Unraveling the Genotype-Phenotype Relationship in Hypertrophic Cardiomyopathy:Obesity-Related Cardiac Defects as a Major Disease Modifier

Hypertrophic cardiomyopathy (HCM) is the most common inherited cardiomyopathy and is characterized by asymmetric septal thickening and diastolic dysfunction. More than 1500 mutations in genes encoding sarcomere proteins are associated with HCM. However, the genotype-phenotype relationship in HCM is incompletely understood and involves modification by additional disease hits. Recent cohort studies identify obesity as a major adverse modifier of disease penetrance, severity, and clinical course. In this review, we provide an overview of these clinical findings. Moreover, we explore putative mechanisms underlying obesity-induced sensitization and aggravation of the HCM phenotype. We hypothesize obesity-related stressors to impact on cardiomyocyte structure, metabolism, and homeostasis. These may impair cardiac function by directly acting on the primary mutation-induced myofilament defects and by independently adding to the total cardiac disease burden. Last, we address important clinical and pharmacological implications of the involvement of obesity in HCM disease modification.</p

Early detection of obstructive coronary artery disease in the asymptomatic high-risk population:objectives and study design of the EARLY-SYNERGY trial

Background: Coronary artery disease (CAD) burden for society is expected to steeply increase over the next decade. Improved feasibility and efficiency of preventive strategies is necessary to flatten the curve. Acute myocardial infarction (AMI) is the main determinant of CAD-related mortality and morbidity, and predominantly occurs in individuals with more advanced stages of CAD causing subclinical myocardial ischemia (obstructive CAD; OCAD). Unfortunately, OCAD can remain subclinical until its destructive presentation with AMI or sudden death. Current primary preventive strategies are not designed to differentiate between non-OCAD and OCAD and the opportunity is missed to treat individuals with OCAD more aggressively. Methods: EARLY-SYNERGY is a multicenter, randomized-controlled clinical trial in individuals with coronary artery calcium (CAC) presence to study (1.) the yield of cardiac magnetic resonance stress myocardial perfusion imaging (CMR-MPI) for early OCAD diagnosis and (2) whether early OCAD diagnosis improves outcomes. Individuals with CAC score ≥300 objectified in 2 population-based trials (ROBINSCA; ImaLife) are recruited for study participation. Eligible candidates are randomized 1:1 to cardiac magnetic resonance stress myocardial perfusion imaging (CMR-MPI) or no additional functional imaging. In the CMR-MPI arm, feedback on imaging results is provided to primary care provider and participant in case of guideline-based actionable findings. Participants are followed-up for clinical events, healthcare utilization and quality of life. Conclusions: EARLY-SYNERGY is the first randomized-controlled clinical trial designed to test the hypothesis that subclinical OCAD is widely present in the general at-risk population and that early differentiation of OCAD from non-OCAD followed by guideline-recommended treatment improves outcomes

Erythropoietin levels in heart failure after an acute myocardial infarction: Determinants, prognostic value, and the effects of captopril versus losartan

Background In patients with chronic heart failure, erythropoietin (Epo) levels are increased and related to a poor prognosis. Furthermore, Epo levels in these patients show a weak correlation with hemoglobin levels. Methods This is a retrospective analysis of a subgroup of the OPTIMAAL (Optimal Trial in Myocardial Infarction with the Angiotensin II Antagonist Losartan) trial in which serum Epo levels were measured at baseline, at 1 month, and at 1 and 2 years in 224 patients with an acute myocardial infarction complicated by signs or symptoms of heart failure. We investigated the determinants and the prognostic role of elevated Epo levels in these patients, and we studied the change in Epo levels by either captopril or losartan. Results The correlation between Epo and hemoglobin at baseline (r* = 0.348, P <.001) and after 1 month (r = 0.272, P <.001) disappeared after 1 year of follow up (r = 0.129, P = .102). At 1 year, C-reactive protein was the only factor associated with Epo levels. Higher Epo levels at baseline were independently related to a higher mortality during 2 years of follow-up (hazard ratio 2.84, P = .014). In the captopril group, IogEpo levels decreased from 1.19 (+/- 0.26) to 0.95 (+/- 0.20) mIU/mL, and in the losartan group. from 1.19 (+/- 0.27) to 1.01 (+/- 0.17) mIU/mL (P = .036 between groups). Conclusion In this substudy of the OPTIMAAL trial, the correlation between Epo and hemoglobin disappeared in early post-acute myocardial infarction heart failure patients. Furthermore, elevated Epo levels at baseline predicted increased mortality. (Am Heart J 2009;157:91-6.

Tubular damage in chronic systolic heart failure is associated with reduced survival independent of glomerular filtration rate

Background The prognostic impact of reduced glomerular filtration rate (GFR) in chronic heart failure (CHF) is increasingly recognised, but little is known about tubular damage in these patients. Objective To investigate the prevalence of tubular damage, and its association with GFR, and prognosis in patients with CHF. Methods and results In 90 patients with CHF, GFR and effective renal plasma flow (ERPF) were measured ([(125)I] iothalamate and [(131)I] hippuran clearances). The tubular markers neutrophil gelatinase-associated lipocalin (NGAL), N-acetyl-beta-D-glucosaminidase (NAG) and kidney injury molecule 1 (KIM-1) as well as urinary albumin excretion were determined in 24 h urine collections. Mean GFR was 78 +/- 26 ml/min/1.73 m(2). Urinary NGAL (175 (70-346) mu g/g creatinine (gCr)), NAG (12 (6-17) U/gCr) and KIM-1 (277 (188-537) ng/gCr) levels were increased compared with 20 healthy controls (all p Conclusion Tubular damage, as indicated by increased urinary concentrations of NGAL, NAG and KIM-1 is common in patients with CHF and mildly reduced GFR. Both urinary KIM-1 and NAG showed prognostic information additional to GFR. These findings suggest an important role for tubular damage and tubular markers in cardiorenal interaction in heart failure

Differential associations between renal function and "modifiable" risk factors in patients with chronic heart failure

Reduced glomerular filtration rate (GFR) is strongly associated with reduced survival in patients with chronic heart failure (CHF). Our aim was to determine different pathophysiologic markers that are associated with reduced renal function in CHF. We studied 86 patients with CHF (58 +/- A 12 years, 78% male). GFR and renal blood flow (RBF) were determined by (125)I-Iothalamate and (131)I-Hippuran clearances. Filtration fraction (FF) was calculated. We determined haemoglobin levels, endothelial function, inflammatory status, plasma renin activity (PRA) and N-terminal pro brain natriuretic peptide (NT-proBNP). Urinay albumin excretion (UAE) was measured in 24 h urine. Mean GFR was 74 +/- A 28 ml/min/1.73 m(2). GFR was strongly related to RBF (r = 0.915, P <0.001), FF (r = 0.546, P <0.001), but only weakly to endothelial function and PRA. In multivariate analysis, RBF (r = 0.938, P <0.001), FF (r = 0.786, P <0.001) and haemoglobin levels (r = -0.520, P <0.001) were independently associated with GFR. UAE was mainly dependent on RBF (r = -0.401, P <0.001) and increased exponentially with decreasing RBF. RBF was mainly associated with NT-proBNP (r = -0.561, P <0.001) and PRA (r = -0.422, P <0.001). Reduced GFR is mainly dependent of decreased RBF in patients with CHF. Endothelial function and neurohormonal activation showed only mild associations with GFR. NT-proBNP showed a strong relationship with RBF, and may be used as a marker of reduced renal perfusion

Anaemia in chronic heart failure is not only related to impaired renal perfusion and blunted erythropoietin production, but to fluid retention as well

Aims Anaemia is prevalent in the chronic heart failure (CHF) population, but its cause is often unknown. The present study aims to investigate the relation between anaemia, renal perfusion, erythropoietin production, and fluid retention in CHF patients. Methods and results We studied 97 patients with CHF, of which 15 had anaemia (Hb <13.0 g/dL in men and Hb <12.0 g/dL in women), without haematinic deficiencies. Glomerular filtration rate (GFR) and extracellular volume (ECV) were measured as the clearance and the distribution volume of constantly infused (125)I-iothalamate, respectively. Effective renal plasma flow (ERPF) was determined as the clearance of (131)I-hippuran. Anaemic CHF patients displayed significantly reduced GFR (P = 0.002), ERPF (P = 0.005) and EPO production (P = 0.001), and an elevated ECV (P = 0.015). Multivariable analysis demonstrated that lower GFR (P = 0.003), lower ERPF (P = 0.004), lower EPO production (P = 0.006), and a higher ECV (P = 0.001) were significant independent predictors of lower haemoglobin levels. Conclusion Anaemia in CHF is not only independently associated with impaired renal perfusion and blunted EPO production, but to fluid retention as well

Mitochondrial Reprogramming Induced by CaMKII delta Mediates Hypertrophy Decompensation

Rationale: Sustained activation of Gq transgenic (Gq) signaling during pressure overload causes cardiac hypertrophy that ultimately progresses to dilated cardiomyopathy. The molecular events that drive hypertrophy decompensation are incompletely understood. Ca2+/calmodulin-dependent protein kinase II (CaMKII) is activated downstream of Gq, and overexpression of Gq and CaMKII recapitulates hypertrophy decompensation. Objective: To determine whether CaMKII contributes to hypertrophy decompensation provoked by Gq. Methods and Results: Compared with Gq mice, compound Gq/CaMKII knockout mice developed a similar degree of cardiac hypertrophy but exhibited significantly improved left ventricular function, less cardiac fibrosis and cardiomyocyte apoptosis, and fewer ventricular arrhythmias. Markers of oxidative stress were elevated in mitochondria from Gq versus wild-type mice and respiratory rates were lower; these changes in mitochondrial function were restored by CaMKII deletion. Gq-mediated increases in mitochondrial oxidative stress, compromised membrane potential, and cell death were recapitulated in neonatal rat ventricular myocytes infected with constitutively active Gq and attenuated by CaMKII inhibition. Deep RNA sequencing revealed altered expression of 41 mitochondrial genes in Gq hearts, with normalization of approximate to 40% of these genes by CaMKII deletion. Uncoupling protein 3 was markedly downregulated in Gq or by Gq expression in neonatal rat ventricular myocytes and reversed by CaMKII deletion or inhibition, as was peroxisome proliferator-activated receptor . The protective effects of CaMKII inhibition on reactive oxygen species generation and cell death were abrogated by knock down of uncoupling protein 3. Conversely, restoration of uncoupling protein 3 expression attenuated reactive oxygen species generation and cell death induced by CaMKII. Our in vivo studies further demonstrated that pressure overload induced decreases in peroxisome proliferator-activated receptor and uncoupling protein 3, increases in mitochondrial protein oxidation, and hypertrophy decompensation, which were attenuated by CaMKII deletion. Conclusions: Mitochondrial gene reprogramming induced by CaMKII emerges as an important mechanism contributing to mitotoxicity in decompensating hypertrophy