Prognostic Value of Elevated Levels of Intestinal Microbe-Generated Metabolite Trimethylamine-N-Oxide in Patients With Heart Failure : Refining the Gut Hypothesis

Background

Altered intestinal function is prevalent in patients with heart failure (HF), but its role in adverse outcomes is unclear.

Objectives

This study investigated the potential pathophysiological contributions of intestinal microbiota in HF.

Methods

We examined the relationship between fasting plasma trimethylamine-N-oxide (TMAO) and all-cause mortality over a 5-year follow-up in 720 patients with stable HF.

Results

The median TMAO level was 5.0 μM, which was higher than in subjects without HF (3.5 μM; p < 0.001). There was modest but significant correlation between TMAO concentrations and B-type natriuretic peptide (BNP) levels (r = 0.23; p < 0.001). Higher plasma TMAO levels were associated with a 3.4-fold increased mortality risk. Following adjustments for traditional risk factors and BNP levels, elevated TMAO levels remained predictive of 5-year mortality risk (hazard ratio [HR]: 2.2; 95% CI: 1.42 to 3.43; p < 0.001), as well as following the addition of estimated glomerular filtration rate to the model (HR: 1.75; 95% CI: 1.07 to 2.86; p < 0.001).

Conclusions

High TMAO levels were observed in patients with HF, and elevated TMAO levels portended higher long-term mortality risk independent of traditional risk factors and cardiorenal indexes.     

Three-Dimensional Speckle Tracking of the Right Ventricle : Toward Optimal Quantification of Right Ventricular Dysfunction in Pulmonary Hypertension

Background

Quantitative assessment of right ventricular (RV) systolic function largely depends on right ventricular ejection fraction (RVEF). Three-dimensional speckle tracking (3D-ST) has been used extensively to quantify left ventricular function, but its value for RV assessment has not been established.

Objectives

This study sought to prospectively assess whether 3D-ST would be a reliable method for assessing RV systolic function and whether strain values were associated with survival.

Methods

Comprehensive 2-dimensional echocardiographic assessment, 3D-ST of the RV free wall, and measurement of RVEF was performed in 97 consecutive patients with established pulmonary hypertension (PHT) (RVEF 31.4 ± 9.6%, right ventricular systolic pressure [RVSP] 76.5 ± 26.2 mm Hg) and 60 healthy volunteers (RVEF 43.8 ± 9.4%, RVSP 25.9 ± 4.3 mm Hg).

Results

Area strain (AS) (−24.3 ± 7.3 vs. −30.8 ± 7.2; p < 0.001), radial strain (23.2 ± 14.4 vs. 34.9 ± 18.2; p < 0.001), longitudinal strain (LS) (−15.5 ± 3.8 vs. −17.9 ± 4.4; p = 0.001), and circumferential strain (CS) (−12.2 ± 4.5 vs. −15.7 ± 6.1; p < 0.001) were all reduced in patients with PHT, compared with normal individuals. AS and CS strongly correlated to RVEF (r = 0.851, r = −0.711; p < 0.001). Systolic dyssynchrony index was greater in PHT (0.14 ± 0.06 vs. 0.11 ± 0.07; p = 0.003) and correlated to RVEF (r = −0.563, p < 0.001). AS (hazard ratio [HR]: 3.49; 95% confidence interval [CI]: 1.21 to 7.07; p = 0.017), CS (HR: 4.17; 95% CI: 1.93 to 12.97; p < 0.001), LS (HR: 7.63; 95% CI: 1.76 to 10.27; p = 0.001), and RVEF (HR: 2.43; 95 CI: 1.00 to 5.92; p = 0.050) were significant determinants of all-cause mortality. Only AS (p = 0.029) and age (p = 0.087) were predictive of death after logistic regression analysis.

Conclusions

PHT patients have reduced RV strain patterns and more dyssynchronous ventricles compared with controls, which was relatable to clinical outcomes. AS best correlated with RVEF and provides prognostic information independent of other variables.     

Sex-Specific Mortality Risk by QRS Morphology and Duration in Patients Receiving CRT : Results From the NCDR

Background

Prior studies have suggested that women have better outcomes than men after cardiac resynchronization therapy-defibrillator (CRT-D) implantation.

Objectives

The purpose of this study was to compare mortality after CRT-D implantation by sex, QRS morphology, and duration.

Methods

Survival curves and covariate adjusted hazard ratios (HR) were used to assess mortality by sex in 31,892 CRT-D patients in the National Cardiovascular Data Registry (NCDR), implantable cardioverter defibrillator (ICD) registry between 2006 and 2009, with up to 5 years’ follow-up (median 2.9 years, interquartile range: 2.0 to 3.9 years). Patients were grouped by QRS morphology and 10-ms increments in QRS duration.

Results

Among patients with left bundle branch block (LBBB), women had a 21% lower mortality risk than men (HR: 0.79; 95% CI: 0.74 to 0.84; p < 0.001); however, there was no sex difference in non-LBBB (HR: 0.95; 95% CI: 0.85 to 1.06; p = 0.37). Longer QRS duration was associated with better survival in both sexes with LBBB, but not in patients without LBBB. Compared with women with LBBB and QRS of 120 to 129 ms, women with LBBB and QRS of 140 to 149 ms had a 27% lower mortality (HR: 0.73; 95% CI: 0.60 to 0.88; p = 0.001); this difference was 18% in men (HR: 0.82; 95% CI: 0.71 to 0.93; p = 0.003). Mortality in LBBB and QRS of 150 ms or longer compared with those with LBBB and QRS of 120 to 129 ms was similar between sexes (HR: 0.61 to 0.68; p < 0.001 for women and HR: 0.58 to 0.66; p < 0.001 for men). Sex interactions within 10-ms groups were not significant.

Conclusions

Among patients with LBBB who received CRT-D, mortality is lower in women than men. Additionally, longer QRS duration in LBBB is associated with better survival in both sexes. In contrast, there is no sex difference in patients without LBBB, regardless of QRS duration. Further studies should include a non-CRT comparator group to confirm these findings.     

Impact of Aortic Valve Calcification,as Measured by MDCT,on Survival in Patients With Aortic Stenosis : Results of an International Registry Study

Background

Aortic valve calcification (AVC) load measures lesion severity in aortic stenosis (AS) and is useful for diagnostic purposes. Whether AVC predicts survival after diagnosis, independent of clinical and Doppler echocardiographic AS characteristics, has not been studied.

Objectives

This study evaluated the impact of AVC load, absolute and relative to aortic annulus size (AVC_density), on overall mortality in patients with AS under conservative treatment and without regard to treatment.

Methods

In 3 academic centers, we enrolled 794 patients (mean age, 73 ± 12 years; 274 women) diagnosed with AS by Doppler echocardiography who underwent multidetector computed tomography (MDCT) within the same episode of care. Absolute AVC load and AVC_density (ratio of absolute AVC to cross-sectional area of aortic annulus) were measured, and severe AVC was separately defined in men and women.

Results

During follow-up, there were 440 aortic valve implantations (AVIs) and 194 deaths (115 under medical treatment). Univariate analysis showed strong association of absolute AVC and AVC_density with survival (both, p < 0.0001) with a spline curve analysis pattern of threshold and plateau of risk. After adjustment for age, sex, coronary artery disease, diabetes, symptoms, AS severity on hemodynamic assessment, and LV ejection fraction, severe absolute AVC (adjusted hazard ratio [HR]: 1.75; 95% confidence interval [CI]: 1.04 to 2.92; p = 0.03) or severe AVC_density (adjusted HR: 2.44; 95% CI: 1.37 to 4.37; p = 0.002) independently predicted mortality under medical treatment, with additive model predictive value (all, p ≤ 0.04) and a net reclassification index of 12.5% (p = 0.04). Severe absolute AVC (adjusted HR: 1.71; 95% CI: 1.12 to 2.62; p = 0.01) and severe AVC_density (adjusted HR: 2.22; 95% CI: 1.40 to 3.52; p = 0.001) also independently predicted overall mortality, even with adjustment for time-dependent AVI.

Conclusions

This large-scale, multicenter outcomes study of quantitative Doppler echocardiographic and MDCT assessment of AS shows that measuring AVC load provides incremental prognostic value for survival beyond clinical and Doppler echocardiographic assessment. Severe AVC independently predicts excess mortality after AS diagnosis, which is greatly alleviated by AVI. Thus, measurement of AVC by MDCT should be considered for not only diagnostic but also risk-stratification purposes in patients with AS.     

Management Practices and Major Infections After Cardiac Surgery

Background

Infections are the most common noncardiac complication after cardiac surgery, but their incidence across a broad range of operations, as well as the management factors that shape infection risk, remain unknown.

Objectives

This study sought to prospectively examine the frequency of post-operative infections and associated mortality, and modifiable management practices predictive of infections within 65 days from cardiac surgery.

Methods

This study enrolled 5,158 patients and analyzed independently adjudicated infections using a competing risk model (with death as the competing event).

Results

Nearly 5% of patients experienced major infections. Baseline characteristics associated with increased infection risk included chronic lung disease (hazard ratio [HR]: 1.66; 95% confidence interval [CI]: 1.21 to 2.26), heart failure (HR: 1.47; 95% CI: 1.11 to 1.95), and longer surgery (HR: 1.31; 95% CI: 1.21 to 1.41). Practices associated with reduced infection risk included prophylaxis with second-generation cephalosporins (HR: 0.70; 95% CI: 0.52 to 0.94), whereas post-operative antibiotic duration >48 h (HR: 1.92; 95% CI: 1.28 to 2.88), stress hyperglycemia (HR: 1.32; 95% CI: 1.01 to 1.73); intubation time of 24 to 48 h (HR: 1.49; 95% CI: 1.04 to 2.14); and ventilation >48 h (HR: 2.45; 95% CI: 1.66 to 3.63) were associated with increased risk. HRs for infection were similar with either <24 h or <48 h of antibiotic prophylaxis. There was a significant but differential effect of transfusion by surgery type (excluding left ventricular assist device procedures/transplant) (HR: 1.13; 95% CI: 1.07 to 1.20). Major infections substantially increased mortality (HR: 10.02; 95% CI: 6.12 to 16.39).

Conclusions

Major infections dramatically affect survival and readmissions. Second-generation cephalosporins were strongly associated with reduced major infection risk, but optimal duration of antibiotic prophylaxis requires further study. Given practice variations, considerable opportunities exist for improving outcomes and preventing readmissions. (Management Practices and Risk of Infection Following Cardiac Surgery; NCT01089712)     

Five-year outcomes of surgical or percutaneous myocardial revascularization in diabetic patients

Background

The study compares five-year clinical outcomes of CABG vs PCI in a real world population of diabetic patients with multivessel coronary disease since it is not clear whether to prefer surgical or percutaneous revascularization.

Methods

Between July 2002 and December 2008, 2885 multivessel coronary diabetic patients underwent revascularization (1466 CABG and 1419 PCI) at hospitals in Emilia-Romagna Region, Italy and were followed for 1827 ± 617 days by record linkage of two clinical registries with the regional administrative database of hospital admissions and the mortality registry. Five-year incidences of MACCE (mortality, acute myocardial infarction [AMI], stroke, and repeat revascularization [TVR]) were assessed with Kaplan–Meier estimates, Cox proportional hazards regression and cumulative incidence functions of death and TVR, to evaluate the competing risk of AMI on death and TVR. The same analyses were applied to the propensity score matched subgroup of patients undergoing CABG or PCI with DES and with complete revascularization.

Results

PCI had higher mortality for all causes (HR: 1.8, 95% CI 1.4–2.2 p < 0.0001), AMI (HR: 3.3, 95% CI 2.4–4.6 p < 0.0001) and TVR (HR: 4.5, 95% CI 3.4–6.1 p < 0.0001). No significant differences emerged for stroke (HR: 0.8, 95% CI 0.5–1.2 p = 0.26).The higher incidence of AMI caused higher mortality in PCI group. Results did not change comparing CABG with PCI patients receiving complete revascularization or DES only.

Conclusions

Diabetics show a higher incidence of MACCE with PCI than with CABG: thus diabetes and its degree of control should be considered when choosing the type of revascularization.     

Fasting Levels of High-Sensitivity Growth Hormone Predict Cardiovascular Morbidity and Mortality : The Malmö Diet and Cancer Study

Background

Both pathological excess and deficiency of growth hormone (GH) are associated with cardiovascular mortality.

Objectives

The goal of this study was to test whether fasting levels of growth hormone measured with a high-sensitivity assay (hs-GH) predict cardiovascular morbidity and mortality at the population level.

Methods

We studied 4,323 participants (age 46 to 68 years; mean age 58 years; 59% women) of the Swedish, population-based Malmö Diet and Cancer study examined in 1991 to 1994. Using multivariate-adjusted Cox proportional hazards models, we related baseline levels of fasting hs-GH to incidence of coronary artery disease, stroke, congestive heart failure, all-cause mortality, and cardiovascular mortality.

Results

During a median follow-up of 16.2 years, hs-GH (hazard ratio [HR]/SD increment of natural logarithm of fasting hs-GH) was independently associated with increased risk of coronary artery disease (397 events; HR: 1.11; 95% confidence interval [CI]: 1.01 to 1.23; p = 0.04), stroke (251 events; HR: 1.18; 95% CI: 1.04 to 1.34; p = 0.01), congestive heart failure (107 events; HR: 1.25; 95% CI: 1.03 to 1.52; p = 0.02), all-cause mortality (645 events; HR: 1.17; 95% CI: 1.08 to 1.26; p < 0.001) and cardiovascular mortality (186 events; HR: 1.43; 95% CI: 1.24 to 1.66; p < 0.001). The addition of hs-GH to a model with conventional cardiovascular risk factors significantly reclassified risk, with a category-free net reclassification improvement (>0) of 0.542 (95% CI: 0.205 to 0.840) in cardiovascular mortality.

Conclusions

Higher values of hs-GH were associated with an increased risk of cardiovascular morbidity and mortality.     

Effect of Serelaxin on Mode of Death in Acute Heart Failure : Results From the RELAX-AHF Study

Background

Little is known about mode of death after acute heart failure (AHF) hospitalization. In the RELAX-AHF (Efficacy and Safety of Relaxin for the Treatment of Acute Heart Failure) study, serelaxin, the recombinant form of human relaxin-2, reduced post-discharge mortality at 180 days in selected patients with AHF.

Objectives

The goal of this study was to assess the effect of serelaxin on specific modes of death in patients with AHF.

Methods

The RELAX-AHF study randomized 1,161 patients with AHF to 48 h of therapy with intravenous serelaxin or placebo. Patients were followed for vital status through 180 days. A blinded clinical events committee reviewed all deaths and adjudicated a cause of death on the basis of pre-specified criteria. Cox proportional hazard models were used to assess the effect of serelaxin on each mode of death, on the basis of pre-specified groupings of mode of death.

Results

There were 107 deaths (9.3%): 37 (35%) due to HF, 25 (23%) due to sudden death, 15 (14%) due to other cardiovascular (CV) causes, 19 (18%) due to non-CV causes, and 11 (10%) classified as unknown. The treatment effect of serelaxin was most pronounced on other CV deaths (hazard ratio [HR]: 0.29; 95% CI: 0.12 to 0.73; p = 0.005) and sudden death (HR: 0.46; 95% CI: 0.20 to 1.07; p = 0.065). There was no apparent impact of serelaxin treatment on HF deaths or non-CV deaths.

Conclusions

In the RELAX-AHF study, the effects of serelaxin on mortality were primarily driven by reduction in mortality from other CV causes and sudden death, without apparent impact on HF deaths. (Efficacy and Safety of Relaxin for the Treatment of Acute Heart Failure [RELAX-AHF]; NCT00520806)     

B-Type Natriuretic Peptides Improve Cardiovascular Disease Risk Prediction in a Cohort of Women

Background

Although N-terminal pro–B-type natriuretic peptide (NT-proBNP) has a strong relationship with incident cardiovascular disease (CVD), few studies have examined whether NT-proBNP adds to risk prediction algorithms, particularly in women.

Objectives

This study sought to evaluate the relationship between NT-proBNP and incident CVD in women.

Methods

Using a prospective case-cohort within the WHI (Women’s Health Initiative) observational study, we selected 1,821 incident cases of CVD (746 myocardial infarctions, 754 ischemic strokes, 160 hemorrhagic strokes, and 161 other cardiovascular [CV] deaths) and a randomly selected reference cohort of 1,992 women without CVD at baseline.

Results

Median levels of NT-proBNP were higher at study entry among incident cases (120.3 ng/l [interquartile range (IQR): 68.1 to 219.5 ng/l]) than among control subjects (100.4 ng/l [IQR: 59.7 to 172.6 ng/l]; p < 0.0001). Women in the highest quartile of NT-proBNP (≥140.8 ng/l) were at 53% increased risk of CVD versus those in the lowest quartile after adjusting for traditional risk factors (1.53 [95% confidence interval (CI): 1.21 to 1.94]; p for trend <0.0001). Similar associations were observed after adjustment for Reynolds Risk Score covariables (1.53 [95% CI: 1.20 to 1.95]; p for trend <0.0001); the association remained in separate analyses of CV death (2.66 [95% CI: 1.48 to 4.81]; p for trend <0.0001), myocardial infarction (1.39 [95% CI: 1.02 to 1.88]; p for trend = 0.008), and stroke (1.60 [95% CI: 1.22 to 2.11]; p for trend <0.0001). When added to traditional risk covariables, NT-proBNP improved the c-statistic (0.765 to 0.774; p = 0.0003), categorical net reclassification (0.08; p < 0.0001), and integrated discrimination (0.0105; p < 0.0001). Similar results were observed when NT-proBNP was added to the Reynolds Risk Score.

Conclusions

In this multiethnic cohort of women with numerous CV events, NT-proBNP modestly improved measures of CVD risk prediction.     

Association Between Frequency of Atrial and Ventricular Ectopic Beats and Biventricular Pacing Percentage and Outcomes in Patients With Cardiac Resynchronization Therapy

Background

A high percentage of biventricular pacing is required for optimal outcome in patients treated with cardiac resynchronization therapy (CRT), but the influence of ectopic beats on the success of biventricular pacing has not been well established.

Objectives

This study sought to determine if increased ectopic beats reduce the chance of high biventricular pacing percentage and are associated with subsequent adverse outcomes.

Methods

From the MADIT-CRT (Multicenter Automatic Defibrillator Implantation Trial With Cardiac Resynchronization Therapy), 801 patients with an implanted CRT-defibrillator device with data available on biventricular pacing percentage and pre-implantation 24-h Holter recordings were included. Using logistic regression, we estimated the influence of ectopic beats on the percentage of biventricular pacing. Reverse remodeling was measured as reductions in atrial and left ventricular end-systolic volumes (LVESV) at 1 year. Cox models were used to assess the influence of ectopic beats on the outcomes of heart failure (HF) or death, ventricular tachyarrhythmias (VTAs), and death.

Results

In the pre-implantation Holter recording, ectopic beats accounted for a mean 3.2 ± 5.5% of all beats. The probability of subsequent low biventricular pacing percentage (<97%) was increased 3-fold (odds ratio: 3.37; 95% confidence interval: 1.74 to 6.50; p < 0.001) in patients with 0.1% to 1.5% ectopic beats and 13-fold (odds ratio: 13.42; 95% confidence interval: 7.02 to 25.66; p < 0.001) in patients with >1.5% ectopic beats compared with those with <0.1% ectopic beats. Patients with ≥0.1% ectopic beats had significantly less reverse remodeling (percent reduction in LVESV 31 ± 15%) than patients with <0.1% ectopic beats (percent reduction in LVESV 39 ± 14%; p < 0.001). The risk of HF/death and VTA was increased significantly in those with 0.1% to 1.5% ectopic beats (hazard ratio: 3.13 and 1.84, respectively) and for >1.5% ectopic beats (hazard ratio: 2.38 and 2.74, respectively).

Conclusions

Relatively low frequencies of ectopic beats (≥0.1%) dramatically increase the probability of low biventricular pacing (<97%), with reduced CRT efficacy by less reverse remodeling and higher risk of HF/death and VTA. This supports pre-implantation Holter monitoring of patients selected for CRT for optimal outcome. (MADIT-CRT: Multicenter Automatic Defibrillator Implantation With Cardiac Resynchronization Therapy; NCT00180271)     

Association of implantable defibrillator therapy risk with body mass index in systolic heart failure

Objectives

To determine whether risk for implantable cardioverter-defibrillator (ICD) therapy varies by body mass index (BMI) in systolic heart failure (HF).

Background

It is unknown whether obesity increases sudden death risk in patients with systolic HF.

Methods

Secondary analysis of patients with HF, left ventricular ejection fraction ≤0.40 and ICD (N = 464) was performed using Cox regression modeling to assess risk for first delivered ICD therapy, with patients grouped by BMI (kg/m²): normal (18.5 to <25), overweight (25 to <30), and obese (≥30).

Results

Overweight patients, compared with patients with normal BMI, had greater adjusted risk for first ICD therapy (HR 1.66; 95% CI 1.02–2.71; P = 0.04), whereas obese BMI was not associated with risk for first ICD therapy.

Conclusions

There was an inverted U-shaped relationship between BMI and risk for first ICD therapy among systolic HF patients, with highest risk in overweight BMI.     

Prognostic implications of quantitative evaluation of baseline Q-wave width in ST-segment elevation myocardial infarction

Objectives

To evaluate quantitative relationships between baseline Q-wave width and 90-day outcomes in ST-segment elevation myocardial infarction (STEMI).

Background

Baseline Q-waves are useful in predicting clinical outcomes after MI.

Methods

3589 STEMI patients were assessed from a multi-centre study.

Results

1156 patients of the overall cohort had pathologic Q-waves. The 90-day mortality and the composite of mortality, congestive heart failure (CHF), or cardiogenic shock (p < 0.001 for both outcomes) rose as Q-wave width increased. After adapting a threshold ≥ 40 ms for inferior and ≥ 20 ms for lateral/apical MI in all patients (n = 3065) with any measureable Q-wave we found hazard ratios (HR) for mortality (HR: 2.44, 95% confidence interval (CI) (1.54–3.85), p < 0.001) and the composite (HR: 2.32, 95% CI (1.70–3.16), p < 0.001). This improved reclassification of patients experiencing the composite endpoint versus the conventional definition (net reclassification index (NRI): 0.23, 95% CI (0.09-0.36), p < 0.001) and universal MI definition (NRI: 0.15, 95% CI (0.02–0.29), p = 0.027).

Conclusions

The width of the baseline Q-wave in STEMI adds prognostic value in predicting 90-day clinical outcomes. A threshold of ≥ 40 ms in inferior and ≥ 20 ms for lateral/apical MI enhances prognostic insight beyond current criteria.     

Electrocardiographic Changes Improve Risk Prediction in Asymptomatic Persons Age 65 Years or Above Without Cardiovascular Disease

Background

Risk prediction in elderly patients is increasingly relevant due to longer life expectancy.

Objectives

This study sought to examine whether electrocardiographic (ECG) changes provide prognostic information incremental to current risk models and to the conventional risk factors.

Methods

In all, 6,991 participants from the Copenhagen Heart Study attending an examination at age ≥65 years were included. ECG changes were defined as Q waves, ST-segment depression, T-wave changes, ventricular conduction defects, and left ventricular hypertrophy based on the Minnesota code. The primary endpoint was fatal cardiovascular disease (CVD) event and the secondary was fatal or nonfatal CVD event. In our study, 2,236 fatal CVD and 3,849 fatal or nonfatal CVD events occurred during a median of 11.9 and 9.8 years of follow-up.

Results

ECG changes were frequently present (30.6%) and associated with conventional risk factors. All ECG changes except 1 univariably predicted both endpoints. Event rates of ECG changes versus no ECG changes were respectively 41.4% versus 27.8% and 64.6% versus 50.8%. When added to existing risk scores, ECG changes independently increased the risk of both endpoints. Fatal CVD events: hazard ratio (HR): 1.33 (95% confidence interval [CI]: 1.29 to 1.36; p < 0.001) and fatal or nonfatal CVD events: HR: 1.21 (95% CI: 1.19 to 1.24; p < 0.001). When added to conventional risk factors, continuous net reclassification improvement was 42.3% (95% CI: 42.0 to 42.4; p < 0.001) for fatal and 29.2% (95% CI: 28.4 to 29.2; p < 0.001) for fatal or nonfatal events. Categorical net reclassification was 7.1% (95% CI: 6.7 to 9.0; p < 0.001) for fatal and 4.2% (95% CI: 3.5 to 5.6; p < 0.001) for fatal or nonfatal events.

Conclusions

Simple assessment of the existence of ECG changes improves risk prediction in the general population of persons age ≥65 years.     

Intestinal Blood Flow in Patients With Chronic Heart Failure : A Link With Bacterial Growth,Gastrointestinal Symptoms,and Cachexia

Background

Blood flow in the intestinal arteries is reduced in patients with stable heart failure (HF) and relates to gastrointestinal (GI) symptoms and cardiac cachexia.

Objectives

The aims of this study were to measure arterial intestinal blood flow and assess its role in juxtamucosal bacterial growth, GI symptoms, and cachexia in patients with HF.

Methods

A total of 65 patients and 25 controls were investigated. Twelve patients were cachectic. Intestinal blood flow and bowel wall thickness were measured using ultrasound. GI symptoms were documented. Bacteria in stool and juxtamucosal bacteria on biopsies taken during sigmoidoscopy were studied in a subgroup by fluorescence in situ hybridization. Serum lipopolysaccharide antibodies were measured.

Results

Patients showed 30% to 43% reduced mean systolic blood flow in the superior and inferior mesenteric arteries and celiac trunk (CT) compared with controls (p < 0.007 for all). Cachectic patients had the lowest blood flow (p < 0.002). Lower blood flow in the superior mesenteric artery and CT was correlated with HF severity (p < 0.04 for all). Patients had more feelings of repletion, flatulence, intestinal murmurs, and burping (p < 0.04). Burping and nausea or vomiting were most severe in patients with cachexia (p < 0.05). Patients with lower CT blood flow had more abdominal discomfort and immunoglobulin A–antilipopolysaccharide (r = 0.76, p < 0.02). Antilipopolysaccharide response was correlated with increased growth of juxtamucosal but not stool bacteria. Patients with intestinal murmurs had greater bowel wall thickness of the sigmoid and descending colon, suggestive of edema contributing to GI symptoms (p < 0.05). In multivariate regression analysis, lower blood flow in the superior mesenteric artery, CT (p < 0.04), and inferior mesenteric artery (p = 0.056) was correlated with the presence of cardiac cachexia.

Conclusions

Intestinal blood flow is reduced in patients with HF. This may contribute to juxtamucosal bacterial growth and GI symptoms in patients with advanced HF complicated by cachexia.     

Prevention of heart failure in older adults may require higher levels of physical activity than needed for other cardiovascular events

Background

Little is known if the levels of physical activity required for the prevention of incident heart failure (HF) and other cardiovascular events vary in community-dwelling older adults.

Methods

We studied 5503 Cardiovascular Health Study (CHS) participants, age ≥ 65 years, free of baseline HF. Weekly metabolic equivalent task-minutes (MET-minutes), estimated using baseline total leisure-time energy expenditure, were used to categorize participants into four physical activity groups: inactive (0 MET-minutes; n = 489; reference), low (1–499; n = 1458), medium (500–999; n = 1086) and high (≥ 1000; n = 2470).

Results

Participants had a mean (± SD) age of 73 (± 6) years, 58% were women, and 15% African American. During 13 years of follow-up, centrally-adjudicated incident HF occurred in 26%, 23%, 20%, and 19% of participants with no, low, medium and high physical activity, respectively (trend p < 0.001). Compared with inactive older adults, age–sex–race-adjusted hazard ratios (95% confidence intervals) for incident HF associated with low, medium and high physical activity were 0.87 (0.71–1.06; p = 0.170), 0.68 (0.54–0.85; p = 0.001) and 0.60 (0.49–0.74; p < 0.001), respectively (trend p < 0.001). Only high physical activity had significant independent association with lower risk of incident HF (HR, 0.79; 95% CI, 0.64–0.97; p = 0.026). All levels of physical activity had significant independent association with lower risk of incident acute myocardial infarction (AMI), stroke and cardiovascular mortality.

Conclusion

In community-dwelling older adults, high level of physical activity was associated with lower risk of incident HF, but all levels of physical activity were associated with lower risk of incident AMI, stroke, and cardiovascular mortality.     

Clinical Implications of Chronic Heart Failure Phenotypes Defined by Cluster Analysis

Background

Classification of chronic heart failure (HF) is on the basis of criteria that may not adequately capture disease heterogeneity. Improved phenotyping may help inform research and therapeutic strategies.

Objectives

This study used cluster analysis to explore clinical phenotypes in chronic HF patients.

Methods

A cluster analysis was performed on 45 baseline clinical variables from 1,619 participants in the HF-ACTION (Heart Failure: A Controlled Trial Investigating Outcomes of Exercise Training) study, which evaluated exercise training versus usual care in chronic systolic HF. An association between identified clusters and clinical outcomes was assessed using Cox proportional hazards modeling. Differential associations between clinical outcomes and exercise testing were examined using interaction testing.

Results

Four clusters were identified (ranging from 248 to 773 patients in each), in which patients varied considerably among measures of age, sex, race, symptoms, comorbidities, HF etiology, socioeconomic status, quality of life, cardiopulmonary exercise testing parameters, and biomarker levels. Differential associations were observed for hospitalization and mortality risks between and within clusters. Compared with cluster 1, risk of all-cause mortality and/or all-cause hospitalization ranged from 0.65 (95% confidence interval [95% CI]: 0.54 to 0.78) for cluster 4 to 1.02 (95% CI: 0.87 to 1.19) for cluster 3. However, for all-cause mortality, cluster 3 had a disproportionately lower risk of 0.61 (95% CI: 0.44 to 0.86). Evidence suggested differential effects of exercise treatment on changes in peak oxygen consumption and clinical outcomes between clusters (p for interaction <0.04).

Conclusions

Cluster analysis of clinical variables identified 4 distinct phenotypes of chronic HF. Our findings underscore the high degree of disease heterogeneity that exists within chronic HF patients and the need for improved phenotyping of the syndrome. (Exercise Training Program to Improve Clinical Outcomes in Individuals With Congestive Heart Failure; NCT00047437)     

Increased Mortality Associated With Digoxin in Contemporary Patients With Atrial Fibrillation : Findings From the TREAT-AF Study

Background

Despite endorsement of digoxin in clinical practice guidelines, there exist limited data on its safety in atrial fibrillation/flutter (AF).

Objectives

The goal of this study was to evaluate the association of digoxin with mortality in AF.

Methods

Using complete data of the TREAT-AF (The Retrospective Evaluation and Assessment of Therapies in AF) study from the U.S. Department of Veterans Affairs (VA) healthcare system, we identified patients with newly diagnosed, nonvalvular AF seen within 90 days in an outpatient setting between VA fiscal years 2004 and 2008. We used multivariate and propensity-matched Cox proportional hazards to evaluate the association of digoxin use with death. Residual confounding was assessed by sensitivity analysis.

Results

Of 122,465 patients with 353,168 person-years of follow-up (age 72.1 ± 10.3 years, 98.4% male), 28,679 (23.4%) patients received digoxin. Cumulative mortality rates were higher for digoxin-treated patients than for untreated patients (95 vs. 67 per 1,000 person-years; p < 0.001). Digoxin use was independently associated with mortality after multivariate adjustment (hazard ratio [HR]: 1.26, 95% confidence interval [CI]: 1.23 to 1.29, p < 0.001) and propensity matching (HR: 1.21, 95% CI: 1.17 to 1.25, p < 0.001), even after adjustment for drug adherence. The risk of death was not modified by age, sex, heart failure, kidney function, or concomitant use of beta-blockers, amiodarone, or warfarin.

Conclusions

Digoxin was associated with increased risk of death in patients with newly diagnosed AF, independent of drug adherence, kidney function, cardiovascular comorbidities, and concomitant therapies. These findings challenge current cardiovascular society recommendations on use of digoxin in AF.     

Stent Thrombosis in New-Generation Drug-Eluting Stents in Patients With STEMI Undergoing Primary PCI : A Report From SCAAR

Background

Some concerns still have not been resolved about the long-term safety of drug-eluting stents (DES) in patients with acute STEMI.

Objectives

The aim of this study was to evaluate the stent thrombosis (ST) rate up to 3 years in patients with ST-segment elevation myocardial infarction (STEMI) treated by primary percutaneous coronary intervention (PCI) with new-generation drug-eluting stents (n-DES) compared with bare-metal stents (BMS) and old-generation drug-eluting stents (o-DES) enrolled in the SCAAR (Swedish Coronary Angiography and Angioplasty Registry).

Methods

From January 2007 to January 2013, 34,147 patients with STEMI were treated by PCI with n-DES (n = 4,811), o-DES (n = 4,271), or BMS (n = 25,065). The risks of early/late (up to 1 year) and very late definite ST (after 1 year) were estimated.

Results

Cox regression landmark analysis showed a significantly lower risk of early/late ST in patients treated with n-DES (hazard ratio [HR]: 0.65; 95% confidence interval [CI]: 0.43 to 0.99; p = 0.04) and o-DES (HR: 0.60; 95% CI: 0.41 to 0.89; p = 0.01) compared with the BMS group. The risk of very late ST was similar between the n-DES and BMS groups (HR: 1.52; 95% CI: 0.78 to 2.98; p = 0.21), whereas a higher risk of very late ST was observed with o-DES compared with BMS (HR: 2.88; 95% CI: 1.70 to 4.89; p < 0.01).

Conclusions

Patients treated with n-DES have a lower risk of early/late ST than patients treated with BMS. The risk of very late ST is low and comparable between n-DES and BMS up to 3 years of follow-up, whereas o-DES treatment is associated with an increased risk of very late ST. The current STEMI guidelines might require an update in light of the results of this and other recent studies.     

Comparison of the prognostic predictive value of the TIMI, PAMI, CADILLAC, and GRACE risk scores in STEACS undergoing primary or rescue PCI

Introduction and objectives

We sought to compare the predictive value of the Thrombolysis In Myocardial Infarction (TIMI), Controlled Abciximab and Device Investigation to Lower Late Angioplasty Complications (CADILLAC), Primary Angioplasty in Myocardial Infarction (PAMI), and Global Registry for Acute Coronary Events (GRACE) scores for the outcome of ST-segment elevation acute coronary syndrome undergoing urgent percutaneous coronary intervention.

Methods

We performed a retrospective analysis of a cohort composed of all consecutive patients with ST-segment elevation acute coronary syndrome treated by urgent percutaneous coronary intervention between 2006 and 2010 (n=1503). TIMI, PAMI, CADILLAC, and GRACE risk scores were calculated for each patient according to different clinical variables. We assessed the predictive accuracy of these scores for death, reinfarction, and target-vessel revascularization at 30 days and 1 year, using the C statistic, which was obtained by means of logistic regression and ROC curves.

Results

The TIMI, PAMI, CADILLAC and GRACE showed an excellent predictive value for 30-day and 1-year mortality (C statistic range, 0.8-0.9), with superiority of the TIMI, CADILLAC, and GRACE risk models. The performance of these 4 scores was poor for both reinfarction and target-vessel revascularization (C statistic, 0.5-0.6).

Conclusions

The TIMI, PAMI, CADILLAC, and GRACE scores provide excellent information to stratify the risk of mortality in patients treated by percutaneous coronary intervention. The TIMI, CADILLAC, and GRACE models have higher predictive accuracy. The usefulness of these models for reinfarction and target-vessel revascularization prediction is questionable.     

Pulmonary hypertension in young adults with repaired coarctation of the aorta: An unrecognised factor associated with premature mortality and heart failure

Background

Adults with repaired coarctation of the aorta (CoA) are at risk for premature cardiovascular death or heart failure (HF). We sought to evaluate risk factors for death or HF in young adults with repaired CoA in childhood.

Methods

The medical records of a cohort of 159 adults diagnosed with CoA repaired at a mean age of 4.1 ± 5.7 years were retrospectively reviewed to identify predictors of a combined endpoint of all cause death or hospitalisation for HF by using Cox proportional hazard models.

Results

Over a follow-up of 26 ± 8 years (median 27 years) after repair, 5 patients died and 7 developed HF requiring hospitalisation. Pulmonary artery systolic pressure > 40 mmHg (PH) was the main predictor of death or admission for HF (HR 32; 95% CI 4.0–250; p = 0.001). Neither systemic hypertension, recoarctation, aortic aneurysm, intracardiac lesions nor treatment with beta-blockers or ACEi/ARBs were statistically related to death or HF. Restrictive left ventricular physiology (RLVP) was the main predictor of PH by logistic regression analysis (OR 31; 95% CI 10–92; p < 0.001). Patients with severe PH (pulmonary artery systolic pressure > 60 mmHg) showed RLVP (9/10), severe elevation of end-diastolic LV pressure at cardiac catheterization (8/8) and subendocardial late gadolinium enhancement on MRI (5/5). Pathological examination of an explanted heart demonstrated extensive left ventricular subendocardial fibrosis.

Conclusions

Pulmonary hypertension related to restrictive left ventricular physiology was the strongest predictor of death or HF in young adults with CoA repaired in childhood. Persistent subendocardial fibrosis might be the structural substrate in some patients.