Journal of Cardiac Failure

Preventing Heart Failure: A Critique of Strategies

Jay N. Cohn — 2013-04-01

Heart failure has a profound effect on the quality and duration of life in afflicted individuals, and its management consumes a considerable proportion of health care resources in the United States. It remains the leading cause of hospitalization for the Medicare population, so hospital costs are staggering. Because the incidence of heart failure rises exponentially with age, the financial burden of the disease falls predominantly on government-financed health care through Medicare. The availability of heart transplants and newer electrical and mechanical support devices and procedures are further contributing to the escalating health care costs.

Differences in Clinical Profile of African-American Women With Peripartum Cardiomyopathy in the United States

Sorel Goland, Kalgi Modi, Parta Hatamizadeh, Uri Elkayam — 2013-04-01

Abstract: Background: Peripartum cardiomyopathy (PPCM) is a rare and heterogeneous disease with a higher prevalence in African Americans (AAs) in the USA. The clinical features and prognosis of PPCM in AAs have not been sufficiently characterized.Methods: We studied 52 AA patients with PPCM and compared clinical characteristics and outcome with those of 104 white patients.Results: AA patients were significantly younger (26 ± 7 vs 30 ± 6 years; P < .001), had a higher prevalence of gestational hypertension (61% vs 41%; P = .03), and were diagnosed more commonly postpartum rather then antepartum (83% vs 64%; P = .03). The rate of left ventricular (LV) recovery (LV ejection fraction [LVEF] ≥50%) was significantly lower in AAs (40% vs 61%; P = .02). AA women also had a larger LV end-diastolic diameter (57 ± 10 vs 51 ± 6 mm; P = .004) as well as lower LVEF (40% ± 16.7% vs 46% ± 14%; P = .002) at the last follow-up. Moreover, AA patients had a significantly higher incidence of the combined end points of mortality and cardiac transplantation (P = .03) and showed a strong trend (P = .09) for increased mortality.Conclusions: AA patients with PPCM in the USA have a different clinical profile and worse prognosis compared with white patients. Further research to evaluate potentially correctable causes for these differences is warranted.

Protein Carbamylation in Chronic Systolic Heart Failure: Relationship With Renal Impairment and Adverse Long-Term Outcomes

2013-03-21

Abstract: Background: Protein carbamylation, a posttranslational modification promoted during uremia and catalyzed by myeloperoxidase (MPO) at sites of inflammation, is linked to altered protein structure, vascular dysfunction, and poor prognosis. We examine the relationship between plasma protein-bound homocitrulline (PBHCit) levels, a marker of protein lysine residue carbamylation, with cardiorenal function and long-term outcomes in chronic systolic heart failure (HF).Methods and Results: In 115 patients with chronic systolic HF (left ventricular ejection fraction ≤35%), we measured plasma PBHCit by quantitative mass spectrometry and performed comprehensive echocardiography with assessment of cardiac structure and performance. Adverse long-term events (death, cardiac transplantation) were tracked for 5 years. In our study cohort, the median PBHCit level was 87 (interquartile range 59–128) μmol/mol lysine. Higher plasma PBHcit levels were associated with poorer renal function (estimated glomerular filtration rate [eGFR]: Spearman r = −0.37; P < .001), cystatin C (r = 0.31; P = .001), and elevated plasma amino-terminal pro–B-type natriuretic peptide (NT-proBNP) levels (r = 0.26; P = .006), but not with markers of systemic inflammation or oxidant stress (high-sensitivity C-reactive protein and myeloperoxidase [MPO]: P > .10 for each). Furthermore, elevated plasma PBHCit levels were not related to indices of cardiac structure or function (P > .10 for all examined) except modestly with increased right atrial volume index (r = 0.31; P = .002). PBHCit levels predicted adverse long-term events (hazard ratio [HR] 1.8, 95% confidence interval [CI] 1.3–2.6; P < .001), including after adjustment for age, eGFR, MPO, and NT-proBNP (HR 1.9, 95% CI 1.2–3.1; P = .006).Conclusions: In chronic systolic HF, protein carbamylation is associated with poorer renal but not cardiac function, and portends poorer long-term adverse clinical outcomes even when adjusted for cardiorenal indices of adverse prognosis.

Adaptive Servoventilation Improves Cardiorenal Function and Prognosis in Heart Failure Patients With Chronic Kidney Disease and Sleep-Disordered Breathing

2013-04-01

Abstract: Background: Chronic kidney disease (CKD) and sleep-disordered breathing (SDB) play critical roles in the progression of chronic heart failure (CHF). However, it still remains unclear whether adaptive servoventilation (ASV) improves cardiorenal function and the prognosis of CHF patients with CKD and SDB.Methods and Results: Eighty CHF patients with CKD (estimated glomerular filtration rate of <60 mL min−1 1.73 cm−2) and SDB (apnea-hypopnea index >15/h) were enrolled and divided into 2 groups: 36 patients were treated with usual care plus ASV (ASV group) and 44 patients were treated with usual care alone (Non-ASV group). Levels of B-type natriuretic peptide, glomerular filtration rate, cystatin C, C-reactive protein, noradrenaline, and left ventricular ejection fraction were measured before treatment and 6 months after treatment. Patients were followed to register cardiac events occurring after enrollment. Six months of ASV therapy reduced levels of B-type natriuretic peptide, cystatin C, C-reactive protein, and noradrenaline and improved the glomerular filtration rate and ejection fraction (all P < .05). However, none of these parameters changed in the Non-ASV group. Thirty-two events (14 deaths and 18 rehospitalizations) occurred during the follow-up period (mean 513 days). Importantly, the event-free rate was significantly higher in the ASV group than in the Non-ASV group (77.8% vs 45.5%; log rank P < .01).Conclusions: ASV improves the prognosis of CHF patients with CKD and SDB, with favorable effects such as the improvement of cardiorenal function and attenuation of inflammation and sympathetic nervous activity.

Temporal Relationship of Conduction System Disease and Ventricular Dysfunction in LMNA Cardiomyopathy

2013-04-01

Abstract: Background: LMNA cardiomyopathy presents with electrocardiogram (ECG) abnormalities, conduction system disease (CSD), and/or arrhythmias before the onset of dilated cardiomyopathy (DCM). Knowing the time interval between the onset of CSD and its progression to DCM would help to guide clinical care.Methods and Results: We evaluated family members from 16 pedigrees previously identified to carry LMNA mutations for the ages of onset of ECG abnormalities, CSD, or arrhythmia and of left ventricular enlargement (LVE) and/or systolic dysfunction. Of 103 subjects, 64 carried their family LMNA mutation, and 51 (79%) had ECG abnormalities with a mean age of onset of 41.2 years (range 18–76). Ventricular dysfunction was observed in 26 with a mean age of onset of 47.6 years (range 28–82); at diagnosis 9 had systolic dysfunction but no LVE, 5 had LVE but no systolic dysfunction, and 11 had DCM. Of 16 subjects identified with ECG abnormalities who later developed ventricular dysfunction, the median ages of onset by log-rank analyses were 41 and 48 years, respectively.Conclusions: ECG abnormalities preceded DCM with a median difference of 7 years. Clinical surveillance should occur at least annually in those at risk for LMNA cardiomyopathy with any ECG findings.

Dietary Habits are Related to Outcomes in Patients With Advanced Heart Failure Awaiting Heart Transplantation

2013-04-01

Abstract: Background: Empirical evidence supporting the benefits of dietary recommendations for patients with advanced heart failure is scarce. We prospectively evaluated the relation of dietary habits to pre-transplant clinical outcomes in the multisite observational Waiting for a New Heart Study.Methods and Results: A total of 318 heart transplant candidates (82% male, age 53 ± 11 years) completed a Food Frequency Questionnaire (foods high in salt, saturated fats, poly-/monounsaturated fats [PUFA+MUFA], fruit/vegetables/legumes, and fluid intake) at time of waitlisting. Cox proportional hazard models controlling for heart failure severity (eg, Heart Failure Survival Score, creatinine) estimated cause-specific hazard ratios (HRs) associated with each dietary habit individually, and with all dietary habits entered simultaneously. During follow-up (median 338 days, range 13–1,394), 54 patients died, 151 received transplants (110 in high-urgency status, 41 electively), and 45 became delisted (15 deteriorated, 30 improved). Two robust findings emerged: Frequent intake of salty foods, which correlated positively with saturated fat and fluid intake, was associated with transplantation in high-urgency status (HR 2.90, 95% confidence interval [CI] 1.55–5.42); and frequent intake of foods rich in PUFA+MUFA reduced the risk for death/deterioration (HR 0.49, 95% CI 0.26–0.92).Conclusions: These results support the importance of dietary habits for the prognosis of patients listed for heart transplantation, independently from heart failure severity.

Echocardiographic Left Ventricular End-Diastolic Pressure Volume Loop Estimate Predicts Survival in Congestive Heart Failure

2013-03-26

Abstract: Background: The left ventricular end-diastolic pressure-volume relationship (LV-EDPVR) is a measure of LV distensibility, conveying the size the LV will assume at a given LV end-diastolic pressure (LV-EDP). Measurement of LV-EDPVR requires invasive testing with specialized equipment. Echocardiography can be used to measure LV end-diastolic volume (EDV) and to grossly estimate LV-EDP noninvasively. We therefore hypothesized that categorization of patients based on these parameters to create an estimate of the end-diastolic pressure-volume loop position (EDPVE) could predict congestive heart failure (CHF) prognosis.Methods and Results: Echocardiograms from 968 CHF clinic patients were reviewed. LV-EDP was considered to be elevated if mitral filling pattern was pseudo-normal or restrictive. EDPVE was categorized into 3 groups. EDPVE was considered to have evidence of rightward shift if the LV was severely dilated (>97 mL/m2). EDPVE was considered to have evidence of leftward shift if the LV was normal size (<76 mL/m2) and there was Doppler evidence of increased LV-EDP. Patients who did not meet criteria for leftward or rightward shift were classified as “intermediate.” Using the intermediate group for comparison, those with evidence of leftward shift in EDPVE had increased mortality (hazard ratio [HR] 1.77; 95% confidence interval [CI]: 1.23-2.54). Rightward shift only correlated with increased mortality in those older than age 70 years. Leftward shift remained an independent predictor of mortality even after adjusting for LV ejection fraction, atrial fibrillation, mitral regurgitation, and Doppler indices of diastolic dysfunction.Conclusion: EDPVE is a strong predictor of CHF survival which is independent of LV ejection fraction and traditional Doppler indices of LV diastolic function.

Flow-Mediated Dilation Normalization Predicts Outcome in Chronic Heart Failure Patients

2013-03-21

Abstract: Background: Reduced flow-mediated dilation (FMD) is a known prognostic marker in heart failure (HF), but may be influenced by the brachial artery (BA) diameter. Aiming to adjust for this influence, we normalized FMD (nFMD) by the peak shear rate (PSR) and tested its prognostic power in HF patients.Methods and Results: BA diameter, FMD, difference in hyperemic versus rest brachial flow velocity (FVD), PSR (FVD/BA), and nFMD (FMD/PSR × 1000) were assessed in 71 HF patients. At follow-up (mean 512 days), 19 HF (27%) reached the combined endpoint (4 heart transplantations [HTs], 1 left ventricle assist device implantation [LVAD], and 14 cardiac deaths [CDs]). With multivariate Cox regression analysis, New York Heart Association functional class ≥III (hazard ratio [HR] 9.36, 95% confidence interval [CI] 2.11–41.4; P = .003), digoxin use (HR 6.36, 95% CI 2.18–18.6; P = .0010), FMD (HR 0.703, 95% CI 0.547–0.904; P = .006), PSR (HR 1.01, 95% CI 1.005–1.022; P = .001), FVD (HR 1.04, 95% CI 1.00–1.06; P = .02), and nFMD (HR 0.535, 95% CI 0.39–0.74; P = .0001) were predictors of unfavorable outcome. Receiver operating characteristic curve for nFMD showed that patients with nFMD >5 seconds had significantly better event-free survival than patients with nFMD ≤5 seconds (log-rank test: P < .0001).Conclusions: nFMD is a strong independent predictor of CD, HT, and LVAD in HF with left ventricular ejection fraction <40%. Patients with nFMD >5 seconds have a better prognosis than those with lower values.

PI3K Inhibitors as Novel Cancer Therapies: Implications for Cardiovascular Medicine

2013-04-01

Abstract: Background: The phosphatidylinositol 3-kinase (PI3K) signaling cascade has fundamental roles in cell growth, survival, and motility; and increased PI3K activity is an important and common contributor to tumorigenesis and cancer progression. This pathway also has a significant role in physiologic hypertrophy, myocardial contractility, and metabolism in the heart and is a central determinant of pathologic remodeling in the cardiovascular system.Methods and Results: PI3K inhibitors are a promising class of anticancer drugs, although systemic inhibition of the PI3K pathway demands careful attention to possible adverse side effects of inhibiting these ubiquitously expressed proteins. Here we review the growing body of basic research on the role of PI3K signaling in the heart and give an overview of the different therapeutic strategies being developed for cancer using PI3K inhibitors, including pan and isoform-selective inhibitors, combination PI3K/mammalian target of rapamycin inhibitors and the use of PI3K inhibitors in combination therapies with other anticancer therapies. We focus on the clinical implications for treating patients with preexisting cardiac risk factors or comorbidities with PI3K inhibitors.Conclusions: PI3K inhibitors are novel cancer drugs that are likely to lead to considerable toxicity to the cardiovascular system, especially in elderly patients and those with preexisting cardiovascular disease.

Regulation of Connective Tissue Growth Factor Gene Expression and Fibrosis in Human Heart Failure

2013-03-21

Abstract: Background: Heart failure (HF) is associated with excessive extracellular matrix (ECM) deposition and abnormal ECM degradation leading to cardiac fibrosis. Connective tissue growth factor (CTGF) modulates ECM production during inflammatory tissue injury, but available data on CTGF gene expression in failing human heart and its response to mechanical unloading are limited.Methods and Results: Left ventricle (LV) tissue from patients undergoing cardiac transplantation for ischemic (ICM; n = 20) and dilated (DCM; n = 20) cardiomyopathies and from nonfailing (NF; n = 20) donor hearts were examined. Paired samples (n = 15) from patients undergoing LV assist device (LVAD) implantation as “bridge to transplant” (34–1,145 days) also were analyzed. There was more interstitial fibrosis in both ICM and DCM compared with NF hearts. Hydroxyproline concentration was also significantly increased in DCM compared with NF samples. The expression of CTGF, transforming growth factor (TGF) β1, collagen (COL) 1-α1, COL3-α1, matrix metalloproteinase (MMP) 2, and MMP9 mRNA in ICM and DCM were also significantly elevated compared with NF samples. Although TGF-β1, CTGF, COL1-α1, and COL3-α1 mRNA levels were reduced by unloading, there was only a modest reduction in tissue fibrosis and no difference in protein-bound hydroxyproline concentration between pre- and post-LVAD tissue samples. The persistent fibrosis may be related to a concomitant reduction in MMP9 mRNA and protein levels following unloading.Conclusions: CTGF may be a key regulator of fibrosis during maladaptive remodeling and progression to HF. Although mechanical unloading normalizes most genotypic and functional abnormalities, its effect on ECM remodeling during HF is incomplete.

Editorial Board

2013-04-01

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2013-04-01

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2013-04-01

Journal of Cardiac Failure

Preventing Heart Failure: A Critique of Strategies

Differences in Clinical Profile of African-American Women With Peripartum Cardiomyopathy in the United States

Protein Carbamylation in Chronic Systolic Heart Failure: Relationship With Renal Impairment and Adverse Long-Term Outcomes

Adaptive Servoventilation Improves Cardiorenal Function and Prognosis in Heart Failure Patients With Chronic Kidney Disease and Sleep-Disordered Breathing

Temporal Relationship of Conduction System Disease and Ventricular Dysfunction in LMNA Cardiomyopathy

Dietary Habits are Related to Outcomes in Patients With Advanced Heart Failure Awaiting Heart Transplantation

Echocardiographic Left Ventricular End-Diastolic Pressure Volume Loop Estimate Predicts Survival in Congestive Heart Failure

Flow-Mediated Dilation Normalization Predicts Outcome in Chronic Heart Failure Patients

PI3K Inhibitors as Novel Cancer Therapies: Implications for Cardiovascular Medicine

Regulation of Connective Tissue Growth Factor Gene Expression and Fibrosis in Human Heart Failure

Editorial Board

Masthead

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Information for Authors