Phospholamban: A Promising Therapeutic Target in Heart Failure?

Dilated cardiomyopathy and end-stage heart failure result in characteristic functional, biochemical and molecular alterations. Multiple defects in cardiac excitation-contraction coupling have been suggested to underlie disturbed myocardial function and progressive remodeling. Ca²⁺ uptake and release by the sarcoplasmic reticulum (SR) have been shown to be altered in various animal models and human conditions. This review will focus on SR Ca²⁺ ATPase and its regulatory protein, phospholamban, as potential therapeutic targets. We summarize structural and genetic approaches, which have helped to elucidate the physiological role of phospholamban as a principal regulator of cardiac contractility and -adrenergic stimulation in the heart. These findings are extended to the clinical arena, indicating a phospholamban/SR Ca²⁺ ATPase mismatch in human heart failure. Evidence is then provided, using genetically engineered mouse models, that SR dysfunction may play a key role in the onset and progression of heart failure. Phospholamban deficiency may prevent such left ventricular dysfunction and its progression to heart failure in some of the animal models with dilated cardiomyopathy. Based on these findings, we discuss the question of whether and how interfering with the phospholamban/SR Ca²⁺ ATPase interaction may be a promising therapeutic approach for heart failure.     

Apoptosis in Heart Failure: A Real Problem?

Progressive left ventricular (LV) dysfunction is a characteristic feature of the failing heart. The mechanism or mechanisms that drive this progression are not known. In recent years, we advanced a working hypothesis that progressive LV dysfunction in heart failure results, in part, from ongoing loss of cardiomyocytes. More recently evidence emerge based on studies in animals with heart failure and in explanted failed human hearts that ongoing cardiomyocyte death through apoptosis occurs in heart failure, a finding that supports the original hypothesis. While these findings created considerable enthusiasm, some skepticism remains even today as to whether cardiomyocyte apoptosis plays an important role in the progression of heart failure. The evidence garnered over the past few years, when considered in aggregate, does favors apoptosis as a key culprit in the progression of the heart failure. Nonetheless, additional key studies are needed to determine if direct inhibition of apoptosis with specific pharmacologic probes prevents progressive LV dysfunction in heart failure. Only then can one fully appreciate the importance of cardiomyocyte apoptosis in the pathophysiology of heart failure.     

Acute Heart Failure—Basic Pathomechanism and New Drug Targets

In view of the high incidence of heart failure and sudden cardiac death, efforts in the development of compounds which target-specific mechanisms such as a reduced expression of SERCA2, the Ca2+ pump of sarcoplasmic reticulum, of hypertrophied cardiomyocytes of pressure-overloaded or infarcted hearts should be strengthened. Lead compounds for correcting a dysregulated gene expression are the carnitine palmitoyltransferase-1 (CPT-1) inhibitors etomoxir and oxfenicine. Since bypassing the CPT-1 inhibition by a medium-chain fatty acid diet had a lesser effect on myosin V1 proportion than on lipid droplet number, one has to infer also other mechanisms such as PPARalpha activation (FOXIB/PPARalpha). In view of the intricate interrelationship between depressed pump function and malignant arrhythmias, stimulation of endogenous antiarrhythmogenic mechanisms linked to an enhanced production of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) could potentially provide alternatives to the administration of 1 g EPA and DHA ethyl esters (minimum 84% EPA + DHA) for secondary prevention of myocardial infarction. The apparently greater efficacy of omega-3 fatty acids in post-myocardial infarction patients (GISSI-Prevention study) compared with ICD patients (SOFA study) can be attributed to the greater ischemia-induced release of membrane-bound EPA and DHA and a better compliance (one vs. four capsules daily).     

Hyperkalaemia in Heart Failure—Pathophysiology,Implications and Therapeutic Perspectives

Purpose of Review

Hyperkalaemia is a frequent and sometimes life-threatening condition that may be associated with arrhythmia and cardiac dysfunction. Evaluating the prevalence of hyperkalaemia in patients with heart failure (HF) and potential treatments of this condition is essential for patients using renin–angiotensin–aldosterone system inhibitors or angiotensin receptor–neprilysin inhibitor and mineralocorticoid receptor antagonists, which represent the cornerstone and highly proven life-saving therapy.

Recent Findings

Novel findings from the past few years include data regarding the epidemiology, pathomechanisms, implications and novel therapeutic approaches to counteract hyperkalaemia in patients with HF. Whilst older potassium-binding agents are associated with serious adverse events, novel potassium-binding drugs are effective in lowering potassium levels and are generally well tolerated.

Summary

Hyperkalaemia represents both a direct risk of cardiovascular complication and an indirect biomarker of the severity of the underlying disease such as neurohormonal activation and renal dysfunction. Novel potassium-binding drugs such as patiromer and sodium zirconium cyclosilicate may help to optimize therapy in HF and achieve guideline-recommended doses.

     

Hyperglycemia in Acute Heart Failure: An Opportunity to Intervene?

In patients with acute heart failure (AHF) syndromes, little data are so far available on the relation between glucose values and insulin resistance and mortality, both in the short and long term. The present review is aimed at summarizing available evidence on the prognostic role of hyperglycemia in acute heart failure syndromes. Despite the fact that glucose values are widely measured, inexpensive, and easy to interpret, hyperglycemia in AHF patients still appears to be (or at least to have been) a neglected factor. Scarce information is available on incidence of admission hyperglycemia (especially in nondiabetic AHF patients) and data on in-hospital and discharge glucose values are lacking. Overall, the scarcity of data and the unanswered questions conjure up the need for trials investigating the clinical and prognostic role of glucose abnormalities (hyperglycemia and acute insulin resistance) on admission and during hospital stay in AHF patients. Preliminary evidence suggests that hyperglycemia is an important prognostic factor in AHF; however, whether targeting hyperglycemia via an aggressive versus permissive glycemic management strategy influences AHF outcomes remains unknown.     

Mid-Regional Pro-Adrenomedullin in Acute Heart Failure: A Better Biomarker or Just Another Biomarker?

Circulating biomarkers have become increasingly important in diagnosing and risk-stratifying patients with heart failure (HF). While the natriuretic peptides have received much focus in the past decade, there is increasing interest in the role of other circulating biomarkers such as mid-regional proadrenomedullin (MR-proADM), a stable peptide of the precursor of adrenomedullin (ADM), responsible for volume regulation and electrolyte homeostasis. Increased levels of MR-proADM are associated with an increased risk of mortality and morbidity in patients with HF, independent of natriuretic peptides. MR-proADM outperforms all other established markers in the identification of patients at highest risk of death, particularly death within 30?days. The prognostic superiority has consistently been shown for various cardiovascular disease states, including acute heart failure. In this article, we discuss the potential role of MR-proADM in the syndrome of acute heart failure and its implication on prognosis and risk stratification.     

Stage A: Can Heart Failure Be Prevented?

Heart failure (HF) is an epidemic associated with significant morbidity and mortality, affecting over 5 million people in the United States and 1-2%of the population worldwide. Observational studies have suggested that a healthy lifestyle can reduce HF risk. Although no clinical trials have targeted the prevention of HF as a primary endpoint, many have evaluated outcomes associated with the development of symptomatic disease (i.e., progression to HF, HF hospitalization or death) as secondary endpoints. Blood pressure treatment represents the most effective strategy in preventing heart failure; each 5 mm Hg decrease in systolic blood pressures reduces the risk of HF development by 24%. Thiazide diuretics appear to be the most efficacious agents in patients with hypertension. Angiotensin converting enzyme inhibitors and angiotensin-II receptor blockers are first line agents for patients with chronic atherosclerosis, diabetes, or chronic kidney disease. Beta blockers appear less effective as single agents and cardioselective agents are preferred. Calcium channel blockers, specifically non-dihydropyridines, should be avoided and alpha blockers should not be used to reduce HF risk.     

Neurohormonal Intervention to Reduce Sudden Cardiac Death in Heart Failure: What is the Optimal Pharmacologic Strategy?

Sudden cardiac death (SCD) accounts for up to 50% of deaths in patients with heart failure (HF), depending on severity of symptomatic impairment and left ventricular dysfunction. Neurohormonal therapy directed at the renin-angiotensin-aldosterone system may reduce the propensity to SCD through improved hemodynamic responsiveness, reduced sympathetic tone in the myocardium and inhibition of cardiac remodelling. Angiotensin converting enzyme (ACE) inhibitors reduce overall mortality in chronic HF, the greatest benefit appearing to arises from reduction of HF progression rather than SCD. In HF patients who experience myocardial infarction (MI) reduced incidence in SCD may make a more marked contribution to the mortality benefits of ACE inhibition. Addition of beta-blocker therapy to ACE inhibition has consistently resulted in a reduction in SCD in patients with either mild-to-moderate or severe HF, and in the presence or absence of MI; the reduction in SCD is of the order of one-third versus placebo. Aldosterone blockade reduces the risk of SCD in advanced chronic heart failure (when added to ACE inhibitor) and in HF associated with acute MI (when given in addition to both ACE inhibitor and beta blocker). The evidence base suggests that for maximal SCD risk reduction in HF, beta-blocker therapy is advisable in combination with standard ACE inhibitor therapy, with addition of aldosterone blockade to this regimen for particular groups of heart failure patients.     

Liver Function,In-Hospital,and Post-Discharge Clinical Outcome in Patients With Acute Heart Failure—Results From the Relaxin for the Treatment of Patients With Acute Heart Failure Study

BackgroundElevated plasma concentrations of liver function tests are prevalent in patients with chronic heart failure (HF). Little is known about liver function in patients with acute HF. We aimed to assess the prevalence and prognostic value of serial measurements of liver function tests in patients admitted with acute decompensated HF.MethodsWe investigated liver function tests from all 234 patients from the Relaxin for the Treatment of Patients With Acute Heart Failure study at baseline and during hospitalization. The end points were worsening HF through day 5, 60-day mortality or rehospitalization, and 180-day mortality.ResultsMean age was 70 ± 10 years, 56% were male, and most patients were in New York Heart Association functional class III/IV (73%). Abnormal liver function tests were frequently found for alanine transaminase (ALT; 12%), aspartate transaminase (AST; 21%), alkaline phosphatase (12%), and total bilirubin (19%), and serum albumin (25%) and total protein (9%) were decreased. In-hospital changes were very small. On a continuous scale, baseline ALT and AST were associated with 180-day mortality (hazard ratios [HRs; per doubling] 1.52 [P = .030] and 1.97 [P = .013], respectively) and worsening HF through day 5 (HRs [per doubling] 1.72 [P = .005] and 1.95 [P = .008], respectively). Albumin was associated with 180-day mortality (HR 0.86; P = .001) but not with worsening HF (HR 0.95; P = .248). Total protein was associated with only worsening HF (HR 0.91; P = .004).ConclusionsAbnormal liver function tests are often present in patients with acute HF and are associated with an increased risk for mortality, rehospitalization, and in-hospital worsening HF.     

Managing Beta-blockers in Acute Heart Failure: When to Start and When to Stop?

The role of β-blockers in heart failure has been long debated. Data from chronic heart failure studies clearly indicate that β-blockers save lives. However, data concerning use of β-blockers in patients with acute heart failure are limited, and only recently have emerged to help guide therapy. In this review, we provide an overview of when to stop and when to start β-blockers in patients with acute heart failure.     

Galectin-3: A Link between Myocardial and Arterial Stiffening in Patients with Acute Decompensated Heart Failure?

Background

Heart failure is accompanied by abnormalities in ventricular-vascular interaction due to increased myocardial and arterial stiffness. Galectin-3 is a recently discovered biomarker that plays an important role in myocardial and vascular fibrosis and heart failure progression.

Objectives

The aim of this study was to determine whether galectin-3 is correlated with arterial stiffening markers and impaired ventricular-arterial coupling in decompensated heart failure patients.

Methods

A total of 79 inpatients with acute decompensated heart failure were evaluated. Serum galectin-3 was determined at baseline, and during admission, transthoracic echocardiography and measurements of vascular indices by Doppler ultrasonography were performed.

Results

Elevated pulse wave velocity and low arterial carotid distensibility are associated with heart failure in patients with preserved ejection fraction (p = 0.04, p = 0.009). Pulse wave velocity, carotid distensibility and Young’s modulus did not correlate with serum galectin-3 levels. Conversely, raised galectin-3 levels correlated with an increased ventricular-arterial coupling ratio (Ea/Elv) p = 0.047, OR = 1.9, 95% CI (1.0‑3.6). Increased galectin-3 levels were associated with lower rates of left ventricular pressure rise in early systole (dp/dt) (p=0.018) and raised pulmonary artery pressure (p = 0.046). High galectin-3 levels (p = 0.038, HR = 3.07) and arterial pulmonary pressure (p = 0.007, HR = 1.06) were found to be independent risk factors for all-cause mortality and readmissions.

Conclusions

This study showed no significant correlation between serum galectin-3 levels and arterial stiffening markers. Instead, high galectin-3 levels predicted impaired ventricular-arterial coupling. Galectin-3 may be predictive of raised pulmonary artery pressures. Elevated galectin-3 levels correlate with severe systolic dysfunction and together with pulmonary hypertension are independent markers of outcome.     

Health Literacy and the Patient With Heart Failure—Implications for Patient Care and Research: A Consensus Statement of the Heart Failure Society of America

BackgroundLow health literacy compromises patient safety, quality health care, and desired health outcomes. Specifically, low health literacy is associated with decreased knowledge of one's medical condition, poor medication recall, nonadherence to treatment plans, poor self-care behaviors, compromised physical and mental health, greater risk of hospitalization, and increased mortality.MethodsThe health literacy literature was reviewed for: definitions, scope, risk factors, assessment, impact on health outcomes (cardiovascular disease and heart failure), and interventions. Implications for future research and for clinical practice to address health literacy in heart failure patients were summarized.ResultsGeneral health literacy principles should be applied to patients with heart failure, similar to others with chronic conditions. Clinicians treating patients with heart failure should address health literacy using five steps: recognize the consequences of low health literacy, screen patients at risk, document literacy levels and learning preferences, and integrate effective strategies to enhance patients' understanding into practice.ConclusionAlthough the literature specifically addressing low health literacy in patients with heart failure is limited, it is consistent with the larger body of health literacy evidence. Timely recognition of low health literacy combined with tailored interventions should be integrated into clinical practice.     

Genetic Evaluation of Cardiomyopathy—A Heart Failure Society of America Practice Guideline

This guideline describes the approach and expertise needed for the genetic evaluation of cardiomyopathy. First published in 2009 by the Heart Failure Society of America (HFSA), the guideline has now been updated in collaboration with the American College of Medical Genetics and Genomics (ACMG). The writing group, composed of cardiologists and genetics professionals with expertise in adult and pediatric cardiomyopathy, reflects the emergence and increased clinical activity devoted to cardiovascular genetic medicine. The genetic evaluation of cardiomyopathy is a rapidly emerging key clinical priority, because high-throughput sequencing is now feasible for clinical testing and conventional interventions can improve survival, reduce morbidity, and enhance quality of life. Moreover, specific interventions may be guided by genetic analysis. A systematic approach is recommended: always a comprehensive family history; an expert phenotypic evaluation of the proband and at-risk family members to confirm a diagnosis and guide genetic test selection and interpretation; referral to expert centers as needed; genetic testing, with pre- and post-test genetic counseling; and specific guidance as indicated for drug and device therapies. The evaluation of infants and children demands special expertise. The approach to managing secondary and incidental sequence findings as recommended by the ACMG is provided.     

High Molecular Weight Calmodulin-Binding Protein: 20?Years Onwards—A Potential Therapeutic Calpain Inhibitor

Apoptosis in cardiovascular diseases is considered to be a major reason for heart failure. Caspase-independent apoptosis due to calpains and other proteases occurs due to increase in intracellular Ca(2+) levels which act on a feed-forward mechanism. Calpains are Ca(2+)-activated cysteine proteases present in the cytosol as inactive proenzymes. Calpastatin is most efficient and specific calpain inhibitor present in vivo. Earlier, we had reported the expression of novel high molecular weight calmodulin-binding protein (HMWCaMBP) in human and animal cardiac tissue and in very minute quantities in brains and lungs. HMWCaMBP showed calpastatin activity and was also found to be highly homologous to calpastatin I and calpastatin II. Decreased expression of HMWCaMBP was observed during ischemia as it is susceptible to proteolysis by calpains during ischemia-reperfusion. In normal myocardium, HMWCaMBP may protect its substrate from calpains. However, during an early stage of ischemia/reperfusion due to increased Ca(2+) influx, calpain activity often exceeds HMWCaMBP activity. This leads to proteolysis of HMWCaMBP and other protein substrates, resulting in cellular damage. The role of HMWCaMBP in ischemia/reperfusion is yet to be elucidated. The present review summarizes the developments in area of HMWCaMBP from the authors' laboratory and its potential for therapy.     

National Trends and Outcomes in Dialysis-Requiring Acute Kidney Injury in Heart Failure: 2002–2013

Background

Dialysis-requiring acute kidney injury (D-AKI) is a serious complication in hospitalized heart failure (HF) patients. However, data on national trends are lacking after 2002.

Proenkephalin,Renal Dysfunction,and Prognosis in Patients With Acute Heart Failure: A GREAT Network Study

Background

Proenkephalin A (PENK) and its receptors are widely distributed. Enkephalins are cardiodepressive and difficult to measure directly. PENK is a stable surrogate analyte of labile enkephalins that is correlated inversely with renal function. Cardiorenal syndrome is common in acute heart failure (HF) and portends poor prognosis.

Dual Vasopressin V1a/V2 Antagonism: The Next Step in Neurohormonal Modulation in Patients With Heart Failure?

Stimulation of the V1a receptor for arginine vasopressin produces myocardial and vascular effects similar to those of angiotensin II while stimulation of the V2 receptor causes fluid retention. There are no data with sustained blockade of the V1a receptor while single-dose experiments suggest benefit. Acute and chronic administration of selective V2 receptor antagonists reliably relieves dyspnea and produces diuresis without adverse effects on renal function or neurohormonal stimulation, either as adjunctive or alternative therapy to loop diuretics, but has not been shown to improve outcomes as adjunctive therapy. Combined antagonism has been tried only in single-dose studies in stable patients or over the short-term in acute heart failure, with encouraging results. Based on the both the pathophysiologic rationale for additional neurohormonal blockade and these results, chronically blocking both receptors, particularly in more congested patients, may offer significant benefit either as adjunctive or alternative therapy to standard diuretics.