Vanessa van Empel

Downregulation of Apoptosis-Inducing Factor in Harlequin Mutant Mice Sensitizes the Myocardium to Oxidative Stress-Related Cell Death and Pressure Overload-Induced Decompensation

Apoptosis-inducing factor (AIF), or programmed cell death 8 (Pdcd8), is a highly conserved, ubiquitous flavoprotein localized in the mitochondrial intermembrane space. In vivo, AIF provides protection against neuronal apoptosis induced by oxidative stress. Conversely, in vitro, AIF has been demonstrated to have a proapoptotic role when, on induction of the mitochondrial death pathway, AIF translocates to the nucleus where it facilitates chromatin condensation and large scale DNA fragmentation. To determine the role of AIF in myocardial apoptotic processes, we examined cardiomyocytes from an AIF-deficient mouse mutant, Harlequin (Hq). Hq mutant cardiomyocytes demonstrated increased sensitivity to H2O2-induced cell death. Further, Hq hearts subjected to ischemia/reperfusion revealed more cardiac damage and, unlike wild-type mice, the amount of damage increased with the age of the animal. Aortic banding caused enhanced hypertrophy, increased cardiomyocyte apoptotic and necrotic cell death, and accelerated progression toward maladaptive left ventricular remodeling in Hq mutant mice compared with wild-type counterparts. These findings correlated with a reduced capacity of subsarcolemmal mitochondria from Hq mutant hearts to scavenge free radicals. Together, these data demonstrate a critical role for AIF as a cardiac antioxidant in the protection against oxidative stress–induced cell death and development of heart failure induced by pressure overload.

Circulating biomarkers of distinct pathophysiological pathways in heart failure with preserved vs. reduced left ventricular ejection fraction

The aim of this study was to evaluate whether biomarkers reflecting pathophysiological pathways are different between heart failure with preserved (HFpEF) and reduced ejection fraction (HFrEF) and whether the prognostic value of biomarkers is different in HFpEF vs. HFrEF.

Circulating miRNAs: reflecting or affecting cardiovascular disease?

MicroRNAs are a class of small, noncoding RNAs encoded by the metazoan genome that regulate protein expression. A collection of studies point to vital roles for microRNAs in the onset and development of cardiovascular diseases. So far, microRNAs have been considered as important intracellular mediators in maintaining proper cardiac function and hemostasis, and have been proposed as potential therapeutic targets in cardiovascular disease. The recent discovery that microRNAs circulate in a stable form in many body fluids, including blood, suggests that circulating microRNAs can serve as a new generation of biomarkers for cardiovascular diseases. In this review, we summarize the findings of studies focusing on circulating microRNAs present in human blood cells or plasma/serum, where they potentially could serve as diagnostic or prognostic markers for a variety of cardiovascular pathologies, including acute myocardial infarction, heart failure, coronary artery disease, stroke, diabetes and hypertension. The significance and limitations of microRNAs as the new biomarker generation for cardiovascular disease are also discussed.MicroRNAs are a class of small, noncoding RNAs encoded by the metazoan genome that regulate protein expression. A collection of studies point to vital roles for microRNAs in the onset and development of cardiovascular diseases. So far, microRNAs have been considered as important intracellular mediators in maintaining proper cardiac function and hemostasis, and have been proposed as potential therapeutic targets in cardiovascular disease. The recent discovery that microRNAs circulate in a stable form in many body fluids, including blood, suggests that circulating microRNAs can serve as a new generation of biomarkers for cardiovascular diseases. In this review, we summarize the findings of studies focusing on circulating microRNAs present in human blood cells or plasma/serum, where they potentially could serve as diagnostic or prognostic markers for a variety of cardiovascular pathologies, including acute myocardial infarction, heart failure, coronary artery disease, stroke, diabetes and hypertension. The significance and limitations of microRNAs as the new biomarker generation for cardiovascular disease are also discussed.

Impaired myocardial oxygen availability contributes to abnormal exercise hemodynamics in heart failure with preserved ejection fraction

Background Hypertension is a frequent risk factor for the development of heart failure with preserved ejection fraction (HFPEF). Progressive extracellular matrix accumulation has been presumed to be the fundamental pathophysiologic mechanism that leads to the transition to impaired diastolic reserve. However, the contribution of other mechanisms affecting active and passive components of diastolic function has not been comprehensively assessed. In this study, we investigated the potential role of impaired myocardial oxygen delivery in the pathophysiology of HFPEF. Methods and Results Patients with HFPEF, those with controlled hypertension, and healthy controls underwent simultaneous right‐heart catheterization, echocardiography, and paired arterial and coronary sinus blood gas sampling at rest and during supine‐cycle ergometry. Despite a lower workload (HFPEF vs control, hypertension: 43±8 versus 114±12, 87±14 W; P<0.001 and P<0.05, respectively), peak exercise pulmonary capillary wedge pressure was markedly higher in HFPEF patients compared with healthy and hypertensive controls (32±2 versus 16±1 and 17±1 mm Hg, both P<0.001). During exercise, the transcardiac oxygen gradient increased significantly in all groups; however, the peak transcardiac oxygen gradient was significantly lower in HFPEF patients (P<0.05). In addition, the left ventricular–work corrected transcardiac oxygen gradient remained significantly lower in HFPEF patients compared with controls (P<0.001). Conclusion The current study provides unique data suggesting that the abnormal diastolic reserve observed during exertion in HFPEF patients may, in part, be explained by impaired myocardial oxygen delivery due possibly to microvascular dysfunction. Further studies are required to confirm the structural and functional basis of these findings and to investigate the influence of potential therapies on this abnormality.

Iron deficiency in patients with idiopathic pulmonary arterial hypertension

BACKGROUND Iron deficiency has been reported to be highly prevalent in idiopathic pulmonary arterial hypertension (iPAH) patients, with the potential to influence cardiac performance, pulmonary artery pressures and the pulmonary vascular response to hypoxia. METHODS Iron status was evaluated in 29 iPAH patients, and was related to haemodynamic, echocardiographic and exercise parameters. RESULTS Iron deficiency was present in 44.8% of all iPAH patients, although anaemia was only present in 13.8%. Iron-deficient patients had similar exercise capacity (6MWD: 446±141 m), compared to iron-sufficient patients (421±193 m), however 46.2% of iron deficient patients had NYHA FC 3 or higher, compared to 12.5% in non-iron deficient group. Additionally iron-deficient patients showed increased mean pulmonary arterial pressure (63.3±12.2 mmHg; iron deficient vs. 38.8±16.7 mmHg; non-iron deficient) and reduced cardiac index (1.3±0.2 L/min/m(2); iron deficient vs. 2.5±0.4 L/min/m(2); non-iron deficient). CONCLUSIONS Iron deficiency is highly prevalent in iPAH, and the extent of iron deficiency is related to haemodynamics and NYHA functional class. While the exact mechanism of iron deficiency is unknown, our study suggests that treatment of iron deficiency should be considered in iPAH patients.

Inflammation in HFpEF: Key or circumstantial?

Heart failure (HF) can be split into HF with reduced ejection fraction (HFrEF) and HF with preserved ejection fraction (HFpEF). Currently the pathophysiologic mechanisms involved in HFpEF remain largely unknown. The neurohumoral and sympathetic nervous systems seem not to play a crucial role in HFpEF, as treatments targeting these pathways do not show beneficial effects in HFpEF patients, in contrast to HFrEF patients. A better understanding of the pathophysiological processes involved in HFpEF is needed, as there is no proven treatment for this disease at the moment. Recent data have yielded growing attention to the role of inflammation in HFpEF. In this review we discuss increased inflammation in HFpEF as demonstrated in translational animal models and human studies. This review evaluates whether inflammation plays a key role in HFpEF or is just a by-product of various comorbidities. Additionally, we analyze the involvement of oxidative stress and endothelial dysfunction and lastly we outline potential therapeutic targets.

Adaptive capacity of the right ventricle: why does it fail?

Only in recent years has the right ventricle (RV) function become appreciated to be equally important to the left ventricle (LV) function to maintain cardiac output. Right ventricular failure is, irrespectively of the etiology, associated with impaired exercise tolerance and poor survival. Since the anatomy and physiology of the RV is distinctly different than that of the LV, its adaptive mechanisms and the pathways involved are different as well. RV hypertrophy is an important mechanism of the RV to preserve cardiac output. This review summarizes the current knowledge on the right ventricle and its response to pathologic situations. We will focus on the adaptive capacity of the right ventricle and the molecular pathways involved, and we will discuss potential therapeutic interventions.

Integration of exercise evaluation into the algorithm for evaluation of patients with suspected heart failure with preserved ejection fraction

Approximately half of all patients with heart failure (HF) have a preserved left ventricular ejection fraction (HFPEF) and the prevalence of this form of HF is increasing. Although dyspnoea on exertion and diminished functional capacity is the key symptom of patients with HFPEF, current diagnostic criteria focus on resting indices of ventricular function. Specifically, current proposed criteria for the diagnosis of HFPEF, include clinical signs of HF; normal left ventricular systolic function; and evidence of abnormal diastolic performance and/or altered natriuretic peptides. By contrast, recent studies demonstrate that the key pathophysiologic features of HFPEF may not be evident at rest, and can only be detected during exertion. This review addresses the potential role of exercise testing using invasive haemodynamic or echocardiographic assessment in patients with suspected HFPEF in which current diagnostic criteria are not met.

Interaction between pulmonary hypertension and diastolic dysfunction in an elderly heart failure population.

BACKGROUND Pulmonary hypertension due to left heart disease is very common. Our aim was to investigate the relationship of the severity of left ventricular diastolic dysfunction with precapillary and postcapillary pulmonary hypertension (PH) in an elderly heart failure (HF) population. METHODS AND RESULTS A post hoc analysis of the Trial of Intensified Medical Therapy in Elderly Patients With Congestive Heart Failure data was done. Baseline transthoracic echocardiography was used to categorize diastolic function, estimate pulmonary artery pressure and pulmonary capillary wedge pressure, and calculate the transpulmonary pressure gradient (TPG). Among 392 HF patients, PH was present in 31% of patients with grade 1, in 37% of patients with grade 2, and in 65% of patients with grade 3 diastolic dysfunction; 54% of all HF patients with PH had a TPG >12 mm Hg, suggesting not only a postcapillary but also an additional precapillary component of PH. Survival was not related to the severity of diastolic dysfunction, but was worse in patients with PH (hazard ratio 1.63, 95% confidence interval 1.07-2.51; P = .024). CONCLUSIONS Our data indicate that HF patients with even mild diastolic dysfunction often have PH. Echocardiographic assessment suggest that the presence of PH might not simply be due to increased PCWP, but in part due to a precapillary component.

Determinants and implications of elevated soluble ST2 levels in heart failure

To the Editor:Recently several new putative cardiac biomarkers detectable inthe peripheral circulation have been described, including moleculessuch as soluble ST2 and galectin-3 [1]. The ST2 gene encodes theIL1RL-1 receptor which is expressed in many tissues and cell types,andpreferentiallybindsinterleukin-33(IL33).InthecontextofHF,pre-vious studies showed that sST2 could be released by cardiomyocytesandcardiacfibroblastsundermechanicalstrain[2].Subsequentlysever-al studies of plasma sST2 have been performed in HF patients, yieldingvariable results although it has recently been proposed that plasmasST2 measurement [3,4] provided prognostic and mechanistic insightsinto HF patients. Presently it remains uncertain as to the source ofplasma sST2 in HF. The aim of the present study was to determinewhether the failing human heart releases sST2.We performed right heart catheterization, with arterial andcoronary sinus blood sampling in 20 patients with advanced HF withreduced left ventricular ejection fraction undergoing evaluation forpotential heart transplantation and 10 healthy volunteers recruitedfrom the general community. All patients and healthy volunteers gavewritten informed consent and the study was conducted with theapproval of the Alfred Hospital Research and Ethics Committee whichacts in concordance with the guiding principles of the National HealthandMedicalResearchCouncilofAustralia.HFwasnon-ischemicdilatedcardiomyopathy in 55% of patients. Eighty eight percent of patientswere NYHA class III and the remaining 12% NYHA class IV. Plasmaconcentrations of sST2 were measured by a commercially availableELISA (Quantikine) and NT-BNP was measured using an automatedanalyzer (Roche Elecys proBNP).As expected HF patients were characterized by significant hemody-namic compromise including reduced LVEF (23 ± 2%), cardiac index(1.9 ± 0.2 L/min/m