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Objectives Our aim in this study was to determine whether increased left ventricular mass (LVM) is a risk factor for the development of a reduced left ventricular ejection fraction (LVEF). Background Prior studies have shown that increased LVM is a risk factor for heart failure but not whether it is a risk factor for a low LVEF. Methods As part of the Cardiovascular Health Study, a prospective population-based longitudinal study, we performed echocardiograms upon participant enrollment and again at follow-up of 4.9 ± 0.14 years. In the present analysis, we identified 3,042 participants who had at baseline a normal LVEF and an assessment of LVM (either by electrocardiogram or echocardiogram), and at follow-up a measurable LVEF. The frequency of the development of a qualitatively depressed LVEF on two-dimensional echocardiography, corresponding approximately to an LVEF Results Baseline quartile of echocardiographic LVM indexed to body surface area was associated with development of a depressed LVEF (4.8% in quartile 1, 4.4% in quartile 2, 7.5% in quartile 3, and 14.1% in quartile 4 [p Conclusions Increased LVM as assessed by electrocardiography or echocardiography is an independent risk factor for the development of depressed LVEF.

The progression from concentric left ventricular (LV) hypertrophy to heart failure has not been well defined. Of 159 predominantly hypertensive African-American patients with LV hypertrophy and a normal ejection fraction (EF), 28 (18%) developed a reduced EF after a median follow-up of approximately 4 years. Risk factors for this outcome included a history of coronary artery disease, pulmonary edema seen on a chest x-ray, or a subsequent myocardial infarction.

The importance placed on the physical examination in the assessment of patients with cardiovascular disorders appears to be declining, perhaps in part due to a paucity of data showing its value in the modern era. To determine whether the physical examination provides important prognostic information in patients with chronic heart failure, the authors performed a post-hoc analysis of 2479 participants from the Studies of Left Ventricular Dysfunction (SOLVD) treatment trial. The presence of elevated jugular venous pressure and a third heart sound at baseline were each associated with subsequent heart failure hospitalization, the composite end point of death or heart failure hospitalization, and pump-failure death, independently of many other markers of disease severity. The subgroup of patients with at least one of these two physical examination findings was at increased risk for all-cause mortality. The authors believe that additional studies assessing the prognostic value of the physical examination should be conducted and, if favorable, likely would lead to a renewed interest in the physical examination.

Heart Failure is a progressive clinical syndrome marked by venous congestion and maladaptive neurohormonal activation in the setting of left ventricular dysfunction. More recently, another face of this syndrome is beginning to emerge involving metabolic derangements implicating other organs - adipose tissue, skeletal muscle - and the endocrine systems (leptin, adiponectin, insulin and insulin-like growth factor) regulating their mass and function. The metabolic abnormalities which have been described thus far include: 1. Systemic and myocardial insulin resistance (IR); 2. Mitochondrial dysfunction; 3. Progressive weight loss leading to "cardiac cachexia" in the more advanced stages; and 4. Myocardial energetic failure associated with a down-regulation of fatty acid uptake and oxidation resulting in a rigid shift from fatty acid to glucose as the primary energy source for maintenance of ATP flux in the heart - a preferential switch to a fetal-like gene program regulating cardiac energetics. Despite the important advances to date, our understanding of all the components comprising the metabolic phenotype of human heart failure is certainly incomplete, if not rudimentary. (SELECT FULL TEXT TO CONTINUE)

Background— The occurrence of periprocedural acute hemodynamic decompensation (AHD) in patients undergoing radiofrequency catheter ablation of scar-related ventricular tachycardia (VT) has not been previously investigated. Methods and Results— We identified univariate predictors of periprocedural AHD in 193 consecutive patients undergoing radiofrequency catheter ablation of scar-related VT. AHD was defined as persistent hypotension despite vasopressors and requiring mechanical support or procedure discontinuation. AHD occurred in 22 (11%) patients. Compared with the rest of the population, patients with AHD were older (68.5±10.7 versus 61.6±15.0 years; P =0.037); had a higher prevalence of diabetes mellitus (36% versus 18%; P =0.045), ischemic cardiomyopathy (86% versus 52%; P =0.002), chronic obstructive pulmonary disease (41% versus 13%; P =0.001), and VT storm (77% versus 43%; P =0.002); had more severe heart failure (New York Heart Association class III/IV: 55% versus 15%, P P =0.003); and more often received periprocedural general anesthesia (59% versus 29%; P =0.004). At 21±7 months follow-up, the mortality rate was higher in the AHD group compared with the rest of the population (50% versus 11%, log-rank P Conclusions— AHD occurs in 11% of patients undergoing radiofrequency catheter ablation of scar-related VT and is associated with increased risk of mortality over follow-up. AHD may be predicted by clinical factors, including advanced age, ischemic cardiomyopathy, more severe heart failure status (New York Heart Association class III/IV, lower ejection fraction), associated comorbidities (diabetes mellitus and chronic obstructive pulmonary disease), presentation with VT storm, and use of general anesthesia.

Background The compensatory actions of the endogenous natriuretic peptide system require adequate processing of natriuretic peptide pro‐hormones into biologically active, carboxyl‐terminal fragments. Natriuretic peptide pro‐peptide processing is accomplished by corin, a transmembrane serine protease expressed by cardiomyocytes. Brain natriuretic peptide (BNP) processing is inadequate in advanced heart failure and is independently associated with adverse outcomes; however, the molecular mechanisms causing impaired BNP processing are not understood. We hypothesized that the development of endoplasmic reticulum stress in cardiomyocytes in advanced heart failure triggers inositol‐requiring protein 1 ( IRE 1)‐dependent corin mRNA decay, which would favor a molecular substrate favoring impaired natriuretic peptide pro‐peptide processing. Methods and Results Two independent samples of hearts obtained from patients with advanced heart failure at transplant demonstrated that corin RNA was reduced as Atrial natriuretic peptide (ANP) / BNP RNA increased. Increases in spliced X‐box protein 1, a marker for IRE 1‐endoribonuclease activity, were associated with decreased corin RNA . Moreover, ≈50% of the hearts demonstrated significant reductions in corin RNA and protein as compared to the nonfailing control sample. In vitro experiments demonstrated that induction of endoplasmic reticulum stress in cultured cardiomyocytes with thapsigargin activated IRE 1's endoribonuclease activity and time‐dependent reductions in corin mRNA . In HL ‐1 cells, overexpression of IRE 1 activated IRE 1 endoribonuclease activity and caused corin mRNA decay, whereas IRE 1‐ RNA interference with sh RNA attenuated corin mRNA decay after induction of endoplasmic reticulum stress with thapsigargin. Pre‐treatment of cells with Actinomycin D to inhibit transcription did not alter the magnitude or time course of thapsigargin‐induced corin mRNA decline, supporting the hypothesis that this was the result of IRE 1‐mediated corin mRNA degradation. Conclusions These data support the hypothesis that endoplasmic reticulum stress‐mediated, IRE 1‐dependent targeted corin mRNA decay is a mechanism leading to corin mRNA resulting in corresponding corin protein deficiency may contribute to the pathophysiology of impaired natriuretic peptide pro‐hormone processing in humans processing in humans with advanced systolic heart failure.

Patients on long-term left ventricular assist device (LVAD) support present unique challenges in the intensive care unit. It is crucial to know the status of end-organ perfusion, which may require invasive hemodynamic monitoring with a systemic arterial and pulmonary artery catheter. Depending on the indication for LVAD support (bridge to decision or cardiac transplantation vs destination therapy), it is important to readdress goals of care with the patient (if possible) and their family after major events have occurred that challenge the survival of the patient.

Background— Allogeneic mesenchymal precursor cells (MPCs) injected during left ventricular assist device (LVAD) implantation may contribute to myocardial recovery. This trial explores the safety and efficacy of this strategy. Methods and Results— In this multicenter, double-blind, sham-procedure controlled trial, 30 patients were randomized (2:1) to intramyocardial injection of 25 million MPCs or medium during LVAD implantation. The primary safety end point was incidence of infectious myocarditis, myocardial rupture, neoplasm, hypersensitivity reaction, and immune sensitization (90 days after randomization). Key efficacy end points were functional status and ventricular function while temporarily weaned from LVAD support (90 days after randomization). Patients were followed up until transplant or 12 months after randomization, whichever came first. Mean age was 57.4 (±13.6) years, mean left ventricular ejection fraction was 18.1%, and 66.7% were destination therapy LVADs. No safety events were observed. Successful temporary LVAD weaning was achieved in 50% of MPC and 20% of control patients at 90 days ( P =0.24); the posterior probability that MPCs increased the likelihood of successful weaning was 93%. At 90 days, 3 deaths (30%) occurred in control patients, and none occurred in MPC patients. Mean left ventricular ejection fraction after successful wean was 24.0% (MPC=10) and 22.5% (control=2; P =0.56). At 12 months, 30% of MPC patients and 40% of control patients were successfully temporarily weaned from LVAD support ( P =0.69), and 6 deaths (30%) occurred in MPC patients. Donor-specific HLA sensitization developed in 2 MPC and 3 control patients and resolved by 12 months. Conclusions— In this preliminary trial, administration of MPCs appeared to be safe, and there was a potential signal of efficacy. Future studies will evaluate the potential for higher or additional doses to enhance the ability to wean LVAD recipients off support. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT01442129.

A 72-year-old man with a history of rheumatic heart disease, prior bioprosthetic mitral and aortic valve replacement, severe nonischemic dilated cardiomyopathy (left ventricular [LV] ejection fraction 5%), and a history of ventricular tachycardia (VT) underwent implantation of a continuous flow LV assist device (LVAD; HeartMate II; Thoratec Corporation) as destination therapy for severe heart failure. The early postoperative period was unremarkable and he had substantial functional improvement with minimal cardiovascular limiting symptoms after postoperative recovery. After ≈3 years on LVAD support, he experienced a series of appropriate implantable cardioverter-defibrillator shocks for sustained VT refractory to antiarrhythmic therapy. He underwent VT ablation targeting the basal LV inferoseptum, but he continued to have recurrent VT. Because VT seemed to originate from a deep septal substrate, he underwent an alcohol …

We observed an apparent increase in the rate of device thrombosis among patients who received the HeartMate II left ventricular assist device, as compared with preapproval clinical-trial results and initial experience. We investigated the occurrence of pump thrombosis and elevated lactate dehydrogenase (LDH) levels, LDH levels presaging thrombosis (and associated hemolysis), and outcomes of different management strategies in a multi-institutional study.We obtained data from 837 patients at three institutions, where 895 devices were implanted from 2004 through mid-2013; the mean (±SD) age of the patients was 55±14 years. The primary end point was confirmed pump thrombosis. Secondary end points were confirmed and suspected thrombosis, longitudinal LDH levels, and outcomes after pump thrombosis.A total of 72 pump thromboses were confirmed in 66 patients; an additional 36 thromboses in unique devices were suspected. Starting in approximately March 2011, the occurrence of confirmed pump thrombosis at 3 months after implantation increased from 2.2% (95% confidence interval [CI], 1.5 to 3.4) to 8.4% (95% CI, 5.0 to 13.9) by January 1, 2013. Before March 1, 2011, the median time from implantation to thrombosis was 18.6 months (95% CI, 0.5 to 52.7), and from March 2011 onward, it was 2.7 months (95% CI, 0.0 to 18.6). The occurrence of elevated LDH levels within 3 months after implantation mirrored that of thrombosis. Thrombosis was presaged by LDH levels that more than doubled, from 540 IU per liter to 1490 IU per liter, within the weeks before diagnosis. Thrombosis was managed by heart transplantation in 11 patients (1 patient died 31 days after transplantation) and by pump replacement in 21, with mortality equivalent to that among patients without thrombosis; among 40 thromboses in 40 patients who did not undergo transplantation or pump replacement, actuarial mortality was 48.2% (95% CI, 31.6 to 65.2) in the ensuing 6 months after pump thrombosis.The rate of pump thrombosis related to the use of the HeartMate II has been increasing at our centers and is associated with substantial morbidity and mortality.

Background— The relation of body fat distribution to left ventricular (LV) structure and function is poorly defined. Methods and Results— A total of 2710 participants without heart failure or LV dysfunction in the Dallas Heart Study underwent dual energy x-ray absorptiometry and MRI assessment of fat distribution, LV morphology, and hemodynamics. Cross-sectional associations of fat distribution with LV structure and function were examined after adjustment for age, sex, race, comorbidities, and lean mass. Mean age was 44 years with 55% women; 48% blacks; and 44% obese. After multivariable adjustment, visceral adipose tissue was associated with concentric remodeling characterized by lower LV end-diastolic volume (β=−0.21), higher concentricity (β=0.20), and wall thickness (β=0.09; P P P P P P Conclusions— Visceral adipose tissue, a marker of central adiposity, was independently associated with concentric LV remodeling and adverse hemodynamics. In contrast, lower body subcutaneous fat was associated with eccentric remodeling. The impact of body fat distribution on heart failure risk requires prospective study.

Background: Advanced heart failure (HF) is characterized by metabolic abnormalities but studies conflict about the nature of these defects. Methods: We investigated the presence or absence of toxic intramyocardial lipid species using carefully procured human myocardium from lean, non-diabetic end-stage heart failure patients. Left ventricular myocardial samples were obtained at the time of heart transplant. Cases included idiopathic dilated (n=5) and ischemic (n=2) cardiomyopathy (n=7), and brain-dead organ donors without any history of heart failure (n=12). The failing hearts were examined before and after support with a left ventricular assist device (LVAD, n=7). Frozen samples were evaluated by liquid chromatography and high-resolution mass spectrometry (LC-HRMS) to identify lipid species and further quantitate their abundance. Samples for LC-HRMS were prepared using the Folch extraction method, and the samples were normalized to protein concentration via BCA protein assay. We selected for masses with p-values less than or equal to (p= .005) and a fold change greater than or equal to 2.5 Results: Diacylglycerols (DAGs), ceramides, sphingosines, and cardiolipins (CLs) were lower in failing samples than in non failing. The figure below for L-Palmitoylcarnitine is representative of the quantitative changes in lipids observed between failing and non-failing groups. Conclusion: Excess intramycellular lipid accumulation is not present in advanced heart failure. A significant deficiency in cardiac lipid species has been identified in end stage non-diabetic heart failure. Future studies in diabetic and obese patients with advanced heart failure are warranted.

There are an increasing number of elderly patients with end-stage heart failure. Destination mechanical circulatory support is often the only therapy available for these patients who are not transplant candidates. The outcomes after continuous flow left ventricular assist device (CF LVAD) implant in older patients remains unclear. We undertook this multi-institutional study to quantify short-term and midterm outcomes after CF LVAD implant in the elderly.We retrospectively analyzed all patients in the Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) national registry that underwent implant of a CF LVAD (June 2006 to April 2012). Patients were divided into 2 cohorts based upon age (70 years [n = 4,439] and ≥ 70 years (n = 590]). Preoperative, intraoperative, and postoperative variables were analyzed. The primary endpoint, survival, was compared between cohorts.Patients age 70 and older were more hemodynamically stable pre-VAD implant as evidenced by INTERMACS profile and inotrope dependence. Perioperative outcomes, including median bypass time (89 vs 89 minutes) and length of stay (0.657 vs 0.657 months) were similar between cohorts (p = not significant). Kaplan-Meier analysis revealed a significant difference in 2-year survival between patients aged 70 years or greater (63%) and less than 70 (71%, p0.001). Multivariable Cox proportional hazard analysis revealed age as an independent predictor of mortality during follow-up (p0.001). Nonetheless, midterm cumulative survival in the older cohort was still reasonable (63% at 2 years).Multi-institutional analysis revealed advanced age as a predictor of increased mortality after CF LVAD implantation. Careful patient selection is critical in the elderly to optimize long-term outcomes after CF LVAD implantation.

Summary Implantable left ventricular assist devices (LVADs) are increasingly being used as a bridge to transplantation or as destination therapy in patients with end stage heart failure refractory to conventional medical therapy. A significant number of these patients have associated renal dysfunction before LVAD implantation, which may improve after LVAD placement due to enhanced perfusion. Other patients develop AKI after implantation. LVAD recipients who develop AKI requiring renal replacement therapy in the hospital or who ultimately require long-term outpatient hemodialysis therapy present management challenges with respect to hemodynamics, volume, and dialysis access. This review discusses the mechanics of a continuous-flow LVAD (the HeartMate II), the effects of continuous blood flow on the kidney, renal outcomes of patients after LVAD implantation, dialysis modality selection, vascular access, hemodynamic monitoring during the dialytic procedure, and other issues relevant to caring for these patients.

Systolic heart failure is a progressive syndrome marked by contractile dysfunction of the myocardium, activation of neurohormonal response systems including adrenergic and renin–angiotensin–aldosterone signaling, as well as cardiac and systemic metabolic abnormalities. Despite major advances in medical therapy, predominantly targeting pharmacologic blockade of neurohormonal systems, the end-result is often progressive pump failure or sudden cardiac death due to malignant ventricular arrhythmias. The implantation of devices for systolic heart failure, including automatic internal cardiac defibrillators (AICD), cardiac resynchronization therapy (CRT), and long-term ventricular assist devices (VADs) has led to a further improvement in functional capacity and survival beyond optimal medical therapy. In this chapter, we will present the biological mechanisms that drive changes in myocardial structure and function, often improving as is the case with myocardial “reverse remodeling” after implantation of cardiac assist devices and cardiac resynchronizing pacemaker/defibrillator therapies.

Objective: Evidence supports an antilipotoxic role for leptin in preventing inappropriate peripheral tissue lipid deposition. Obese, leptin-deficient mice develop left ventricular (LV) hypertrophy and myocardial steatosis with increased apoptosis and decreased longevity. Here we investigated the cardiac effects of caloric restriction versus leptin repletion in obese leptin-deficient ( ob/ob) mice. Methods: Echocardiography was performed on 7 mo old C57BL/6 wild-type mice (WT) and ob/ob mice fed ad libitum, leptin-repleted (LR- ob/ob), or calorie-restricted (CR- ob/ob) for 4 wk. Ventricular tissue was examined by electron microscopy (EM), triglyceride (TAG) content, oil red O staining, mitochondrial coupling assay, and microarray expression profiling. Results: LR and CR- ob/ob mice showed decreased body and heart weight, and LV wall thickness compared with ad libitum ob/ob mice. LV fractional shortening was decreased in ad libitum ob/ob mice, but restored to WT in LR and CR groups. However, myocardial lipid content by EM and TAG analysis revealed persistent cardiac steatosis in the CR- ob/ob group. Although CR restored mitochondrial coupling to WT levels, PPARα was suppressed and genes associated with oxidative stress and cell death were upregulated in CR- ob/ob animals. In contrast, LR eliminated cardiac steatosis, normalized mitochondrial coupling, and restored PGC1α and PPARα expression, while inducing core genes involved in glycerolipid/free fatty acid (GL/FFA) cycling, a thermogenic pathway that can reduce intracellular lipids. Conclusions: Thus, CR in the absence of leptin fails to normalize cardiac steatosis. GL/FFA cycling may be, at least in part, leptin-dependent and a key pathway that protects the heart from lipid accumulation.

Background— Soluble ST2 reflects activity of an interleukin-33–dependent cardioprotective signaling axis and is a diagnostic and prognostic marker in acute heart failure. The use of ST2 in chronic heart failure has not been well defined. Our objective was to determine whether plasma ST2 levels predict adverse outcomes in chronic heart failure in the context of current approaches. Methods and Results— We determined the association between ST2 level and risk of death or transplantation in a multicenter, prospective cohort of 1141 chronic heart failure outpatients. Adjusted Cox models, receiver operating characteristic analyses, and risk reclassification metrics were used to assess the value of ST2 in predicting risk beyond currently used factors. After a median of 2.8 years, 267 patients (23%) died or underwent heart transplantation. Patients in the highest ST2 tertile (ST2 >36.3 ng/mL) had a markedly increased risk of adverse outcomes compared with the lowest tertile (ST2 ≤22.3 ng/mL), with an unadjusted hazard ratio of 3.2 (95% confidence interval [CI], 2.2 to 4.7; P P =0.002). In receiver operating characteristic analyses, the area under the curve for ST2 was 0.75 (95% CI, 0.69 to 0.79), which was similar to N-terminal pro-B–type natriuretic peptide (NT-proBNP) (area under the curve, 0.77; 95% CI, 0.72 to 0.81; P =0.24 versus ST2) but lower than the Seattle Heart Failure Model (area under the curve, 0.81 (95% CI, 0.77 to 0.85; P =0.014 versus ST2). Addition of ST2 and NT-proBNP to the Seattle Heart Failure Model reclassified 14.9% of patients into more appropriate risk categories ( P =0.017). Conclusions— ST2 is a potent marker of risk in chronic heart failure and when used in combination with NT-proBNP offers moderate improvement in assessing prognosis beyond clinical risk scores.

This case report describes a pregnant female patient who presented with new-onset congestive heart failure symptoms and prolonged QTc, with strong family history of sudden death. Endomyocardial biopsy and genetic testing revealed myocardial desmin accumulation and a previously described mutation in the DES (desmin) gene, as well as variants in two LQT genes, SCN5A and KCNH2. The case highlights the phenotypic variability for a particular desmin genotype, and the possible interaction of desminopathy with LQT variants not independently associated with large differences in current properties or QT prolongation from wild type.

Background— B-type natriuretic peptide (BNP) is produced as a biologically inactive prohormone (proBNP 1-108 ), processed, and released as an inactive amino acid N-terminal fragment (proBNP 1-76 ) and a biologically active carboxyl-terminal fragment (proBNP 77-108 or BNP32). We hypothesized that simultaneous assessment of proBNP 1-108 and active BNP32, as an index of natriuretic peptide processing efficiency, would improve risk stratification in patients with chronic systolic heart failure. Methods and Results— We quantified plasma proBNP 1-108 and BNP32 in 756 participants in the Penn Heart Failure Study, a prospective cohort of outpatients with predominantly systolic heart failure. Cox models were used to determine the association between biomarker level at the time of study entry and incident risk of adverse cardiovascular outcomes. A significant amount of unprocessed proBNP 1-108 circulates in patients with systolic heart failure (median, 271 pg/mL; interquartile range, 65 to 825). Higher levels of proBNP 1-108 were associated with an increased risk of all-cause death or cardiac transplantation (adjusted hazard ratio, 4.9; 95% CI, 2.5 to 9.7; P 1-108 tertile). ProBNP 1-108 provided additive information to BNP32 risk assessment, particularly in patients with BNP32 less than the median of 125 pg/mL (adjusted hazard ratio, 1.4; 95% CI, 1.2 to 1.8; P 1-108 ). Conclusions— Circulating proBNP 1-108 is independently associated with an increased risk of adverse cardiovascular outcomes in ambulatory patients with chronic systolic heart failure. The combined assessment of BNP32 and proBNP 1-108 provides additional information in determining risk of adverse clinical outcomes, particularly in patients with low BNP32 values that might otherwise be reassuring to the clinician.

Mutations in genes that encode components of the sarcomere are well established as the cause of hypertrophic and dilated cardiomyopathies. Sarcomere genes, however, are increasingly being associated with other cardiomyopathies. One phenotype more recently recognized as a disease of the sarcomere is restrictive cardiomyopathy (RCM). We report on two patients with RCM associated with multiple mutations in sarcomere genes not previously associated with RCM. Patient 1 presented with NYHA Class III/IV heart failure at 22 years of age. She was diagnosed with RCM and advanced heart failure requiring heart transplantation. Sequencing of sarcomere genes revealed previously reported homozygous p.Glu143Lys mutations in MYL3, and a novel heterozygous p.Gly57Glu mutation in MYL2. The patient's mother is a double heterozygote for these mutations, with no evidence of cardiomyopathy. Patient 2 presented at 35 years of age with volume overload while hospitalized for oophorectomy. She was diagnosed with RCM and is being evaluated for heart transplantation. Sarcomere gene sequencing identified homozygous p.Asn279His mutations in TPM1. The patient's parents are consanguineous and confirmed heterozygotes. Her father was diagnosed with HCM at 42 years of age. This is the first report of mutations in TPM1, MYL3, and MYL2 associated with primary, non-hypertrophied RCM. The association of more sarcomere genes with RCM provides further evidence that mutations in the various sarcomere genes can cause different cardiomyopathy phenotypes. These cases also contribute to the growing body of evidence that multiple mutations have an additive effect on the severity of cardiomyopathies.

Systolic heart failure is characterized by ventricular dilation and reduced ejection fraction, and this syndrome may be either chronic or acute. Left ventricular remodeling is the principal cause of progression of systolic heart failure. Acute heart failure resulting from cardiomyopathy has similar functional and morphologic abnormalities. This review discusses remodeling, initial therapy based on neurohormonal modulation, and treatment of decompensated and refractory heart failure. Diagnosis, prognosis, and management of acute myocarditis are also discussed.

We thank Drs. Guha and Estep very much for their endorsement of our concept to explore the use of mechanical circulatory support (MCS) as a treatment for heart failure with preserved ejection fraction (HFpEF) [(1)][1]. As ours is a concept paper, its publication was largely intended to initiate

Left ventricular failure is the final common pathway for a wide spectrum of myocardial insults, including systemic hypertension and myocardial infarction. Although left ventricular hypertrophy is an adaptive response to pressure and volume overload, this process becomes maladaptive if left untreated and pathologic cardiac hypertrophy then becomes an important and independent risk factor for the development of heart failure. Despite its importance, the transition from hypertrophy to heart failure in humans is poorly understood. The focus of treatment should be prevention of heart failure and other cardiovascular events, such as stroke and atrial fibrillation. When heart failure is present, treatment with medical and device therapy is then focused on improving functional capacity, increasing survival, and preventing progression to end-stage heart failure.

African American men with hypertension (HTN) in low socioeconomic urban environments continue to achieve poor rates of HTN control.In a 5-year randomized clinical trial with 309 hypertensive urban African American men aged 21 to 54 years, the effectiveness of a more intensive educational/behavioral/pharmacologic intervention provided by a nurse practitioner/community health worker/physician team was compared to less intensive information and referral intervention. Changes in behavioral factors, health care utilization, blood pressure (BP) control, left ventricular hypertrophy (LVH), and renal insufficiency were evaluated.Follow-up rates exceeded 89% of available men. The ranges of mean annual systolic BP/diastolic BP change from the baseline to each year follow-up were -3.7 to -10.1/-4.9 to -12.3 mm Hg for the more intensive group and +3.4 to -3.0/-1.8 to -8.7 mm Hg for the less intensive group. The annual proportion of men with controlled BP (140/90 mm Hg) ranged from 17% to 44% in the more intensive group and 21% to 36% in the less intensive group. At 5 years the more intensive group had less LVH than the less intensive group and 17% of the men were deceased primarily due to narcotic or alcohol intoxication (36%) and cardiovascular causes (19%).An appropriate educational/behavioral intervention significantly improved BP control and reduced some sequelae of HTN in a young African American male population. Improvement in risk factors other than HTN was limited and sustained control of HTN was difficult to maintain during 5 years.

Purpose To determine the independent prognostic value of a third heart sound (S 3 ) and elevated jugular venous pressure in patients with asymptomatic left ventricular dysfunction. Methods We performed a post hoc analysis of 4102 participants from the Studies of Left Ventricular Dysfunction (SOLVD) prevention trial. In that trial, participants with asymptomatic or minimally symptomatic left ventricular dysfunction (New York Association class I or II, left ventricular ejection fraction ≤0.35, no treatment for heart failure) were allocated randomly to enalapril or placebo and followed for a mean (± SD) of 34 ± 14 months. The presence of an S 3 and elevated jugular venous pressure was ascertained by physical examination at study enrollment. We used multivariate proportional hazards models to determine whether these physical examination findings were associated with the development of heart failure, a prespecified endpoint of the SOLVD prevention trial. Results At baseline, 209 subjects (5.1%) had an S 3 and 70 (1.7%) had elevated jugular venous pressure. Heart failure developed in 1044 subjects (25.5%). After adjusting for other markers of disease severity, an S 3 was associated with an increased risk of heart failure (relative risk [RR] = 1.38; 95% confidence interval [CI]: 1.09 to 1.73; P = 0.007) and the composite endpoint of death or development of heart failure (RR = 1.34; 95% CI: 1.09 to 1.64; P = 0.005). Elevated jugular venous pressure was also associated with these outcomes in multivariate models. Conclusion The physical examination provides prognostic information among patients with asymptomatic or minimally symptomatic left ventricular dysfunction.

The independent prognostic value of elevated jugular venous pressure or a third heart sound in patients with heart failure is not well established.We performed a retrospective analysis of the Studies of Left Ventricular Dysfunction treatment trial, in which 2569 patients with symptomatic heart failure or a history of it were randomly assigned to receive enalapril or placebo. The mean (+/-SD) follow-up was 32+/-15 months. The presence of elevated jugular venous pressure or a third heart sound was ascertained by physical examination on entry into the trial. The risks of hospitalization for heart failure and progression of heart failure as defined by death from pump failure and the composite end point of death or hospitalization for heart failure were compared in patients with these findings on physical examination and patients without these findings.Data on 2479 patients were complete and analyzed. In multivariate analyses that were adjusted for other markers of the severity of heart failure, elevated jugular venous pressure was associated with an increased risk of hospitalization for heart failure (relative risk, 1.32; 95 percent confidence interval, 1.08 to 1.62; P0.01), death or hospitalization for heart failure (relative risk, 1.30; 95 percent confidence interval, 1.11 to 1.53; P0.005), and death from pump failure (relative risk, 1.37; 95 percent confidence interval, 1.07 to 1.75; P0.05). The presence of a third heart sound was associated with similarly increased risks of these outcomes.In patients with heart failure, elevated jugular venous pressure and a third heart sound are each independently associated with adverse outcomes, including progression of heart failure. Clinical assessment for these findings is currently feasible and clinically meaningful.

Background Pulmonary arterial hypertension is a rare disorder associated with poor survival. Endothelial dysfunction plays a central role in the pathogenesis and progression of pulmonary arterial hypertension. Inflammation appears to drive this dysfunctional endothelial phenotype, propagating cycles of injury and repair in genetically susceptible patients with idiopathic and disease-associated pulmonary arterial hypertension. Therapy targeting pulmonary vascular inflammation to interrupt cycles of injury and repair and thereby delay or prevent right ventricular failure and death has not been tested. Spironolactone, a mineralocorticoid and androgen receptor antagonist, has been shown to improve endothelial function and reduce inflammation. Current management of patients with pulmonary arterial hypertension and symptoms of right heart failure includes use of mineralocorticoid receptor antagonists for their diuretic and natriuretic effects. We hypothesize that initiating spironolactone therapy at an earlier stage of disease in patients with pulmonary arterial hypertension could provide additional benefits through anti-inflammatory effects and improvements in pulmonary vascular function. Methods/Design Seventy patients with pulmonary arterial hypertension without clinical evidence of right ventricular failure will be enrolled in a randomized, double-blinded, placebo-controlled trial to investigate the effect of early treatment with spironolactone on exercise capacity, clinical worsening and vascular inflammation in vivo. Our primary endpoint is change in placebo-corrected 6-minute walk distance at 24 weeks and the incidence of clinical worsening in the spironolactone group compared to placebo. At a two-sided alpha level of 0.05, we will have at least 84% power to detect an effect size (group mean difference divided by standard deviation) of 0.9 for the difference in the change of 6-minute walk distance from baseline between the two groups. Secondary endpoints include the effect of spironolactone on the change in placebo-corrected maximal oxygen consumption; plasma markers of vascular inflammation and peripheral blood mononuclear cell gene expression profiles; sympathetic nervous system activation, renin-angiotensin-aldosterone system activation and sex hormone metabolism; and right ventricular structure and function using echocardiography and novel high-resolution magnetic resonance imaging-based techniques. Safety and tolerability of spironolactone will be assessed with periodic monitoring for hyperkalemia and renal insufficiency as well as the incidence of drug discontinuation for untoward effects. Trial registration ClinicalTrials.gov: NCT01712620

ObjectivesWe examined whether B-type natriuretic peptides (BNP) can serve as noninvasive markers of pulmonary capillary wedge pressure (PCWP) in the setting of critical illness.BackgroundThe BNP and N-terminal pro-B-type natriuretic peptide (NT-proBNP) are highly correlated with left ventricular (LV) filling pressures in patients with depressed LV systolic function. However, their relationship to PCWP in a heterogeneous intensive care unit (ICU) population has not been established.MethodsWe prospectively studied 40 patients in the ICU requiring invasive hemodynamic monitoring. Hemodynamics were recorded simultaneously with blood sampling for BNP and NT-proBNP.ResultsThe BNP (median 420 pg/ml) and NT-proBNP (median 3,304 pg/ml) levels were markedly elevated, but weakly correlated with PCWP (BNP, r = 0.40, NT-proBNP, r = 0.32) and other cardiac parameters. Peptide levels were approximately four-fold greater in patients with impaired (estimated glomerular filtration rate [eGFR] 60 ml/min) renal function, despite similar PCWP, cardiac index, and LV ejection fraction. In addition, both BNP and NT-proBNP showed stronger correlations with PCWP in patients with preserved (BNP, r = 0.58, NT-proBNP, r = 0.73) versus impaired renal function (BNP, r = 0.48, NT-proBNP, r = 0.34). Interaction terms between eGFR and BNP (p = 0.06) and NT-proBNP (p = 0.04) suggest that eGFR modulates the relationship of these peptides to filling pressures.ConclusionsThe BNPs are markedly elevated, yet show only weak correlations to PCWP in ICU patients requiring invasive hemodynamic monitoring. Thus, a single value for BNP or NT-proBNP may not be a clinically useful noninvasive marker of filling pressures in the critically ill patient. This appears to be especially true in patients with impaired renal function.

Mechanical circulatory support (MCS) frequently is used to treat medically refractory end-stage heart failure. Initially designed to be a bridge to transplantation, MCS also has proven itself as a durable therapy for patients who are not transplant candidates. As outcomes for patients with MCS have improved, research interest in device development has flourished, with many new device types under investigation. In addition to improvement of MCS devices, investigational work continues to achieve appropriate patient selection and complication management.