Fractional exhaled nitric oxide (eNO) is recognized as a marker of pulmonary endothelial function. Oxidative stress is associated to systemic endothelial nitric oxide production but its correlation with eNO in heart failure (HF) patients has not been described. Previous studies have reported increased eNO levels after exercise in symptomatic HF patients but decreased levels in pulmonary arterial hypertension. Our objective is to prospectively examine the potential myocardial and functional determinants of exercise-induced rise of eNO in HF.
Methods and Results
Thirty-four consecutive ambulatory patients with chronic systolic HF (left ventricular ejection fraction [LVEF] ≤45%) underwent symptom-limited cardiopulmonary stress testing and echocardiography. eNO was determined immediately after exercise. Systemic endothelial dysfunction was assessed by asymmetric dimethylarginine (ADMA) and the L-arginine/ADMA ratio. In our study cohort (mean age 53 ±13 years, 76% male, median LVEF 31%, interquartile range [IQR]: 25 to 40), the mean eNO was 23 ±9 ppb. eNO levels were higher in patients with diastolic dysfunction stages 2 or 3 than stage 1 or normal diastology (26.1±9 vs. 19.5±7 ppb, p=0.013). eNO had a positive correlation with estimated systolic pulmonary artery pressure (r= 0.57; p=0.0009) and indexed left atrium volume (r= 0.43; p= 0.014), but did not correlate with cardiopulmonary exercise test parameters, ADMA, or symptom score.
In contrast to prior reports, the increase in post-exercise eNO observed in stable chronic systolic HF patients may be attributed to the presence of underlying pulmonary venous hypertension probably secondary to advanced diastolic dysfunction.
Exhaled nitric oxide; congestive heart failure; pulmonary hypertension; echocardiography; asymmetric dimethylarginine
Reports that patients with heart failure and anemia incur greater costs and medical resource use have relied largely on data with limited clinical detail.
HF-ACTION, a large trial of exercise training in heart failure, recorded hemoglobin at baseline. Medical resource use and hospital bills for inpatient and emergency department visits were collected throughout the study. We analyzed hemoglobin as a continuous variable to evaluate relationships with medical resource use and costs over 1 year.
Among 1,763 patients with baseline hemoglobin levels, those with lower hemoglobin levels tended to be older, African American, and women and to have more severe heart failure. Lower hemoglobin was significantly associated with more hospital admissions, inpatient days, outpatient visits, and urgent care or emergency department visits (all P < .005, unadjusted). Although cost outliers influenced estimates, these observations were distributed across hemoglobin levels. Mean 1-year costs across hemoglobin levels defined as ≤11, >11–12, >12–13, >13–14, >14–15, and >15 g/dL were $21,106, $20,189, $16,249, $17,989, $13,216, and $12,492, respectively (P < .001, unadjusted). Significant associations remained after multivariable adjustment.
Patients with lower baseline hemoglobin levels experienced progressively greater resource use and higher costs.
Anemia; health care costs; heart failure
Prolonged electrocardiogram (ECG) QRS duration (≥120 ms) is a risk factor for death in systolic heart failure, but its effects in heart failure with preserved systolic function (HFPSF) have not been extensively studied. We hypothesized that prolonged ECG QRS duration would independently predict long-term mortality in hospitalized HFPSF patients.
Methods and Results
We analyzed 872 HFPSF patients (defined as left ventricular ejection fraction ≥50%) admitted to Michigan community hospitals between 2002 and 2004 and followed for a median of 660 days. We used Cox proportional hazards models to assess mortality hazard for prolonged QRS duration (≥120 ms) on the last available predischarge ECG, first on a univariable basis and then after multivariable adjustment for other known risk factors. Prolonged QRS duration increased univariable all-cause mortality (HR 1.71; 95% CI 1.33–2.19, P < .001) and after multivariable adjustment (HR 1.31; 95% CI 1.01–1.71, P = .04). The univariable effect size was larger in younger patients. In multivariable models, there was no significant interaction between prolonged QRS and age, hypertension, or coronary artery disease status.
Prolonged QRS duration (≥120 ms) on a predischarge ECG is an independent and consistent predictor of long-term mortality in hospitalized HFPSF patients.
Diastolic heart failure; normal ejection fraction; outcomes; intraventricular conduction delay; elderly
In the failing human heart, abnormalities of Ca2+ cycling have been described, but there is scant knowledge about Ca2+ handling in the skeletal muscle of humans with HF. We tested the hypothesis that in humans with HF, Ca2+ cycling proteins in skeletal muscle are abnormal.
Methods and Results
Ten advanced HF patients (50.4±3.7 years), and 9 age matched controls underwent vastus lateralis biopsy. Western blot analysis showed that sarco(endo)plasmic reticulum Ca2+-ATPase (SERCA)2a, which is responsible for Ca2+ sequestration into the sarcoplasmic reticulum(SR), was lower in HF vs controls (4.8±0.5vs7.5±0.8AU, p=0.01). Although phospholamban (PLN), which inhibits SERCA2a, was not different in HF vs controls, phosphorylation (SER16 site) of PLN, which relieves this inhibition, was reduced (0.8±0.1vs3.9±0.9AU, p=0.004). Dihydropyridine receptors were reduced in HF, (2.1±0.4vs3.6±0.5AU, p=0.04). We tested the hypothesis that these abnormalities of Ca2+ handling protein content and regulation were due to increased oxidative stress, but oxygen radical scavenger proteins were not elevated in the skeletal muscle of HF patients.
In chronic HF, marked abnormalities of Ca2+ handling proteins are present in skeletal muscle, which mirror those in failing heart tissue. This suggests a common mechanism, such as chronic augmentation of sympathetic activity and autophosphorylation of Ca2+-calmodulin-dependent-protein kinase II.
exercise intolerance; sarco(endo)plasmic reticulum Ca2+-ATPase (SERCA)2a; sympathetic nerve activity; oxidative stress
Fatigue is a prominent and poorly understood symptom of heart failure with reduced ejection fraction (HFrEF). The purpose of this study was to determine whether fatigue correlated with immune biomarkers and prognosis.
In patients with HFrEF (N = 59) and healthy controls (N = 25), we prospectively measured fatigue (Profile of Mood States), depressive symptoms (Patient Health Questionnaire-8), sleep quality (Pittsburgh Sleep Quality Index), and immune biomarkers (plasma C-reactive protein [CRP], tumor necrosis factor-α [TNFα], and interleukins [IL-6 and IL-10]). Seattle Heart Failure Model (SHFM) mortality risk scores were determined. Patients with HFrEF had significantly greater fatigue and depressive symptoms and poorer sleep quality compared to control subjects. When controlling for depressive symptoms, however, fatigue did not differ significantly between patients with HFrEF and controls. Patients with HFrEF had significantly lower levels of IL-10 compared to controls. Cytokines did not correlate significantly with fatigue, but fatigue was significantly associated with higher SHFM scores.
Depressive symptoms were an important covariate of fatigue in patients with HFrEF. Our study findings were the first to show a positive association between fatigue and the SHFM score, indicating that fatigue was associated with poorer prognosis.
Sudden cardiac death (SCD) due to ventricular tachyarrhythmias accounts for approximately 450,000 annual deaths in the U.S.; many of these cases involve patients with chronic heart failure (HF). Prediction of which HF patients are most susceptible to SCD is difficult, and it is uncertain whether gene polymorphisms associated with HF outcomes are also linked to arrhythmic risk.
We evaluated 485 patients with chronic HF to see whether the Angiotensin Receptor Type 1 (AT1) A1166C or Angiotensin Converting Enzyme Insertion/Deletion (ACE I/D) polymorphisms were associated with a higher rate of ventricular arrhythmias requiring implantable cardioverter defibrillator (ICD) therapies over a 5-year period. We assessed the correlation between polymorphisms and antitachycardia pacing (ATP) and/or ICD shocks.
Patients with AT1-1166 CC genotype had an increased rate of all events: ATP plus ICD shocks (p=0.02). There was no association between ACE I/D genotype and ICD therapies. Furthermore, circulating levels of microRNA-155 (miR-155), a microRNA known to posttranscriptionally regulate AT1R expression, were significantly decreased in the CC compared to the AC and AA genotypes and were associated with ICD events.
Our study suggests that the AT1R-1166 CC genotype is associated with increased ICD therapies in patients with chronic HF, and the level of circulating miR-155 may be a potential marker for arrhythmic risk. While these findings are novel, they will need replication and validation in larger cohorts of chronic HF patients.
Genetic Polymorphisms; Angiotensin; Angiotensin Type 1 Receptor; Sudden Cardiac Death; Heart Failure; microRNA
To evaluate nocturia severity and nocturia-related differences in sleep, daytime symptoms and functional performance among patients with stable heart failure (HF).
Method & Results
In this cross-sectional observational study we recruited 173 patients [M age = 60.3 ±16.8 years; n = 60 (35%) female; left ventricular ejection fraction M = 32 ±14.6] with stable chronic HF from HF disease management programs in the Northeastern United States. Participants reported nocturia and completed a Six Minute Walk test (6 MWT), one night of ambulatory polysomnography (PSG), and the Medical Outcomes Study SF 36, Epworth Sleepiness, Pittsburgh Sleep Quality Index, Multi-Dimensional Assessment of Fatigue, and the Centers for the Epidemiological Studies of Depression scales. Participants reported no (n = 30/17.3%), one or more (n = 87/50.2%), and three or more (n = 56/32.4%) nightly episodes of nocturia. There were decreases in sleep duration and efficiency, stages REM and 3–4 sleep, physical function, and 6 MWT distance; and increases in the percent wake after sleep onset, insomnia symptoms, fatigue and sleepiness across levels of nocturia severity.
Nocturia is common, severe, and closely associated with decrements in sleep and functional performance and increases in fatigue and sleepiness in patients with stable HF.
heart failure; insomnia; nocturia; sleep; fatigue; physical function; quality of life
Heart failure (HF) self-care interventions can improve outcomes, but less than optimal adherence may limit their effectiveness. We evaluated if adherence to weight monitoring and diuretic self-adjustment was associated with HF-related ED visits or hospitalizations.
Methods and Results
We performed a case-control analysis nested in a HF self-care randomized trial. Participants received HF self-care training including weight monitoring and diuretic self-adjustment, which they were to record in a diary. We defined cases as HF-related ED visits or hospitalizations and the 7 preceding days; controls were defined as 7-day periods free of ED visits and hospitalizations. We used logistic regression to compare weight monitoring and diuretic self-adjustment adherence in cases and controls, adjusted for demographic and clinical covariates. Among 303 participants, we identified 81 HF-related ED visits or hospitalizations (cases) in 54 patients over one year of follow-up. Weight monitoring adherence (OR 0.42, 95% CI 0.23, 0.76) and diuretic self-adjustment adherence (OR 0.44, 95% CI 0.19, 0.98) were both associated with lower adjusted odds of HF-related ED visits or hospitalizations.
Adherence to weight monitoring and diuretic self-adjustment was associated with lower odds of HF-related ED visits or hospitalizations. Adherence to these activities may reduce HF-related morbidity.
Congestive Heart Failure; Compliance
Placement of an elastic and biodegradable patch onto a sub-acute myocardial infarct (MI) provides temporary elastic support that may act to effectively alter adverse left ventricular (LV) remodeling processes.
Two weeks after permanent left coronary ligation in Lewis rats, the infarcted anterior wall was covered with poly(ester urethane)urea PEUU (MI+PEUU, n=15) or expanded polytetrafluoroethylene (MI+ePTFE, n=15) patches, or had no implantation (MI+sham, n=12). Eight weeks after surgery, cardiac function and histology were assessed.
The ventricular wall in the MI+ePTFE and MI+sham groups was comprised of fibrous tissue, while PEUU implantation induced α-smooth muscle actin positive muscle bundles co-expressing sarcomeric α-actinin and cardiac specific troponin-T. This pattern of co-localization was also found in developing embryonic myocardium. Cardiac transcription factors Nkx-2.5 and GATA-4 were strongly expressed in the muscle bundles. In the MI+sham group end-diastolic LV cavity area (EDA) increased and the %fractional area change (%FAC) decreased. For ePTFE patched animals, both EDA and %FAC decreased. In contrast, with MI+PEUU patching %FAC increased while EDA was maintained. With dobutamine stress echocardiography MI+PEUU patched LVs possessed contractile reserve significantly larger than the MI+sham group.
MI+PEUU patch implantation onto sub-acute infarcted myocardium induced muscle cellularization with characteristics of early developmental cardiomyocytes as well as providing a functional reserve.
infarction; remodeling; patch implantation; cellularization
Hospitalized heart failure patients have a high readmission rate. We sought to determine the independent risk due to central sleep apnea (CSA) of readmission in patients with systolic heart failure (SHF)
Methods and Results
Prospective observational cohort study of hospitalized patients with SHF. Patients underwent sleep studies during the hospitalization and were followed for 6 months to determine their rate of cardiac readmissions. 784 consecutive patients were included. 165 patients had CSA and 139 had no sleep disordered breathing (SDB). The remainder had obstructive sleep apnea (OSA). The rate ratio for 6 months cardiac readmissions was 1.53 (95% CI (1.1, 2.2), p=.03) in CSA patients compared to no SDB. This rate ratio is adjusted for systolic function, type of cardiomyopathy, age, weight, sex, diabetes, coronary disease, length of stay, admission sodium, creatinine, hemoglobin, blood pressure and discharge medications. Severe OSA was also an independent predictor of readmissions with an adjusted rate ratio of 1.49 (p=.04).
In this first evaluation of the impact of SDB on cardiac readmissions in heart failure, CSA was an independent risk factor for 6 month cardiac readmissions. The effect size of CSA exceeded that of all known predictors of heart failure readmissions.
Sleep Disordered breathing; Central sleep apnea; Obstructive sleep apnea; heart failure; readmissions
Transient changes in the composition of the myocardial extracellular matrix may contribute to the ventricular systolic dysfunction in Stress-induced cardiomyopathy (SIC). We examined the changes in plasma matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) that occur early after the clinical presentation of SIC.
Methods and Results
Ten patients with SIC were enrolled. Plasma concentrations of the six major MMPs (MMP-1,-2,-3,-7,-8,-9) and all 4 tissue inhibitors of MMPs (TIMP-1,-2,-3,-4) were analyzed and compared with data from fifteen control subjects. Within 24 hours of the clinical presentation, SIC patients had lower MMP-1 levels (0.41±0.13 vs 0.70±0.13 pg/mL, p = 0.048) and MMP-8 levels (1.61±0.34 vs 4.84±1.38 pg/mL, p = 0.001) and higher TIMP-4 levels (3.06±0.40 vs 2.16±0.18 pg/mL, p =0.05) compared to control. Seven of nine SIC patients had elevated LV end-diastolic pressures, and all had normal LV end-diastolic dimensions and volumes.
Patients afflicted with SIC had MMPs and TIMPs profiles similar to those described in hypertensive heart disease and diastolic heart failure and different than the profiles following myocardial infarction. Our findings uncovered a unique biomolecular profile in SIC during the first 24 hours of presentation.
Metalloproteinases; Cardiomyopathy; Stress; Stress-induced cardiomyopathy
Familial involvement is common in dilated cardiomyopathy (DCM) and >40 genes have been implicated in causing disease. However, the role of genetic testing in clinical practice is not well defined. We examined the experience of clinical genetic testing in a diverse DCM population to characterize the prevalence and predictors of gene mutations.
Methods and Results
We studied 264 unrelated adult and pediatric DCM index patients referred to 1 reference lab for clinical genetic testing. Up to 10 genes were analyzed (MYH7, TNNT2, TNNI3, TPM1, MYBPC3, ACTC, LMNA, PLN, TAZ, and LDB3), and 70% of patients were tested for all genes. The mean age was 26.6 ± 21.3 years, and 52% had a family history of DCM. Rigorous criteria were used to classify DNA variants as clinically relevant (mutations), variants of unknown clinical significance (VUS), or presumed benign. Mutations were found in 17.4% of patients, commonly involving MYH7, LMNA, or TNNT2 (78%). An additional 10.6% of patients had VUS. Genetic testing was rarely positive in older patients without a family history of DCM. Conversely in pediatric patients, family history did not increase the sensitivity of genetic testing.
Using rigorous criteria for classifying DNA variants, mutations were identified in 17% of a diverse group of DCM index patients referred for clinical genetic testing. The low sensitivity of genetic testing in DCM reflects limitations in both current methodology and knowledge of DCM-associated genes. However, if mutations are identified, genetic testing can help guide family management.
Clinical genetics; heart failure; dilated cardiomyopathy; sarcomere genes; lamin A/C
Cardiomyopathy is a heterogeneous disease with a strong genetic component. A research-based pediatric cardiomyopathy registry (PCMR) identified familial, syndromic, or metabolic causes in 30% of children. However, these results pre-dated clinical genetic testing.
Methods and Results
We determined the prevalence of familial, syndromic, or metabolic causes in eighty-three consecutive unrelated patients referred for genetic evaluation of cardiomyopathy from 2006–2009. Seventy-six percent of probands (n=63) were categorized as familial, syndromic, or metabolic. Forty-three percent (n=18) of hypertrophic cardiomyopathy (HCM) patients had mutations in sarcomeric genes, with MYH7 and MYBPC3 mutations predominating. Syndromic (17%, n=7) and metabolic (26%, n=11) causes were frequently identified in HCM patients. The metabolic subgroup was differentiated by decreased endocardial shortening fraction on echocardiography. Dilated cardiomyopathy (DCM) patients had similar rates of syndromic (20%, n=5) and metabolic (16%, n=4) causes, but fewer familial cases (24%, n=6) than HCM patients.
The cause of cardiomyopathy is identifiable in a majority of affected children. An underlying metabolic or syndromic cause is identified in greater than 35% of children with HCM or DCM. Identification of etiology is important for management, family based risk assessment, and screening.
cardiomyopathy; heart failure; genetics; mutation; genetic testing
Given the association of depression with poorer cardiac outcomes, an American Heart Association Science Advisory has advocated routinly screening cardiac patients for depression using the two-item Patient Health Questionnaire (PHQ-2) “at a minimum.” Yet, the prognostic value of the PHQ-2 among HF patients is unknown.
Methods and Results
We screened hospitalized HF patients (ejection fraction (EF) <40%) that staff suspected may be depressed with the PHQ-2, and then determined vital status at up to 12-months follow-up. At baseline, PHQ-2 depression-screen positive patients (PHQ-2 (+); N=371) compared to PHQ-2 screen-negative patients (PHQ-2 (−); N=100) were younger (65 vs. 70), and more likely to report NYHA class III/IV than class II symptoms (67% vs. 39%) and lower levels of physical and mental health-related quality of life (all p ≤ 0.002), but were similar on other characteristics (65% male, 26% mean EF). At 12-months, 20% of PHQ-2 (+) vs. 8% of PHQ-2 (−) patients had died (p=0.007) and PHQ-2 status remained associated with both all-cause (hazard ratio (HR): 3.1 (95% CI: 1.4–6.7); p=0.003) and cardiovascular mortality (HR: 2.7 (1.1–6.6); p=0.03) even after adjustment for age, gender, EF, NYHA class, and a variety of other covariates.
Among hospitalized HF patients, a positive PHQ-2 depression screen is associated with an elevated 12-month mortality risk.
Depression; heart failure; Patient Health Questionnaire; mortality
Worsening renal function is common among patients hospitalized for acute decompensated heart failure (ADHF). When this occurs, subsequent management decisions often pit the desire for effective decongestion against concerns about further worsening renal function. There are no evidence-based treatments or guidelines to assist in these difficult management decisions. Ultrafiltration is a potentially attractive alternative to loop diuretics for the management of fluid overload in patients with ADHF and worsening renal function.
Methods and Results
The National Heart, Lung, and Blood Institute Heart Failure Clinical Research Network designed a clinical trial to determine if ultrafiltration results in improved renal function and relief of congestion compared with stepped pharmacologic care when assessed 96 hours after randomization in patients with ADHF and cardiorenal syndrome. Enrollment began in June 2008. This paper describes the rationale and design of the Cardiorenal Rescue Study in Acute Decompensated Heart Failure (CARRESS-HF).
Treating the signs and symptoms of congestion in ADHF is often complicated by worsening renal function. CARRESS-HF compares treatment strategies (ultrafiltration vs stepped pharmacologic care) for the management of worsening renal function in patients with ADHF. The results of the CARRESS-HF trial are expected to provide information and evidence as to the most appropriate approaches for treating this challenging patient population.
Cardiorenal syndrome; congestion; diuretics; ultrafiltration; heart failure
Single RDW assessment is a consistent prognostic marker of poor outcomes in heart failure as well as in other patient cohorts. The objective of this study is to determine the prognostic value of sequential red cell distribution width (RDW) assessment in ambulatory patients with chronic heart failure.
Methods and Results
We reviewed 6,159 consecutive ambulatory patients with chronic heart failure between 2001–2006, and examined changes in RDW values from baseline to 1-year follow-up. Clinical, demographic, laboratory, and ICD-9 coding data were extracted from electronic health records, and all-cause mortality was followed over a mean follow-up of 4.4 ± 2.4 years. In our study cohort, median baseline RDW was 14.9%. Subjects with RDW >16% at baseline (18.5% of cohort) was associated with a higher mortality rates than those ≤16%. For each +1% increment of baseline RDW, the risk ratio for all-cause mortality was 1.17 (95% confidence interval 1.15–1.19, p<0.0001). At 12-month follow-up (n=1,601), a large majority of subjects (68% in 1st tertile, 56% in 2nd tertile of baseline RDW) showed rising RDW, and correspondingly higher risk for all-cause mortality (risk ratio for +1% increase in changes in RDW was 1.08 [95% CI: 1.03–1.13, p=0.001]). This effect was independent of anemia status or other baseline cardiac or renal indices, and particularly strong in those with lower baseline RDW.
In our ambulatory cohort of patients with chronic heart failure, baseline and serial increase in RDW was associated with poor long-term outcomes independent of standard cardiac, hematologic, and renal indices.
Red cell distribution width; heart failure; prognosis
Implantable Cardioverter-Defibrillators (ICDs) reduce mortality in heart failure (HF). In patients requiring ventricular assist device (VAD), the benefit from ICD therapy is not well established. The aim of the study is to define the impact of ICD on outcomes in VAD - supported patients.
Methods and Results
We reviewed data for consecutive adult HF patients receiving VAD as bridge-to-transplantation from 1996 to 2003. Primary outcome was survival to transplantation. A total of 144 VADs were implanted [85 left ventricular (LVAD), 59 biventricular (BIVAD), age 50±12 years, 77% male, LVEF 18±9%, 54% ischemic]. Mean length of support was 119 days (range 1–670); 103 (72%) patients survived to transplantation. Forty-five patients had an ICD (33 LVAD, 12 BIVAD). More LVAD patients had an appropriate ICD shock before implantation than afterwards (16 vs. 7, p=0.02). There was a trend towards higher shock frequency before LVAD implant than after (3.3±5.2 vs 1.1±3.8 shocks/year, p=0.06). Mean time to first shock after VAD implant was 129±109 days. LVAD-supported patients with an ICD were significantly more likely to survive to transplantation (LVAD: 1-year actuarial survival to transplantation 91% with ICD vs. 57% without ICD, log-rank p=0.01; BIVAD: 54% vs. 47%, log-rank p=NS). An ICD was associated with significantly increased survival in a multivariate model controlling for confounding variables (OR 2.54, 95% CI 1.04-6.21, p=0.04).
Shock frequency decreases after VAD implantation, likely due to ventricular unloading, but appropriate ICD shocks still occur in 21% of patients. An ICD is associated with improved survival in LVAD-supported HF patients.
Implantable Cardioverter Defibrillators; Heart failure; Ventricular assist devices; Transplantation; Ventricular arrhythmias
Patients with heart failure (HF) experience depressive symptoms which contribute to poorer outcomes. We tested the effects of a brief cognitive therapy intervention on depressive symptoms, negative thinking, health-related quality of life, and cardiac event-free survival.
Methods and Results
Hospitalized patients with depressive symptoms (N=41, 66±11 yrs, 45% female, 81% NYHA Class III/IV) were randomly assigned to control group or a brief, nurse-delivered cognitive therapy intervention, delivered during hospitalization and followed by a one week booster phone call. Depressive symptoms, negative thinking and health-related quality of life were measured at one week and three months. Cardiac event-free survival was assessed at three months. Mixed models repeated measures ANOVA, Kaplan-Meier, and Cox regression were used for data analysis.
There were significant improvements in depressive symptoms and health-related quality of life in both groups but no interactions between group and time. The control group had shorter three-month cardiac event-free survival (40% vs 80%, p<.05) and a 3.5 greater hazard of experiencing a cardiac event (p=.04) than the intervention group.
Nurses can deliver a brief intervention to hospitalized patients with HF that may improve short-term event-free survival. Future research is needed to verify these results with a larger sample size.
Cardiovascular; Depression; Cognitive behavioral therapy
Autonomic abnormalities have been implicated in both diastolic dysfunction and abnormal heart rate (HR) recovery; however, few studies have assessed whether diastolic dysfunction is associated with abnormal HR recovery, and whether both modify exercise capacity.
Methods and Results
Exercise echocardiography with diastolic assessment was performed in 2826 patients with normal wall motion responses to symptom-limited exercise testing. HR recovery was defined as the difference in HR from peak exercise to 1 minute in recovery; abnormal HR recovery was defined as the lowest quartile. Mean HR recovery was 32±14 beats per minute. Patients with diastolic dysfunction or abnormal HR recovery had lower exercise capacity, and those with both had the lowest exercise capacity (p<0.0001 for comparison to normal responses). Indices of abnormal diastolic function were correlated with abnormal HR recovery. In multivariable analysis, after age, diastolic dysfunction (referent: normal diastolic function) was the strongest predictor of abnormal HR recovery (adjusted OR 1.47; 95% CI 1.20-1.80) and incrementally predictive of chronotropic incompetence (adjusted OR 1.42; 95% CI 1.16-1.74).
Diastolic dysfunction is independently associated with abnormal HR recovery after symptom-limited exercise. Further studies are needed to determine if diastolic function modifies the adverse outcomes observed in those with abnormal HR recovery.
Medication nonadherence contributes to hospitalization and mortality, yet there have been few interventions tested that improve adherence and reduce hospitalization and mortality in heart failure (HF).
To determine whether an education intervention improved medication adherence and cardiac event-free survival.
A randomized controlled trial was conducted on 82 HF patients. The intervention was based on the Theory of Planned Behavior (TPB) and included feedback of medication-taking behavior using the Medication Event Monitoring System (MEMS). Patients were assigned to one of three groups: 1) theory-based education plus MEMS feedback (PLUS), 2) theory-based education only (LITE), or 3) a usual care control group. Cardiac events were collected for 9 months.
Patients in both intervention groups were more adherent over follow-up compared to control group. In Cox regression, patients in either intervention group had a longer event-free survival compared to those in the control group before and after controlling age, marital status, financial status, ejection fraction, New York Heart Association functional class, angiotensin-converting enzyme inhibitor use, and presence or absence of a significant other during the intervention (p < .05).
Use of an intervention based on the TPB improves medication adherence and outcomes in patients with HF, and as such, offers promise as a clinically applicable intervention to help patients with HF adhere to their prescribed regimen.
medication adherence; intervention; randomized control trial; heart failure; outcomes; MEMS feedback; theory of planned behavior
Diabetes is associated with increased risk of mortality in heart failure. We examined the association of diabetes with expenditures, hospitalizations, and procedures among Medicare beneficiaries with heart failure during the last six months of life.
Methods and Results
In a 5% national Medicare sample, the prevalence of diabetes was 41.7% among 16,613 beneficiaries who died in 2007 with a diagnosis of heart failure. Diabetes was associated with higher expenditures during the last six months of life (mean $39,042 vs $29,003, p<0.001), even after adjusting for covariates, including age, gender, race, geographic location, comorbidities, and prior hospitalizations (cost ratio 1.08, 95% CI 1.05–1.12). For both diabetic and non-diabetic adults, over half of Medicare expenditures were related to hospitalization costs (mean $22,516 vs $15,721, p<0.001). When compared to their counterparts without diabetes, beneficiaries with diabetes had higher rates of hospitalization (adjusted incidence rate ratio (aIRR) 1.09, 95% CI 1.05–1.12) and days spent in the ICU.
Comorbid diabetes was common in heart failure and associated with higher expenditures, much of which was driven by increased rates of hospitalizations. Programs that focus on prevention of hospitalizations may reduce the substantial costs associated with heart failure near the end of life.
Whether myocardial recovery occurs more frequently in peripartum cardiomyopathy (PPCM), than in recent onset cardiomyopathies in men and non-peripartum women has not been prospectively evaluated. This was examined through an analysis of outcomes in the Intervention in Myocarditis and Acute Cardiomyopathy 2 (IMAC2) registry.
Methods and Results
IMAC 2 enrolled 373 subjects with recent onset non-ischemic dilated cardiomyopathy. LVEF was assessed at entry and six months, and subjects followed for up to 4 years. Myocardial recovery was compared between men (group1), non-peripartum women (group 2) and subjects with PPCM (group 3).
The cohort included 230 subjects in group 1, 104 in group 2, and 39 in group 3. The mean LVEF at baseline in groups 1, 2, and 3 was 0.23±0.08, 0.24±0.08, and 0.27±0.07 (p=0.04), and at six months was 0.39±0.12, 0.42±0.11, and 0.45±0.14 (p=0.007). Subjects in group 3 had a much greater likelihood of achieving an LVEF >0.50 at 6 months than groups 1 or 2 (19 %, 34%, and 48% respectively, p=0.002).
Prospective evaluation confirms myocardial recovery is greatest in women with PPCM, poorest in men, and intermediate in non-peripartum women. On contemporary therapy, nearly half of women with PPCM normalize cardiac function by six months.
Patients with heart failure (HF) develop metabolic derangements including increased adipokine levels, insulin resistance, inflammation and progressive catabolism. It is not known whether metabolic dysfunction and adipocyte activation worsen in the setting of acute clinical decompensation, or conversely, improve with clinical recovery.
Methods and Results
We assessed insulin resistance using HOMA-IR, and measured plasma levels of NT-proBNP, adiponectin, visfatin, resistin, leptin, and TNFα in 44 patients with acute decompensated HF (ADHF) due to left ventricular (LV) systolic dysfunction and again early (<1 week) and late (> 6 months) after clinical recovery; 26 patients with chronic stable HF; and 21 patients without HF. NT-proBNP was not increased in controls, mildly elevated in patients with stable HF, markedly elevated in patients with ADHF, and decreased progressively early and late after treatment. Compared to controls, plasma adiponectin, visfatin, leptin, resistin and TNFα were elevated in patients with chronic stable HF and increased further in patients with ADHF. Likewise, HOMA-IR was increased in chronic stable HF and increased further during ADHF. Adiponectin, visfatin and HOMA-IR remained elevated at the time of discharge from the hospital, but returned to chronic stable HF levels. Adipokine levels were not related to BMI in HF patients. HOMA-IR correlated positively with adipokines and TNFα in HF patients.
ADHF is associated with worsening of insulin resistance and elevations of adipokines and TNFα indicative of adipocyte activation. These metabolic abnormalities are reversible, but temporally lag behind the clinical resolution of decompensated HF.
Heart Failure; Metabolism; Insulin resistance; Adipokines
Activated vitamin D analog, paricalcitol, has been shown to attenuate the development of cardiac hypertrophy in Dahl salt sensitive (DSS) rats. To determine whether an anti-hypertrophic effect is class specific, we tested if doxercalciferol (a pro-hormone vitamin D2 analog) could also attenuate the development of cardiac hypertrophy in DSS rats.
Methods and Results
Male DSS rats were fed a high salt (HS) diet for 6 weeks beginning at 6 weeks of age. Doxercalciferol was administered intraperitoneally (i.p.) at 150ng, 3 times a week (Mon, Wed, Fri) for six weeks. Pathological and echocardiographic findings demonstrated that rats on HS diet with doxercalciferol administration had significant decrease in cardiac hypertrophy and improved cardiac function compared to the HS + vehicle. In addition, there was a significant decrease in plasma brain natriuretic peptide (BNP) level and tissue atrial natriuretic factor (ANF) mRNA level with doxercalciferol treatment. Doxercalciferol also significantly reduced the level of protein kinase C-α (PKCα) suggesting that PKC-mediated cardiac hypertrophy may be associated with vitamin D deficiency.
Administration of doxercalciferol attenuated the development of HS diet induced cardiac hypertrophy and cardiac dysfunction in DSS rats.
heart failure; high salt; Dahl rats; cardiac dysfunction
In the setting of acute decompensated heart failure, worsening renal function (WRF) and improved renal function (IRF) have been associated with similar hemodynamic derangements and poor prognosis. Our aim was to further characterize IRF and its associated mortality risk.
Methods and Results
Consecutive patients with a discharge diagnosis of congestive heart failure at the Hospital of the University of Pennsylvania were reviewed. IRF was defined as a ≥20% improvement and WRF as a ≥20% deterioration in glomerular filtration rate. Overall, 903 patients met eligibility criteria, 31.4% experiencing IRF. Baseline venous congestion/right sided cardiac dysfunction was more common (p≤0.04) and volume of diuresis (p=0.003) was greater in patients with IRF. IRF was associated with a greater incidence of pre-admission (OR=4.2, 95% CI 2.6–6.7, p<0.0001) and post-discharge (OR=1.8, 95% CI 1.2–2.7 p=0.006) WRF. IRF was associated with increased mortality (adjusted HR=1.3, 95% CI 1.1–1.7, p=0.011), a finding largely restricted to patients with post-discharge recurrence of renal dysfunction (p interaction=0.038).
IRF is associated with significantly worsened survival and may represent the resolution of venous congestion induced pre-admission WRF. Unlike WRF, the renal dysfunction in IRF patients occurs independent of the confounding effects of acute decongestion and may provide incremental information for the study of cardio-renal interactions.
Cardio-renal syndrome; Worsening renal function; Venous congestion