Patients with heart failure (HF) have higher fasting insulin levels and a higher prevalence of insulin resistance (IR) as compared with matched controls. IR leads to structural abnormalities in the heart, such as increased left atrial (LA) size, left ventricular (LV) mass, and alterations in transmitral velocity that can precede the diagnosis of HF. It is not known whether IR precedes the development of HF or whether the relationship between IR and HF is present among adults with HF due to non-ischemic heart disease.
Methods and Results
We examined 4425 participants (60% female) from the Cardiovascular Health Study after excluding those with HF, myocardial infarction, or treated diabetes at baseline. We used Cox proportional hazards models to estimate the relative risk of incident HF associated with fasting insulin measured at study entry.
There were 1216 cases of incident HF (1103 without antecedent MI) during a median follow-up of 12 years (maximum, 19 years). Fasting insulin levels were positively associated with the risk of incident HF (HR = 1.10, 95% CI 1.05, 1.15, per SD change) when adjusted for age, gender, race, field center, physical activity, smoking, alcohol intake, HDL cholesterol, total cholesterol, and systolic blood pressure, and waist circumference. The association between fasting insulin levels and incident HF was similar for HF without antecedent MI (HR= 1.10, 95% CI 1.05, 1.15). Measures of LA size, LV mass, and peak A velocity at baseline were associated both with fasting insulin levels and with heart failure ; however, additional statistical adjustment for these parameters did not completely attenuate the insulin-HF estimate (HR= 1.08, 95% CI 1.03, 1.14 per1-SD increase in fasting insulin).
Fasting insulin was positively associated with adverse echocardiographic features and risk of subsequent HF in CHS participants, including those without an antecedent MI.
heart failure; insulin; epidemiology
More than 25% of Medicare patients hospitalized for heart failure are readmitted within 30 days. The contributions of numeracy and health literacy to recidivism for patients with acute heart failure (AHF) are not known.
Methods and Results
A cohort of patients with AHF who presented to four emergency departments between January 2008 and September 2011. Research assistants administered subjective measures of numeracy and health literacy; thirty-day follow up was performed by phone interview. Recidivism was defined as any unplanned return to the emergency department or hospital within 30-days of the index emergency department visit for AHF. Multivariable logistic regression adjusting for patient age, gender, race, insurance status, hospital site, days eligible for recidivism, chronic kidney disease, abnormal hemoglobin, and low ejection fraction evaluated the relationships between numeracy and health literacy with 30-day recidivism. Of the 709 patients included in the analysis, 390 (55%) had low numeracy skills and 258 (37%) had low literacy skills. Low numeracy was associated with increased odds of recidivism within 30 days (adjusted odds ratio (OR) 1.41, 95% confidence interval 1.00-1.98, P=0.048). For low health literacy, adjusted OR of recidivism was 1.17 (95% CI 0.83-1.65, P=0.37).
Low numeracy was associated with greater odds of 30-day recidivism. Further investigation is warranted to determine whether addressing numeracy and health literacy may reduce 30-day recidivism for patients with acute heart failure.
emergency; heart failure; heart failure readmission follow-up studies
Right ventricular dysfunction (RVD) is the most frequent cause of death in patients with pulmonary arterial hypertension. Whereas abnormal energy substrate utilization has been implicated in the development of chronic left heart failure, data describing such metabolic remodeling in RVD remain incomplete. Thus, we sought to characterize metabolic gene expression changes and mitochondrial dysfunction in functional and dysfunctional RV hypertrophy.
Methods and Results
Two different rat models of RV hypertrophy were studied. The model of RVD (SU5416/hypoxia) exhibited a significantly decreased gene expression of PPAR-gamma coactivator-1 alpha (PGC-1α), PPAR-α and ERR-α. The expression of multiple PCG-1α target genes required for fatty acid oxidation (FAO) was similarly decreased. Decreased PGC-1α expression was also associated with a net loss of mitochondrial protein and oxidative capacity. Reduced mitochondrial number was associated with a downregulation of TFAM and other genes required for mitochondrial biogenesis. Electron microscopy demonstrated that in RVD tissue, mitochondria had abnormal shape and size. Lastly, respirometric analysis demonstrated that mitochondria isolated from RVD-tissue had a significantly reduced ADP-stimulated (state 3) rate for complex I. Conversely, functional RV hypertrophy in the pulmonary artery banding (PAB) model showed normal expression of PGC-1α, whereas the expression of FAO genes was either preserved or unregulated. Moreover, PAB-RV tissue exhibited preserved TFAM expression and mitochondrial respiration despite elevated RV pressure-overload.
Right ventricular dysfunction, but not functional RV hypertrophy in rats, demonstrates a gene expression profile compatible with a multilevel impairment of fatty acid metabolism and significant mitochondrial dysfunction, partially independent of chronic pressure-overload.
pulmonary heart disease; metabolism; pressure; fatty acids; mitochondria
Interleukin (IL)-33 via its receptor ST2 protects the heart from myocardial infarct and hypertrophy in animal models, but paradoxically increases autoimmune disease. In this study we examined the effect of IL-33 or ST2 administration on autoimmune heart disease.
Methods and Results
We used pressure volume relationships and isoproterenol challenge to assess the effect of recombinant (r)IL-33 or rST2 (e.g. soluble ST2) administration on the development of autoimmune coxsackievirus (CVB3) myocarditis and dilated cardiomyopathy (DCM) in male BALB/c mice. rIL-33 treatment significantly increased acute perimyocarditis (p=0.006) and eosinophilia (p=1.3×10−5), impaired cardiac function (maximum ventricular power p=0.0002), and increased ventricular dilation (end diastolic volume p=0.01). rST2 treatment prevented eosinophilia and improved heart function compared to rIL-33 treatment (ejection fraction, p=0.009). Neither treatment altered viral replication. rIL-33 increased IL-4, IL-33, IL-1β and IL-6 levels in the heart during acute myocarditis. To determine whether IL-33 altered cardiac function on its own, we administered rIL-33 to undiseased mice and found that rIL-33 induced eosinophilic pericarditis and adversely affected heart function. We used cytokine knockout mice to determine that this effect was due to IL-33-mediated signaling but not IL-1β or IL-6.
We show for the first time that IL-33 induces eosinophilic pericarditis while sST2 prevents eosinophilia and improves systolic function, and that IL-33 independently adversely affects heart function via the IL-33 receptor.
myocarditis; cytokines; inflammation; dilation; eosinophils
Heart failure (HF) readmission rates are primarily derived from Medicare enrollees. Given increasing public scrutiny of HF readmissions, understanding the rate and predictors in populations covered by other payers is also important, particularly among patients with systolic dysfunction, for whom most HF-specific therapies are targeted.
Methods and Results
MarketScan Commercial and Medicaid Administrative Claims Databases were used to identify all first hospitalizations with an International Classification of Diseases-9 discharge diagnosis code for HF (primary position) and systolic HF (any position) between January 1, 2005, and June 30, 2008. Among 4584 unique systolic HF index admissions (mean age 55 years), 30-day crude readmission rates were higher for Medicaid than commercially insured patients: all-cause 17.4% versus 11.8%; HF-related 6.7% versus 4.0%, respectively. In unadjusted analysis, higher comorbidity and prior healthcare utilization predicted readmission; age, sex, and plan type did not. After adjustment for case mix, the odds of all-cause and HF-related readmission were 32% and 68% higher, respectively, among Medicaid than commercially insured patients (P<0.02 for both). No significant differences in readmission rates were seen for managed care versus fee-for-service or capitated versus noncapitated plan types.
Compared with commonly cited Medicare HF readmission rates of 20% to 25%, Medicaid patients with systolic HF had lower 30-day readmission rates, and commercially insured patients had even lower rates. Even after adjustment for case mix, Medicaid patients were more likely to be readmitted than commercially insured patients, suggesting that more attention should be focused on readmissions among socioeconomically disadvantaged populations.
heart failure; systolic; hospitalization; readmission; payer
destination therapy; elderly; heart failure; LVAD
Despite improvements in the care of patients who have received cardiac transplants, coronary allograft vasculopathy (CAV) remains the most prevalent cause of late allograft failure and cardiac mortality. Few proven therapies are available for this important disease. The presence of coronary collaterals imparts a favorable prognosis in patients with native ischemic heart disease; however, the impact of collaterals in CAV is unknown.
Methods and results
To determine whether the development of coronary collaterals is associated with improved outcomes in patients with CAV, we performed a retrospective analysis of patients followed in the heart transplant program at Barnes Jewish Hospital from 1994–2008. The primary endpoints included all cause mortality and the composite of all cause mortality, retransplantation, and inotrope dependence. We screened 493 patients and identified 59 (12%) subjects with moderate to severe CAV. Angiographically visible coronary collaterals were present in 34 (57%) subjects. Kaplan-Meier and Cox multivariable analyses revealed that patients with collaterals had reduced incidence of all cause mortality HR 0.20, p<0.001 and the composite endpoint HR 0.17, p<0.001. In addition, patients with collaterals had less severe heart failure symptoms as measured by NYHA class. Immunostaining of biopsy specimens revealed that among patients with CAV, the presence of coronary collaterals correlated with increased microvascular density, reduced fibrosis and lower LVEDP.
Together, these data demonstrate that the presence of coronary collaterals predicts a favorable prognosis in patients with CAV and suggests that interventions aimed at promoting collateral and microvascular growth may serve as effective therapies for this disease.
collateral; transplant; vasculopathy; transplant; coronary
By promoting salt and water excretion, the corin and the atrial natriuretic peptide (ANP) system should help to maintain fluid balance in heart failure. Yet, the development of fluid retention despite high levels of ANP-related peptides, suggests that this compensatory system is limited.
Methods and Results
Levels of circulating corin (the pro-ANP converting enzyme) and pro-ANP were measured in hospitalized patients with heart failure, using novel immunoassays. Patients (n = 14) had severe heart failure (NYHA class III–IV) with a median ejection fraction of 18 % and median BNP levels of 1940 pg/ml. In heart failure, median plasma corin levels were 7.6-fold lower than measured in plasma from 16 normal controls (180 vs. 1368 pg/ml, p<0.01). In contrast, in heart failure patients, levels of plasma N-terminal ANP peptides (N-ANP and pro-ANP) levels were markedly elevated (42.0 vs. 7.5 ng/ml, p<0.01). Levels of uncleaved pro-ANP, measured by novel immunoassays, were significantly higher in heart failure patients (p < 0.01) suggesting that corin cleavage of pro-ANP was impaired. Median plasma levels of cGMP were elevated in heart failure patients (150.0 vs. 7.6 pmol/ml, p<0.01) and plasma cGMP levels positively correlated with the fractional amount of cleaved pro-ANP (rs = 0.59, p < 0.03) but not with levels of uncleaved pro-ANP, implying that the cellular response to ANP remained intact.
Taken together these data suggest that there may be patients for whom low corin levels and impaired pro-ANP cleavage contribute to acute decompensation.
atrial natriuretic peptide; natriuretic peptides; heart failure
Hypertension (HTN) causes concentric left ventricular (LV) remodeling, defined as an increased relative wall thickness or overt LV hypertrophy, and associated diastolic dysfunction. HTN and concentric remodeling are also common precursors to heart failure with a preserved ejection fraction (EF). It is not known if the myofilament contributes to diastolic dysfunction in patients with concentric remodeling.
Methods and Results
Intra-operative myocardial biopsies were obtained in 15 male patients undergoing coronary bypass grafting (CBG), all with normal LV EF and wall motion. Eight patients had a history of HTN and concentric remodeling. Seven without HTN or remodeling served as controls. Myocardial strips were dissected and demembranated with detergent. Isometric tension was measured and sinusoidal length perturbation analysis performed at sarcomere length 2.2μm and pCa 8 –4.5. Sinusoidal analysis provides estimates of cross-bridge dynamics, including rate constants of attachment and detachment and cross-bridge attachment time (ton). The normalized isometric tension-pCa relation was similar in HTN and controls. However, ton was significantly prolonged at submaximal [Ca2+] (pCa ≥ 6.5) in HTN patients. Analysis of protein phosphorylation revealed ~25% reduction in phosphorylation of troponin I in HTN patients (P < 0.05).
Compared with controls, patients with HTN and concentric remodeling display prolonged ton at submaximal [Ca2+] without a change in the tension-pCa relation. Prolonged ton implicates altered cross-bridge dynamics as a cause of slowed relaxation in these patients. This finding was associated with reduced phosphorylation of troponin I, suggesting decreased phosphorylation of protein kinase A/G sites as a mechanism.
diastole; heart failure; hypertrophy; myocardium; remodeling
Depression is a common comorbidity in heart failure (HF) and is strongly associated with increased mortality, morbidity, and reduced health status. Whether depression treatment may result in improvement of health status in HF patients with comorbid depression remains unknown.
Methods and Results
The SADHART-CHF study randomized 469 participants with chronic HF (LVEF 45% and NYHA class II) and major depressive disorder (MDD) DSM-IV criteria) to sertraline or placebo for 12 weeks. The Kansas City Cardiomyopathy Questionnaire (KCCQ), Short Form Health Survey (SF-36), and 6-minute walk test (6MWT) were used to assess health status. Health status changes between treatment arms and remission status were evaluated adjusting for baseline variables and treatment assignment. The final HDRS scores were 3.50±2.08 and 12.97±4.33 in the remission and non-remission groups, respectively (p-value = 0.0001). Of 469 total participants, 378 (80.6%) completed the 6MWT and 285 (70.1%) completed KCCQ and SF-36, at baseline and at week-12. Depression remission was significantly associated with higher improvements in KCCQ subscale scores (p < 0.001) except on the Self-Efficacy (p=0.18) and Symptom Stability (p=0.91). On the SF-36, depression remission was associated with significant improvement in subscales of the Physical and Mental Component Summary except the Pain Index (p=0.34). The 6MWT improved more in depression remission compared to non-remission group (difference from baseline: 63.51±238.78 vs. 16.24±115.70 meters, p=0.03).
HF patients whose depressive symptoms remitted had significantly greater improvement in physical function, social function, and quality of life.
heart failure; depression; health status; Kansas City Cardiomyopathy Questionnaire; 6-Minute Walk Test
RV dysfunction frequently occurs and independently prognosticates in left-sided HF. It is not clear which right ventricular (RV) afterload measure has the greatest impact on RV function and prognosis. We examined the determinants, prognostic role and response to treatment of pulmonary arterial capacitance (PAC, ratio of stroke volume over pulmonary pulse pressure), in relation to pulmonary vascular resistance (PVR) in heart failure (HF).
Methods and Results
We reviewed 724 consecutive patients with HF who underwent right heart catheterization between 2000 and 2005. Changes in PAC were explored in an independent cohort of 75 subjects treated for acute decompensated HF. PAC showed a strong inverse relation with PVR (r=−0.64) and wedge pressure (r=−0.73), and provides stronger prediction of significant RV failure than PVR (AUC ROC 0.74 vs 0.67 respectively, p = 0.003). During a mean follow-up of 3.2 ± 2.2 years, both lower PAC (p<0.0001) and higher PVR (p<0.0001) portend more adverse clinical events (all-cause mortality and cardiac transplantation). In multivariate analysis, PAC (but not PVR) remains an independent predictor (Hazard ratio =0.92 [95% confidence interval: 0.84–1.0, p=0.037]). Treatment of HF resulted in a decrease in PVR (270±165 to 211±88 dynes·sec·cm−5, p=0.002), a larger increase in PAC (1.65±0.64 to 2.61±1.42 ml/mmHg, p<0.0001), leading to an increase in pulmonary arterial time constant (PVR × PAC) (0.29±0.12 to 0.37±0.15 sec, p<0.0001).
PAC bundles the effects of PVR and left sided filling pressures on RV afterload, explaining its strong relation with RV dysfunction, poor long-term prognosis, and response to therapy.
heart failure; hemodynamics; pulmonary arterial capacitance; pulmonary vascular resistance
While plasma palmitoleic acid has been positively associated with blood pressure, inflammation, and insulin resistance, its association with heart failure has not been investigated. We assessed whether plasma phospholipid cis palmitoleic acid was associated with heart failure risk.
Methods and Results
This ancillary study of the Physicians’ Health Study used a risk set sampling method to select 788 matched pairs. For each case of incident heart failure, we randomly selected a control among subjects that were free of heart failure and alive at the time of index case diagnosis and matched on age, year of birth, race, and time of blood collection. Plasma phospholipid fatty acids were measured using gas chromatography. Heart failure was ascertained using annual follow-up questionnaire and validated in a subsample. In a multivariable conditional logistic regression, odds ratios (95% CI) for heart failure were 1.0 (ref), 1.06 (0.75-1.48), 1.20 (0.85-1.68), and 1.58 (1.11-2.25) across consecutive quartiles of cis palmitoleic acid (p for trend 0.009). Each standard deviation increase in plasma cis palmitoleic acid was associated with 17% higher odds of heart failure (95% CI: 2% to 33%) in a multivariable model. In a secondary analysis, each standard deviation increase of log-stearoyl-coA desaturase activity (16:1n-7/16:0 ratio) was positively associated with the risk of heart failure [OR: 1.14 (95% CI: 1.00-1.29)] whereas oleic acid and cis-vaccenic acid concentrations were not related to heart failure risk.
Our data showed a positive association between plasma phospholipid cis-palmitoleic acid and heart failure risk in male physicians.
heart failure; epidemiology; fatty acids; cis-palmitoleic acids; risk factors
Heart failure (HF) can occur in patients with preserved (HFpEF, EF 50%) or reduced (HFrEF, EF<50%) ejection fraction (EF), but changes in EF after HF diagnosis are not well described.
Methods and Results
Among a community cohort of incident HF patients diagnosed from 1984–2009 in Olmsted County, Minnesota, we obtained all EFs assessed by echocardiography from initial HF diagnosis until death or last follow-up through March 2010. Mixed effects models fit a unique linear regression line for each person using serial EF data. Compiled results allowed estimates of the change in EF over time in HFpEF and HFrEF. Among 1233 HF patients (48.3% male, mean age 75.0 years, mean follow-up 5.1 years), 559 (45.3%) had HFpEF at diagnosis. In HFpEF, on average, EF decreased by 5.8% over 5 years (p<0.001) with greater declines in older individuals and those with coronary disease. Conversely, EF increased in HFrEF (average increase 6.9% over 5 years, p<0.001). Greater increases were noted in women, younger patients, individuals without coronary disease, and those treated with evidence-based medications. Overall, 39% of HFpEF patients had an EF<50% and 39% of HFrEF patients had an EF≥50% at some point after diagnosis. Decreases in EF over time were associated with reduced survival while increases in EF were associated with improved survival.
These data suggest that progressive contractile dysfunction may contribute to the pathophysiology of HFpEF. Prospective longitudinal studies are needed to confirm these observations and establish the mechanism and clinical relevance of decline in EF over time in HFpEF.
heart failure; echocardiography; ejection fraction; community; longitudinal
Patients with heart failure and preserved ejection fraction (HFpEF) display increased adiposity and multiple comorbidities, factors that in themselves may influence cardiovascular (CV) structure and function. This has sparked debate as to whether HFpEF represents a distinct disease or an amalgamation of comorbidities. We hypothesized that fundamental CV structural and functional alterations are characteristic of HFpEF, even after accounting for body size and comorbidities.
Methods and Results
Comorbidity adjusted CV structural and functional parameters scaled to independently generated and age appropriate allometric powers were compared in community-based cohorts of HFpEF patients (n=386) and age/gender-matched healthy (CON, n=193) and hypertensive (HTN, n=386) controls. Within HFpEF patients, body size and concomitant comorbidity adjusted CV structural and functional parameters and survival were compared in those with and without individual comorbidities. Among HFpEF patients, comorbidities (obesity, anemia, diabetes and renal dysfunction) were each associated with unique clinical, structural, functional and prognostic profiles. However, after accounting for age, gender, body size and comorbidities, greater concentric hypertrophy, atrial enlargement and systolic, diastolic and vascular dysfunction were consistently observed in HFpEF compared to CON and HTN.
Comorbidities influence ventricular-vascular properties and outcomes in HFpEF, yet fundamental disease-specific changes in cardiovascular structure and function underlie this disorder. These data support the search for mechanistically-targeted therapies in this disease.
heart failure with preserved ejection fraction; hypertension; diabetes; renal dysfunction; obesity
Despite a national organ donor shortage and a growing population of patients with end-stage heart disease, the acceptance rate of donor hearts for transplantation is low. We sought to identify donor predictors of allograft non-utilization, and to determine whether these predictors are in fact associated with adverse recipient post-transplant outcomes.
Methods and Results
We studied a cohort of 1,872 potential organ donors managed by the California Transplant Donor Network from 2001–2008. Forty five percent of available allografts were accepted for heart transplantation. Donor predictors of allograft non-utilization included age>50 years, female sex, death due to cerebrovascular accident, hypertension, diabetes, a positive troponin assay, left ventricular dysfunction and regional wall motion abnormalities, and left ventricular hypertrophy. For hearts that were transplanted, only donor cause of death was associated with prolonged recipient hospitalization post-transplant, and only donor diabetes was predictive of increased recipient mortality.
While there are many donor predictors of allograft discard in the current era, these characteristics appear to have little effect on recipient outcomes when the hearts are transplanted. Our results suggest that more liberal use of cardiac allografts with relative contraindications may be warranted.
Organ donor; Heart transplantation; Transplant recipients; Transplant outcomes
Arginine vasopressin (AVP) levels are elevated in proportion to heart failure (HF) severity and are associated with higher cardiovascular mortality in ambulatory patients. However, the relationship between baseline and trends in AVP with outcomes in patients hospitalized for worsening HF with reduced ejection fraction (EF) is unclear.
Methods and Results
The EVEREST (Efficacy of Vasopressin Antagonism in Heart Failure Outcome Study with Tolvaptan) trial investigated the effects of tolvaptan in patients with worsening HF and EF≤40%. The present analysis examined baseline and follow-up AVP levels in 3,196 EVEREST patients with valid AVP measurements. Co-primary endpoints included all-cause mortality (ACM), and the composite of cardiovascular mortality or HF hospitalization (CVM/H). Median follow-up was 9.9 months. Times to events were compared with univariate log-rank tests and multivariable Cox regression models, adjusted for baseline risk factors. After adjusting for baseline covariates, elevated AVP levels were associated with increased ACM (hazard ratio [HR] 1.33, 95% confidence interval [CI] 1.13 –1.55) and CVM/H (HR 1.23, 95% CI 1.08 –1.39). There was no interaction of baseline AVP with treatment assignment in terms of survival (p=0.515). Tolvaptan therapy increased the proportion of patients with elevated AVP (p<0.001), but this had no effect on mortality (HR 0.95, 95% CI 0.72 – 1.24).
Elevated baseline AVP level was independently predictive of mortality, but did not identify a group of patients who had improved outcomes with tolvaptan treatment. Tolvaptan treatment increased AVP levels during follow-up, but this incremental increase was not associated with worsened outcomes.
heart failure; drugs; hormones; outcomes
Adenosine (AD) elicits cardioprotection through A1-receptor (A1R) activation. Therapy with AD A1R agonists, however, is limited by undesirable actions of full agonism such as bradycardia. This study examined the effects of capadenoson (CAP), a partial AD A1R agonist, on left ventricular (LV) function and remodeling in dogs with heart failure (HF).
Methods and Results
12 dogs with microembolization-induced HF were randomized to 12 weeks oral therapy with CAP (7.5 mg Bid, n=6) or to no therapy (Control, n=6). LV end-diastolic (EDV) and end-systolic (ESV) volumes, ejection fraction (EF), plasma norepinephrine (NE) and n-terminal pro-brain natriuretic peptide (nt-pro BNP) were measured before (PRE) and 1 and 12 weeks after therapy (POST). LV tissue obtained at POST was used to assess volume fraction of interstitial fibrosis (VFIF), SERCA-2a activity, expression of mitochondria uncoupling proteins (UCP) and glucose transporters (GLUT). In controls, EDV and ESV increased and EF decreased significantly from PRE to POST (EF: 30±2 vs. 27±1 %, p<0.05). In CAP-treated dogs, EDV was unchanged; EF increased significantly after one week (36±2 vs. 27±2 %, p<0.05) with a further increase at POST (39±2 %, p<0.05) while ESV decreased. CAP significantly decreased VFIF, normalized SERCA-2a activity and expression of UCP-2 and -3, and GLUT-1 and -2 and significantly decreased NE and nt-pro BNP.
In HF dogs, CAP improves LV function and prevents progressive remodeling. Improvement of LV systolic function occurs early after initiating therapy. The results support development of partial AD A1R agonists for the treatment of chronic HF.
Heart failure; Ventricular remodeling; Protein expression; Adenosine receptors
Acculturation to U.S. society among minority patients may influence health outcomes beyond race and ethnicity alone. In particular, those who are foreign-born and who do not speak English as their primary language may have greater challenges interacting with the health care system and thus be at greater risk for adverse outcomes.
Methods and Results
We studied patients hospitalized with a principal discharge diagnosis of HF between January 2000 and December 2007 in an integrated delivery system that cares for minority patients. Individuals were defined as having low acculturation if their primary language was not English and their country of birth was outside of the U.S. Multivariable logistic regression and Cox proportional hazards regression were used to determine the independent risk of 30-day rehospitalization and 1-year mortality, respectively. Candidate adjustment variables included demographics (age, gender, race/ethnicity), coexisting illnesses, laboratory values, left ventricular systolic function, and characteristics of the index admission. Of 1,268 patients, 30% (n=379) were Black, 39% (n=498) Hispanic, and 27% (n= 348) White. Eighteen percent (n=228) had low acculturation. After adjustment, low acculturation was associated with a higher risk of readmission at 30 days (OR 1.70; 95% CI 1.07-2.68) but not 1-year all-cause mortality (HR 0.69; 95% CI 0.42-1.14).
Patients with HF who are foreign-born and do not speak English as their primary language have a greater risk of rehospitalization, independent of clinical factors and race/ethnicity. Future studies should evaluate whether culturally concordant interventions focusing on such patients may improve outcomes for this patient population.
heart failure; readmission; survival; risk factors; health disparities
Renal function is a strong predictor of adverse events in heart failure. Current renal function measures are imperfect and Cystatin C (CysC) is promoted as a better marker of glomerular filtration rate (GFR). This study compares the prognostic utility of CysC and derived GFR estimates with other measures of renal function in patients with chronic heart failure.
Methods and Results
We measured serum CysC levels in 823 heart failure patients undergoing coronary angiography with follow-up of major adverse cardiovascular events (MACE = death, myocardial infarction, stroke). Cystatin C levels strongly correlated with creatinine (r = 0.73), blood urea nitrogen (r = 0.70), and eGFRMDRD (r = −0.62) (all p < 0.001). However, the correlation was lower in eGFR ≥ 60ml/min/1.73m2. CysC-based measures significantly improved areas under the ROC curve for the prediction of MACE, especially in eGFR ≥ 60ml/min/1.73m2 (p < 0.01). Net reclassification improvement was 22.2% (p < 0.001) in this group. CysC remained an independent predictor of MACE (p < 0.001) after adjustment for traditional risk factors and BNP.
Cystatin C is an independent predictor of adverse events in chronic heart failure. It adds prognostic value to creatinine, particularly in patients with “preserved” renal function.
heart failure; kidney; prognosis
Heart failure (HF) with preserved ejection fraction (HFpEF) or “diastolic HF” accounts for approximately half of HF cases. To date, neurohumoral antagonists have failed to show a significant benefit on clinical outcomes in HFpEF. While our understanding of the pathophysiology of HFpEF continues to develop, multiple therapeutic targets have been identified in HFpEF which may be modifiable by augmentation of the intracellular second messenger cyclic guanosine monophosphate (cGMP) via phosphodiesterase-5 inhibition (PDE5I) in HFpEF. The PhosphodiesteRasE-5 Inhibition to Improve CLinical Status And EXercise Capacity in Diastolic Heart Failure (RELAX trial; clinicaltrials.gov NCT00763867) is being conducted within the NHLBI sponsored HF clinical research network and tests the hypothesis that chronic PDE5I (sildenafil® 20 mg tid for 12 weeks followed by 60 mg tid for 12 weeks) improves exercise capacity and clinical status in patients with HFpEF. Here we provide the rationale for RELAX by summarizing the pathophysiologic derangements in HFpEF and the evidence that PDE5I may ameliorate these derangements. The design of the RELAX trial is described and the rationale for the primary endpoint in RELAX (change in peak oxygen consumption) is provided.
Heart Failure; Diastolic Heart Failure; Phosphodiesterase Inhibitor, Heart Failure
The prognostic ability of a single measurement of peak oxygen uptake (VO2) is well established in patients with chronic heart failure (HF). The relation between a change in peak VO2 and clinical outcomes is not well defined.
Methods and Results
This investigation determined if an increase in peak VO2 was associated with a lower risk of the primary endpoint of time to all-cause mortality or all-cause hospitalization and three secondary endpoints. In Heart Failure and a Controlled Trial to Investigate Outcomes of Exercise Training (HF-ACTION), an exercise training trial for patients with systolic HF, cardiopulmonary exercise tests were performed at baseline and approximately three months later in 1620 participants. Median peak VO2 in the combined sample increased from 15.0 (11.9–18.0 Q1–Q3) to 15.4 (12.3–18.7 Q1–Q3) mL-kg−1-min−1. Every 6% increase in peak VO2, adjusted for other significant predictors, was associated with a 5% lower risk of the primary endpoint (HR = 0.95; CI = 0.93–0.98; p < 0.001); a 4% lower risk of the secondary endpoint of time to cardiovascular mortality or cardiovascular hospitalization (HR = 0.96; CI = 0.94–0.99; p < 0.001); an 8% lower risk of cardiovascular mortality or HF hospitalization (HR = 0.92; CI = 0.88–0.96; p < 0.001) and a 7% lower all-cause mortality (HR = 0.93; CI = 0.90–0.97; p < 0.001).
Among patients with chronic systolic HF, a modest increase in peak VO2 over three months was associated with a more favorable outcome. Monitoring the change in peak VO2 for such patients may have benefit in assessing prognosis.
exercise testing; heart failure; peak VO2
The BIO14.6 hamster provides a useful model of hereditary cardiomyopathies and muscular dystrophy. Previous delta-sarcoglycan (δSG) gene therapy (GT) studies were limited to neonatal and young adult animals, and prevented the development of cardiac and skeletal muscle dysfunction. GT of a pseudo-phosphorylated mutant of phospholamban (S16EPLN) moderately alleviated the progression of cardiomyopathy.
Methods and Results
We treated 4 month-old BIO14.6 hamsters with established cardiac and skeletal muscle diseases intravenously with a serotype-9 adeno-associated viral vector carrying δSG alone or in combination with S16EPLN. Prior to treatment at age 14 weeks, the left ventricular (LV) fractional shortening by echocardiography was 31.3% vs. 45.8% in normal hamsters. In a randomized trial, GT halted progression of LV dilation and LV dysfunction. Also, respiratory function improved. Addition of S16EPLN had no significant additional effects. δSG-GT prevented severe degeneration of the transverse tubular system in cardiomyocytes (electron tomography), and restored distribution of dystrophin and caveolin-3. All placebo-treated hamsters, except animals removed for the hemodynamic study, died with heart failure between 34 and 67 weeks of age. In the GT group, signs of cardiac and respiratory failure did not develop, and animals lived for 92 weeks or longer, an age comparable to that reported in normal hamsters.
GT was highly effective in BIO14.6 hamsters even when given in late stage disease, a finding that may carry implications for the future treatment of hereditary cardiac and muscle diseases in humans.
gene therapy; cardiomyopathy; muscles; heart failure; ventilation
Elevated resting pulmonary arterial pressure (PAP) in patients with left ventricular systolic dysfunction (LVSD) purports a poor prognosis. However, PAP response patterns to exercise in LVSD and their relationship to functional capacity and outcomes have not been characterized.
Methods and Results
Sixty consecutive patients with LVSD (age 60±12 years, LV ejection fraction 0.31±0.07, mean±SD) and 19 controls underwent maximum incremental cardiopulmonary exercise testing with simultaneous hemodynamic monitoring. During low-level exercise (30 Watts), LVSD subjects compared to controls, had greater augmentation in mean PAPs (15±1 vs. 5±1 mmHg), transpulmonary gradients (5±1 vs. 1±1 mmHg), and effective PA elastance (0.05±0.02 vs. −0.03±0.01 mmHg/ml, p<0.0001 for all). A linear increment in PAP relative to work (0.28±0.12 mmHg/watt) was observed in 65% of LVSD patients, which exceeded that observed in controls (0.07±0.02 mmHg/watt, P<0.0001). Exercise capacity and survival was worse in patients with a PAP/watt slope above the median than in patients with a lower slope. In the remaining 35% of LVSD patients, exercise induced a steep initial increment in PAP (0.41±0.16 mmHg/watt) followed by a plateau. The plateau pattern, compared to a linear pattern, was associated with reduced peak VO2 (10.6±2.6 vs. 13.1±4.0 ml/kg/min, P=0.005), lower right ventricular stroke work index augmentation with exercise (5.7±3.8 vs. 9.7±5.0 g/m2, P=0.002), and increased mortality (HR 8.1, 95% CI 2.7-23.8, P<0.001).
A steep increment in PAP during exercise and failure to augment PAP throughout exercise are associated with decreased exercise capacity and survival in patients with LVSD, and may therefore represent therapeutic targets.
Clinical Trial Information
http://www.clinicaltrials.gov. Unique Identifier: NCT00309790)
hypertension, pulmonary; exercise; heart failure
Although right-sided filling pressures often mirror left-sided filling pressures in systolic heart failure, it is not known whether a similar relationship exists in heart failure with preserved ejection fraction.
Methods and Results
Eleven subjects with heart failure with preserved ejection fraction underwent right heart catheterization at rest and under loading conditions manipulated by lower body negative pressure and saline infusion. Right atrial pressure (RAP) was classified as elevated when ≥10 mm Hg and pulmonary capillary wedge pressure (PCWP) when ≥22 mm Hg. If both the RAP and the PCWP were elevated or both not elevated, they were classified as concordant; otherwise, they were classified as discordant. Correlation of RAP and PCWP was determined by a repeated measures model. Among 66 paired measurements of RAP and PCWP, 44 (67%) had a low RAP and PCWP and 8 (12%) a high RAP and PCWP, yielding a concordance rate of 79%. In a sensitivity analysis performed by varying the definition of elevated RAP (from 8 to 12 mm Hg) and PCWP (from 15 to 25 mm Hg), the mean±SD concordance of RAP and PCWP was 76±10%. The correlation coefficient of RAP and PCWP for the overall cohort was r=0.86 (P<0.0001).
Right-sided filling pressures often reflect left-sided filling pressures in heart failure with preserved ejection fraction, supporting the role of estimation of jugular venous pressure to assess volume status in this condition.
heart failure; hemodynamics; physical examination; jugular venous pressure