined as a clinical syndrome characterized by severe and persistent symptoms, most commonly with severe ventricular dysfunction, despite optimized medical therapy. This review covers the management of the advanced heart failure patient from pharmacologic therapy with disease-modifying drugs, to the use of electrical therapy devices, percutaneous valve repair and finally to the role of left ventricular assist devices and heart transplantation. The review also explores future directions in the management of advanced heart failure, including translational perspectives for the treatment of this syndrome.

Angiotensin-converting enzyme inhibitor therapy after heart transplant: From molecular basis to clinical effects.

The use of angiotensin-converting enzyme inhibitors is an important therapy for various cardiovascular diseases, such as hypertension, ischemic heart disease and heart failure (HF). In heart transplant recipients, angiotensin-converting enzyme inhibitors have been demonstrated to be a keystone for the treatment of hypertension with a wide spectrum of pleiotropic molecular effects ranging from improvement of the peripheral vascular system to regulation of the fluid and sodium balance. In addition, angiotensin-converting enzyme inhibitors may be also useful in the prevention of graft failure, cardiac allograft vasculopathy (CAV) and chronic kidney disease (CKD) progression. Further tailored multicenter and randomized studies are warranted to confirm the pleiotropic clinical effects of ACEi therapy in HTRs and to support more extended use in daily clinical practice. Finally in the near future, the use of novel pharmacological agents that inhibit the renin-angiotensin-aldosterone system (RAAS) such as the neprilysin inhibitor sacubitril should be investigated in heart transplant recipients.

Hemodynamic Effects of Levosimendan in Outpatients With Advanced Heart Failure: An Echocardiographic Pilot Study.

ABSTRACT: Infusions of levosimendan delivered in ambulatory/outpatient settings have been shown to improve quality of life and reduce hospitalizations in patients with advanced heart failure (HF). The aim of this pilot study was to evaluate the effects of ambulatory infusion of levosimendan on echocardiographic markers of perfusion, congestion, and cardiovascular efficiency. Thirty patients with diagnosed advanced HF underwent ambulatorial infusion of levosimendan at a total dose of 6.25 mg as a part of a repetitive biweekly treatment strategy with the inotrope. Standardized transthoracic echocardiography and Doppler examinations, were performed 1 hour before and 48 hours after completion of ambulatory infusion. At 48 hours after ambulatory infusion of levosimendan, a significant increase in the stroke volume (37.47 ± 12.38 mL/beat vs. 45.47 ± 14.48 mL/beat; P < 0.05) and cardiac output (2.64 ± 0.66 L/min vs. 3.26 ± 0.57 L/min; P < 0.05) occurred. Significant postreductions versus prereductions were also recorded in left atrial pressure (27.37 ± 6.62 mm Hg vs. 22.82 ± 4.17 mm Hg; P < 0.01), mean pulmonary artery pressure (27.69 ± 4.64 mm Hg vs. 23.24 ± 5.32; P < 0.01), and inferior vena cava diameter (23.81 ± 7.63 mm vs. 18.53 ± 4.82 mm; P < 0.01). Significant improvements were noted in the resting cardiac power output (0.46 ± 0.15 watt vs. 0.53 ± 0.22 watt; P < 0.01) and the resting cardiac power index (0.24 ± 0.08 watt/m2 vs. 0.28 ± 0.11 watt/m2; P < 0.01). In outpatients with advanced HF, infusion of levosimendan was associated with hemodynamic responses that may contribute to the clinical benefit previously reported in such patients.

Add-on Therapy With Sacubitril/Valsartan and Clinical Outcomes in CRT-D Nonresponder Patients.

ABSTRACT: No data on the add-on sacubitril/valsartan (S/V) therapy among cardiac resynchronization therapy with a defibrillator (CRT-D) nonresponder patients are currently available in literature. We conducted a prospective observational study including 190 CRT-D nonresponder patients with symptomatic heart failure with reduced ejection fraction despite the optimal medical therapy from at least 1 year. The primary endpoint was the rate of additional responders (left ventricular end-systolic volume reduction >15%) at 12 months from the introduction of S/V therapy. At the end of the 12 months follow-up, 37 patients (19.5%) were deemed as "additional responders" to the combination use of CRT + S/V therapy. The only clinical predictor of additional response was a lower left ventricular ejection fraction [OR 0.881 (0.815-0.953), P = 0.002] at baseline. At 12 months follow-up, there were significant improvements in heart failure (HF) symptoms and functional status [New York Heart Association 2 (2-3) vs. 1 (1-2), P < 0.001; physical activity duration/day: 10 (8-12) vs. 13 (10-18) hours, P < 0.001]. Compared with the 12 months preceding S/V introduction, there were significant reductions in the rate of HF rehospitalization (35.5% vs. 19.5%, P < 0.001), in atrial tachycardia/atrial fibrillation burden [6.0 (5.0-8.0) % vs. 0 (0-2.0) %, P < 0.001] and in the proportions of patients experiencing ventricular arrhythmias (21.6% vs. 6.3%; P < 0.001). Our results indicate that S/V add-on therapy in CRT-D nonresponder patients is associated with 19.5% of additional responders, a reduction in HF symptoms and rehospitalizations, AF burden, and ventricular arrhythmias.

Nonresponse to Acute Vasodilator Challenge and Prognosis in Heart Failure With Pulmonary Hypertension.

BACKGROUND: An acute vasodilator challenge is recommended in patients with heart failure and pulmonary hypertension during heart transplant evaluation. The aim of the study was to assess which hemodynamic parameters are associated with nonresponsiveness to the challenge. METHODS AND RESULTS: This study is a retrospective analysis of 402 patients with heart failure with pulmonary hypertension who underwent right heart catheterization and a pulmonary vasodilator challenge. Among the 140 who fulfilled the transplant guidelines eligibility criteria for the vasodilator challenge, 38 were responders and 102 nonresponders. At multivariable analysis, a diastolic blood pressure of <70 mm Hg, pulmonary vascular resistance of >5 Woods units, and pulmonary artery compliance of <1.2 mL/mm Hg were independently associated with poor response to vasodilator challenge (all P < .001). The presence of any 2 of these 3 conditions was associated with a 90% probability of being a nonresponder. The covariate-adjusted hemodynamic predictors of death in the entire population were a low baseline systolic blood pressure (P = .0017) and a low baseline right ventricular stroke work index (P = .0395). CONCLUSIONS: In patients with heart failure and pulmonary hypertension, low pulmonary arterial compliance, high pulmonary vascular resistance, and low diastolic blood pressure predict the nonresponsiveness to acute vasodilator challenge whilst a poor right ventricular function predicts a dismal prognosis.

Exercise-based rehabilitation strategies in heart transplant recipients: Focus on high-intensity interval training.

Despite progressive improvement in medical therapy and standard care, the exercise capacity of heart transplant recipients is reduced compared with age-matched healthy individuals. Exercise-based rehabilitation programs have been shown to improve the exercise capacity of transplant patients through a multifactorial effect. In this context, high-intensity interval exercise is a growing field of research, with current evidence suggesting a major benefit in heart transplant recipients compared with a conventional training protocol. Therefore, this study aimed to provide an overview of the mechanisms involved in the reduced exercise capacity of heart transplant patients and a review of current rehabilitation strategies with a special focus on the mechanisms and clinical effects of high-intensity interval training exercise.

Echocardiography in Advanced Heart Failure for Diagnosis, Management, and Prognosis.

Advanced heart failure, an end-stage disease characterized by high mortality and morbidity despite standard medical therapy, requires various therapeutic strategies like heart transplant and long-term mechanical circulatory support. Echocardiography is the main imaging technique to identify transitions to advanced stages of disease and guide risk stratification and therapeutic decision-making processes. Progressive development of advanced echocardiographic techniques allows more comprehensive assessment of the hemodynamic and structural profiles of patients with advanced heart failure, and its use in clinical practice continues to expand. This article provides an overview of basic and emerging echocardiographic tools to assess patients with advanced heart failure.

Inotropes in Patients with Advanced Heart Failure: Not Only Palliative Care.

Patients with advanced heart failure suffer from severe and persistent symptoms, often not responding disease-modifying drugs, a marked limitation of functional capacity and poor quality of life that can ameliorate with inotropic drugs therapy. In small studies, pulsed infusions of classical inotropes (ie, dobutamine and milrinone) are associated with improvement in hemodynamic parameters and quality of life in patients with advanced heart failure. However, because of the adverse effects of these drugs, serious safety issues have been raised. Levosimendan is a calcium-sensitizing inodilators with a triple mechanism of action, whose infusion results in hemodynamic, neurohormonal, and inflammatory cytokine improvements in patients with chronic advanced HF. In addition, levosimendan has important pleiotropic effects, including protection of myocardial, renal, and liver cells from ischemia-reperfusion injury, and anti-inflammatory and antioxidant effects; these properties possibly make levosimendan an "organ protective" inodilator. In clinical trials and real-world evidence, infusion of levosimendan at fixed intervals is safe and effective in patients with advanced HF, alleviating clinical symptoms, reducing hospitalizations, and improving the quality of life. Therefore, the use of repeated doses of levosimendan could represent the therapy of choice as a bridge to transplant/left ventricular assist device implantation or as palliative therapy in patients with advanced heart failure.

Beta-blocker therapy in heart transplant recipients: A review.

Beta-blockers are essential drugs for the treatment of many cardiovascular diseases, such as heart failure, acute and chronic ischemic heart disease, tachyarrhythmias, and hypertension. However, these drugs have not been used in cardiac transplant patients for many years owing to the fear that they could reduce cardiac output and functional capacity. In recent years, however, some evidence has shown that even in cardiac transplanted patients, ß-blockers are useful and effective in the treatment of sinus tachycardia, supraventricular and ventricular tachyarrhythmias, left ventricular systolic dysfunction, and arterial hypertension. Furthermore, some data have shown that the use of ß-blockers is associated with reduced mortality in heart transplant recipients. In this review, we summarize this evidence with particular emphasis on the practical aspects of the use of ß-blockers in post-transplantation patients to promote the use of this important class of drugs in clinical practice.

Management of Bradyarrhythmias in Heart Failure: A Tailored Approach.

Patients with heart failure (HF) may develop a range of bradyarrhythmias including sinus node dysfunction, various degrees of atrioventricular block, and ventricular conduction delay. Device implantation has been recommended in these patients, but the specific etiology should be sought as it may influence the choice of the type of device required (pacemaker vs. implantable cardiac defibrillator). Also, pacing mode must be carefully set in patients with heart failure (HF) and left ventricular systolic dysfunction.In this chapter, we summarize the knowledge required for a tailored approach to bradyarrhythmias in patients with heart failure.

Mutations in the GLA Gene and LysoGb3: Is It Really Anderson-Fabry Disease?

Anderson-Fabry disease (FD) is a rare, progressive, multisystem storage disorder caused by the partial or total deficit of the lysosomal enzyme α-galactosidase A (α-Gal A). It is an X-linked, lysosomal enzymopathy due to mutations in the galactosidase alpha gene (GLA), encoding the α-Gal A. To date, more than 900 mutations in this gene have been described. In our laboratories, the study of genetic and enzymatic alterations related to FD was performed in about 17,000 subjects with a symptomatology referable to this disorder. The accumulation of globotriaosylsphingosine (LysoGb3) was determined in blood of positives. Exonic mutations in the GLA gene were detected in 471 patients (207 Probands and 264 relatives): 71.6% of mutations were associated with the classic phenotype, 19.8% were associated with the late-onset phenotype, and 8.6% of genetic variants were of unknown significance (GVUS). The accumulation of LysoGb3 was found in all male patients with a mutation responsible for classic or late-onset FD. LysoGb3 levels were consistent with the type of mutations and the symptomatology of patients. α-Gal A activity in these patients is absent or dramatically reduced. In recent years, confusion about the pathogenicity of some mutations led to an association between non-causative mutations and FD. Our study shows that the identification of FD patients is possible by associating clinical history, GLA gene analysis, α-Gal A assay, and blood accumulation of LysoGB3. In our experience, LysoGB3 can be considered a reliable marker, which is very useful to confirm the diagnosis of Fabry disease.

Epidemiology and Clinical Aspects of Genetic Cardiomyopathies.

Cardiomyopathies (CMPs) are an increasingly recognized cause of heart failure and sudden death, particularly in young patients. Since their original description, major advances were achieved in the phenotype knowledge, natural history, and nosography of CMPs leading to different classification systems and therapies. However, a deeper knowledge of different causes, genotype-phenotype link, and natural history in different disease stages (preclinical, overt disease, and end-stage disease) according to a recognized standard of care (ie, international guidelines) is needed. Clinical registries can fill gaps in our knowledge regarding the uncovered issues on cause, clinical course, and management of CMPs.

Genetics of Takotsubo Syndrome.

Takotsubo syndrome (TTS) is an enigmatic disease with a multifactorial and still unresolved pathogenesis. A genetic predisposition has been suggested based on the few familial TTS cases. Conflicting results have been published regarding the role of functional polymorphisms in relevant candidate genes, such as α1-, ß1-, and ß2-adrenergic receptors; G protein-coupled receptor kinase 5; and estrogen receptors. Further research is required to help clarify the role of genetic susceptibility in TTS.

Renal function and peak exercise oxygen consumption in chronic heart failure with reduced left ventricular ejection fraction.

BACKGROUND: Chronic kidney disease is associated with sympathetic activation and muscle abnormalities, which may contribute to decreased exercise capacity. We investigated the correlation of renal function with peak exercise oxygen consumption (V̇O2) in heart failure (HF) patients. METHODS AND RESULTS: We recruited 2,938 systolic HF patients who underwent clinical, laboratory, echocardiographic and cardiopulmonary exercise testing. The patients were stratified according to estimated glomerular filtration rate (eGFR). Mean follow-up was 3.7 years. The primary outcome was a composite of cardiovascular death and urgent heart transplantation at 3 years. On multivariable regression, eGFR was predictor of peakV̇O2(P<0.0001). Other predictors were age, sex, body mass index, HF etiology, NYHA class, atrial fibrillation, resting heart rate, B-type natriuretic peptide, hemoglobin, and treatment. After adjusting for significant covariates, the hazard ratio for primary outcome associated with peakV̇O2<12 ml·kg(-1)·min(-1)was 1.75 (95% confidence interval (CI): 1.06-2.91; P=0.0292) in patients with eGFR ≥60, 1.77 (0.87-3.61; P=0.1141) in those with eGFR of 45-59, and 2.72 (1.01-7.37; P=0.0489) in those with eGFR <45 ml·min(-1)·1.73 m(-2). The area under the receiver-operating characteristic curve for peakV̇O2<12 ml·kg(-1)·min(-1)was 0.63 (95% CI: 0.54-0.71), 0.67 (0.56-0.78), and 0.57 (0.47-0.69), respectively. Testing for interaction was not significant. CONCLUSIONS: Renal dysfunction is correlated with peakV̇O2. A peakV̇O2cutoff of 12 ml·kg(-1)·min(-1)offers limited prognostic information in HF patients with more severely impaired renal function.

Right ventricular cardiomyopathies: a multidisciplinary approach to diagnosis.

The physiological importance of the right ventricle (RV) has been underestimated over the past years. Finally in the early 1950s through the 1970s, cardiac surgeons recognized the importance of RV function. Since then, the importance of RV function has been recognized in many acquired cardiac heart disease. RV can be mainly or together with left ventricle (LV) affected by inherited or acquired cardiomyopathy. In fact, RV morphological and functional remodeling occurs more common during cardiomyopathies than in ischemic cardiomyopathies and more closely parallels LV dysfunction. Moreover, there are some cardiomyopathy subtypes showing a predominant or exclusive involvement of the RV, and they are probably less known by cardiologists. The clinical approach to right ventricular cardiomyopathies is often challenging. Imaging is the first step to raise the suspicion and to guide the diagnostic process. In the differential diagnosis, cardiologists should consider athlete's heart, congenital heart diseases, multisystemic disorders, and inherited arrhythmias. However, a multiparametric and multidisciplinary approach, involving cardiologists, experts in imaging, geneticists, and pathologists with a specific expertise in these heart muscle disorders is required.