Objectives This study sought to determine the frequency and magnitude of impaired systolic deformation in heart failure with preserved ejection fraction (HFpEF). Background Although diastolic ...dysfunction is widely considered a key pathophysiologic mediator of HFpEF, the prevalence of concomitant systolic dysfunction has not been clearly defined. Methods We assessed myocardial systolic and diastolic function in 219 HFpEF patients from a contemporary HFpEF clinical trial. Myocardial deformation was assessed using a vendor-independent 2-dimensional speckle-tracking software. The frequency and severity of impaired deformation was assessed in HFpEF, and compared to 50 normal controls free of cardiovascular disease and to 44 age- and sex-matched hypertensive patients with diastolic dysfunction (hypertensive heart disease) but no HF. Among HFpEF patients, clinical, echocardiographic, and biomarker correlates of left ventricular strain were determined. Results The HFpEF patients had preserved left ventricular ejection fraction and evidence of diastolic dysfunction. Compared to both normal controls and hypertensive heart disease patients, the HFpEF patients demonstrated significantly lower longitudinal strain (LS) (−20.0 ± 2.1 and −17.07 ± 2.04 vs. −14.6 ± 3.3, respectively, p < 0.0001 for both) and circumferential strain (CS) (−27.1 ± 3.1 and −30.1 ± 3.5 vs. −22.9 ± 5.9, respectively; p < 0.0001 for both). In HFpEF, both LS and CS were related to LVEF (LS, R = −0.46; p < 0.0001; CS, R = −0.51; p < 0.0001) but not to standard echocardiographic measures of diastolic function (E' or E/E'). Lower LS was modestly associated with higher NT-proBNP, even after adjustment for 10 baseline covariates including LVEF, measures of diastolic function, and LV filling pressure (multivariable adjusted p = 0.001). Conclusions Strain imaging detects impaired systolic function despite preserved global LVEF in HFpEF that may contribute to the pathophysiology of the HFpEF syndrome. (LCZ696 Compared to Valsartan in Patients With Chronic Heart Failure and Preserved Left-ventricular Ejection Fraction; NCT00887588 )
Objectives This study sought to explore whether subclinical alterations of sarcoplasmic reticulum (SR) Ca2+ release through cardiac ryanodine receptors (RyR2) aggravate cardiac remodeling in mice ...carrying a human RyR2R4496C+/– gain-of-function mutation in response to pressure overload. Background RyR2 dysfunction causes increased diastolic SR Ca2+ release associated with arrhythmias and contractile dysfunction in inherited and acquired cardiac diseases, such as catecholaminergic polymorphic ventricular tachycardia and heart failure (HF). Methods Functional and structural properties of wild-type and catecholaminergic polymorphic ventricular tachycardia–associated RyR2R4496C+/– hearts were characterized under conditions of pressure overload induced by transverse aortic constriction (TAC). Results Wild-type and RyR2R4496C+/– hearts had comparable structural and functional properties at baseline. After TAC, RyR2R4496C+/– hearts responded with eccentric hypertrophy, substantial fibrosis, ventricular dilation, and reduced fractional shortening, ultimately resulting in overt HF. RyR2R4496C+/– -TAC cardiomyocytes showed increased incidence of spontaneous SR Ca2+ release events, reduced Ca2+ transient peak amplitude, and SR Ca2+ content as well as reduced SR Ca2+ -ATPase 2a and increased Na+ /Ca2+ -exchanger protein expression. HF phenotype in RyR2R4496C+/– -TAC mice was associated with increased mortality due to pump failure but not tachyarrhythmic events. RyR2-stabilizer K201 markedly reduced Ca2+ spark frequency in RyR2R4496C+/– -TAC cardiomyocytes. Mini-osmotic pump infusion of K201 prevented deleterious remodeling and improved survival in RyR2R4496C+/– -TAC mice. Conclusions The combination of subclinical congenital alteration of SR Ca2+ release and pressure overload promoted eccentric remodeling and HF death in RyR2R4496C+/– mice, and pharmacological RyR2 stabilization prevented this deleterious interaction. These findings suggest potential clinical relevance for patients with acquired or inherited gain-of-function of RyR2-mediated SR Ca2+ release.
Abstract Background Asymmetric dimethylarginine (ADMA), symmetric dimethylarginine (SDMA), and homoarginine are considered to modulate nitric oxide synthesis. We evaluated whether ADMA, SDMA, and ...homoarginine are associated with diastolic dysfunction. Methods and Results We investigated primary care patients at cardiovascular risk with preserved left ventricular ejection fraction from the multicenter DIAST-CHF study. We measured serum concentrations of ADMA, SDMA, and homoarginine and performed standardized echocardiographic examinations. Among 1,396 patients (mean age 65.3 ± 8.3 y, 54.6% women), diastolic dysfunction was ruled out in 261 patients (18.7%). Mild and moderate/severe grades of diastolic dysfunction were present in 900 (64.5%) and 235 (16.8%) study participants, respectively. After adjustments for cardiovascular risk factors, ADMA and SDMA were positively and homoarginine negatively associated with N-terminal pro–B-type natriuretic peptide and midregional pro-adrenomedullin ( P < .05 for all). Lower homoarginine levels were associated with diastolic dysfunction, and higher ADMA and SDMA levels were associated with the severity of diastolic dysfunction ( P < .05 for all). Conclusions Higher levels of ADMA and SDMA and lower levels of homoarginine are associated with an adverse cardiovascular risk profile and diastolic dysfunction. Further studies should clarify the potential of these amino acid derivatives for the therapy of cardiovascular diseases.
Recent international phase III clinical trials of novel therapies for hospitalized heart failure (HHF) have failed to improve the unacceptably high postdischarge event rate. These large studies have ...demonstrated notable geographic and site-specific variation in patient profiles and enrollment. Possible contributors to the lack of success in HHF outcome trials include challenges in selecting clinical sites capable of (1) providing adequate numbers of appropriately selected patients and (2) properly executing the study protocol. We propose a “pretrial registry” as a novel tool for improving the efficiency and quality of international HHF trials by focusing on the selection and cultivation of high-quality sites. A pretrial registry may help assess a site’s ability to achieve adequate enrollment of the target patient population, integrate protocol requirements into clinical workflow, and accomplish appropriate follow-up. Although such a process would be associated with additional upfront resource investment, this appropriation may be modest in comparison with the downstream costs associated with maintenance of poorly performing sites, failed clinical trials, and the global health and economic burden of HHF. This review is based on discussions between scientists, clinical trialists, and regulatory representatives regarding methods for improving international HHF trials that took place at the United States Food and Drug Administration on January 12th, 2012.
Benefit of Exercise in Atrial Fibrillation Halle, Martin, MD; Adams, Volker, PhD; Edelmann, Frank, MD ...
Journal of the American College of Cardiology,
03/2016, Letnik:
67, Številka:
10
Journal Article
Peripartum cardiomyopathy (PPCM) is a rare disease of unclear etiology with a frequent poor outcome, despite optimal medical therapy. Recent experimental data implicate a causal role of prolactin. We ...report a patient with PPCM who responded well to treatment with Bromocriptine in addition to standard therapy of heart failure.
Low levels of the amino acid homoarginine and parathyroid hormone (PTH) excess are both independently related to an increased risk of cardiovascular morbidity and mortality. Accumulating evidence ...points to a mutual interplay between homoarginine and PTH. The authors therefore aimed to investigate circulating homoarginine levels in patients with and without primary hyperparathyroidism (PHPT).
The authors performed a cross-sectional analysis of serum homoarginine levels in 59 patients with mild and severe PHPT and in 92 control persons matched for age, sex and estimated glomerular filtration rate.
Median PTH and serum homoarginine concentrations were 99.1 (79.7-120.2) pg/mL and 1.16 (0.95-1.66) µmol/L in patients with PHPT (79.7% female; 42.4% with normocalcemia) as compared with 45.8 (36.4-53.9) pg/mL and 1.62 (1.33-2.04) µmol/L in the control group (P < 0.001 for both), respectively. The authors observed no statistically differences between cases and controls for 25-hydroxyvitamin D 25(OH)D, serum albumin, hemoglobin, waist-to-hip ratio, C-reactive protein and NT-pBNP values. Multivariate analysis of covariance revealed that patients with PHPT had significantly lower homoarginine levels than controls (P < 0.001). This difference remained significant after adjusting for multiple confounders such as 25(OH)D, body mass index, LDL cholesterol, albumin, calcium, hemoglobin, smoking status and current antihypertensive medication. The differences of homoarginine levels persisted even after exclusion of patients with estimated glomerular filtration rate <60 mL/min (P = 0.003) and 25(OH)D levels <30 ng/mL (P = 0.001), respectively.
Patients with PHPT have lower homoarginine levels compared with matched controls irrespective of age, sex, kidney function and 25(OH)D status. Further studies are needed to evaluate whether low homoarginine accounts for higher cardiovascular risk conferred by PTH excess.
Abstract Heart failure (HF) is a major and increasing global public health problem. In Asia, aging populations and recent increases in cardiovascular risk factors have contributed to a particularly ...high burden of HF, with outcomes that are poorer than those in the rest of the world. Representation of Asians in landmark HF trials has been variable. In addition, HF patients from Asia demonstrate clinical differences from patients in other geographic regions. Thus, the generalizability of some clinical trial results to the Asian population remains uncertain. In this article, we review differences in HF phenotype, HF management, and outcomes in patients from East and Southeast Asia. We describe lessons learned in Asia from recent HF registries and clinical trial databases and outline strategies to improve the potential for success in future trials. This review is based on discussions among scientists, clinical trialists, industry representatives, and regulatory representatives at the CardioVascular Clinical Trialist Asia Forum in Singapore on July 4, 2014.
Abstract Mechanisms underlying atrial remodeling toward atrial fibrillation (AF) are incompletely understood. We induced AF in 16 pigs by 6 weeks of rapid atrial pacing (RAP, 600 bpm) using a ...custom-built, telemetrically controlled pacemaker. AF evolution was monitored three times per week telemetrically in unstressed, conscious animals. We established a dose–response relationship between RAP duration and occurrence of sustained AF > 60 minutes. Left atrial (LA) dilatation was present already at 2 weeks of RAP. There was no evidence of left ventricular heart failure after 6 weeks of RAP. As a proof-of-principle, arterial hypertension was induced in 5/16 animals by implanting desoxycorticosterone acetate (DOCA, an aldosterone-analog) subcutaneously to accelerate atrial remodeling. RAP + DOCA resulted in increased AF stability with earlier onset of sustained AF and accelerated anatomical atrial remodeling with more pronounced LA dilatation. This novel porcine model can serve to characterize effects of maladaptive stimuli or protective interventions specifically during early AF.
Abstract Objectives This study evaluated the tolerability and feasibility of titration of 2 distinctly acting beta-blockers (BB) in elderly heart failure patients with preserved (HFpEF) and reduced ...(HFrEF) left ventricular ejection fraction. Background Broad evidence supports the use of BB in HFrEF, whereas the evidence for beta blockade in HFpEF is uncertain. Methods In the CIBIS-ELD (Cardiac Insufficiency Bisoprolol Study in Elderly) trial, patients >65 years of age with HFrEF (n = 626) or HFpEF (n = 250) were randomized to bisoprolol or carvedilol. Both BB were up-titrated to the target or maximum tolerated dose. Follow-up was performed after 12 weeks. HFrEF and HFpEF patients were compared regarding tolerability and clinical effects (heart rate, blood pressure, systolic and diastolic functions, New York Heart Association functional class, 6-minute-walk distance, quality of life, and N-terminal pro–B-type natriuretic peptide). Results For both of the BBs, tolerability and daily dose at 12 weeks were similar. HFpEF patients demonstrated higher rates of dose escalation delays and treatment-related side effects. Similar HR reductions were observed in both groups (HFpEF: 6.6 beats/min; HFrEF: 6.9 beats/min, p = NS), whereas greater improvement in NYHA functional class was observed in HFrEF (HFpEF: 23% vs. HFrEF: 34%, p < 0.001). Mean E/e′ and left atrial volume index did not change in either group, although E/A increased in HFpEF. Conclusions BB tolerability was comparable between HFrEF and HFpEF. Relevant reductions of HR and blood pressure occurred in both groups. However, only HFrEF patients experienced considerable improvements in clinical parameters and left ventricular function. Interestingly, beta-blockade had no effect on established and prognostic markers of diastolic function in either group. Long-term studies using modern diagnostic criteria for HFpEF are urgently needed to establish whether BB therapy exerts significant clinical benefit in HFpEF. (Comparison of Bisoprolol and Carvedilol in Elderly Heart Failure HF Patients: A Randomised, Double-Blind Multicentre Study CIBIS-ELD; ISRCTN34827306 )
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