Hussain, Imad

Background: Galectin-3 (Gal-3) may promote cardiac and renal fibrosis in heart failure (HF). Plasma Gal-3 levels predict outcome in HF but are tightly correlated with renal function. The source of Gal-3 in human HF, chronic kidney disease (CKD) or cardio-renal failure (HF+CKD) is unclear. Objective: To assess Gal-3 presence and location in human heart or kidney tissue from patients with HF, CKD or HF+CKD. Methods: Plasma Gal-3 levels and LV tissue explanted at time of cardiac transplant in systolic HF (n=15) and autopsy renal sections from patients with normal kidneys (n=4), CKD (n=17) or CKD+HF (n=14) were examined (H&E, Masson’s trichrome and CD-68 and Gal-3 immunohistochemistry). In the systolic HF patients, we quantified the number of Gal-3+/CD-68+ cells per HPF in LV tissue and assessed the correlation with plasma Gal-3 levels. In autopsy renal tissue, we derived a Composite Gal-3 Score (CG3S) incorporating the % of Gal-3+ tubules per HPF, % of Gal-3+ cells/tubule per HPF, and intensity of Gal-3 staining and assessed the correlation of the CG3S with ante-mortem estimated glomerular filtration rate(eGFR). Renal macrophage Gal-3 staining was also assessed. Results: In systolic HF LV tissue, Gal-3 was present in macrophages rather than myocytes but Gal-3+/CD-68+ cells per HPF was not correlated with plasma Gal-3 levels (p> 0.9) which correlated inversely with eGFR (r = -0.89 for log Gal-3 vs eGFR, p<0.0001). In the kidney, Gal-3 was not present in macrophages but was localized to renal tubular cells (Figure). The CG3S increased exponentially as eGFR decreased (r = - 0.88 for log CG3S versus eGFR; p<0.0001) and this relationship was not different (p=0.44) in patients with or without HF (Figure). The log CG3S correlated with the degree of fibrosis (tubulointerstitial scarring) in the kidney (r=0.88; p<0.0001). Conclusion: Collectively, these data suggest that plasma Gal-3 is predominantly of renal tubular epithelial origin in human HF, CKD, and CKD+HF.

Background: The Acute Decompensated Heart Failure National Registry (ADHERE) Classification and Regression Tree (CART) algorithm is an accepted method to assess a heart failure (HF) patient’s risk of inpatient mortality based on the patient’s systolic blood pressure (≥115 vs. <115 mmHg), blood urea nitrogen (BUN; ≥43 vs. <43 mg/dL), and creatinine (≥2.75 vs. <2.75 mg/dL) at the time of admission. Whether the ADHERE CART algorithm identifies risk of longer term poor outcomes and is predictive in patients with systolic (EF < 50%) or diastolic (EF ≥ 50%) HF in the community is unclear. Methods: We identified all hospitalizations for a primary diagnosis of HF occurring between 2000-2013 in a community-based cohort living within 40 miles of Rochester, MN. Outcomes including length of stay, in-hospital mortality, 30 and 90 day post-discharge mortality and readmission for any cause at 30 and 90 days were compared across the ADHERE CART risk groups using logistic regression for the entire cohort and separately for systolic (EF < 50%) and diastolic (EF ≥ 50%) HF. Results: See Table. We examined 5,918 heart failure hospitalizations among 3,628 individual patients. Distribution of hospitalizations across the risk categories is shown in table. Length of stay, in-hospital mortality, 30 and 90 day mortality and 30 and 90 day readmission rates all increased with increasing ADHERE risk categories. Similar results were obtained separately for systolic and diastolic HF. Conclusion: The ADHERE CART algorithm is simple, uses data universally available on admission, and identifies groups that differ substantially in their post-discharge adverse outcomes regardless of HF type (systolic vs diastolic) in the community. The ADHERE CART algorithm may inform clinical decision regarding advanced HF treatments, end-of-life planning and care transition services in patients hospitalized for HF in the community.

Background The Acute Decompensated Heart Failure National Registry (ADHERE) and Get With The Guidelines (GWTG) registries have developed simple heart failure (HF) in-hospital mortality risk scores. We hypothesized that HF scores predictive of in-hospital mortality would perform as well for early postdischarge mortality risk stratification. Methods and Results In this single-center, community-based, retrospective study of all consecutive primary HF hospitalizations (6203 hospitalizations in 3745 patients) from 2000 to 2013, the ADHERE and GWTG risk scores were calculated from admission data. There were 176 (3.0%) and 399 (6.7%), 869 (14.7%), and 1272 (21.5%) deaths in-hospital and at 30, 90, and 180 days postdischarge, respectively. The GWTG but not ADHERE risk score was well calibrated for in-hospital mortality. Both the ADHERE (C statistic 0.66 and 0.67, 0.64, and 0.64) and GWTG (C statistic 0.74 and 0.73, 0.71, and 0.70) HF risk scores were similarly predictive of in-hospital and 30-, 90-, and 180-day postdischarge mortality. The ADHERE risk score identified 10% and the GWTG risk score identified 20% of hospitalizations where 180-day postdischarge mortality was 50%, a prognostic bench mark for hospice referral. In contrast, hospitalizations characterized as lowest risk by the ADHERE (57% of hospitalizations; 180-day mortality 16.2%) or GWTG score (20% of hospitalizations; 180-day mortality 8.0%) had substantially lower mortality (odds ratios high versus low risk of 5–8 [ADHERE] and 11–18 [GWTG] across time points; P <0.0001 for all). Conclusions The simple ADHERE and GWTG scores stratify hospitalized HF patients for both inpatient and early postdischarge mortality risk, allowing comprehensive risk assessment on admission.

Background— Right ventricular (RV) dysfunction (RVD) is a poor prognostic factor in heart failure with preserved ejection fraction (HFpEF). The physiological perturbations associated with RVD or RV function indexed to load (RV–pulmonary arterial [PA] coupling) in HFpEF have not been defined. HFpEF patients with marked impairment in RV–PA coupling may be uniquely sensitive to sildenafil. Methods and Results— In a subset of HFpEF patients enrolled in the Phosphodiesteas-5 Inhibition to Improve Clinical Status And Exercise Capacity in Diastolic Heart Failure (RELAX) trial, physiological variables and therapeutic effect of sildenafil were examined relative to the severity of RVD (tricuspid annular plane systolic excursion [TAPSE]) and according to impairment in RV–PA coupling (TAPSE/pulmonary artery systolic pressure) ratio. The prevalence of atrial fibrillation and diuretic use, n-terminal probrain natriuretic peptide levels, renal dysfunction, neurohumoral activation, myocardial necrosis and fibrosis biomarkers, and the severity of diastolic dysfunction all increased with severity of RVD. Peak oxygen consumption decreased and ventilatory inefficiency (VE/VCO 2 slope) increased with increasing severity of RVD. Many but not all physiological derangements were more closely associated with the TAPSE/pulmonary artery systolic pressure ratio. Compared with placebo, at 24 weeks, TAPSE decreased, and peak oxygen consumption and VE/CO 2 slope were unchanged with sildenafil. There was no interaction between RV–PA coupling and treatment effect, and sildenafil did not improve TAPSE, peak oxygen consumption, or VE/VCO 2 in patients with pulmonary hypertension and RVD. Conclusions— HFpEF patients with RVD and impaired RV–PA coupling have more advanced heart failure. In RELAX patients with RVD and impaired RV–PA coupling, sildenafil did not improve RV function, exercise capacity, or ventilatory efficiency. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT00763867.

Background— The prevalence and clinical significance of right ventricular (RV) systolic dysfunction (RVD) in patients with heart failure and preserved ejection fraction (HFpEF) are not well characterized. Methods and Results— Consecutive, prospectively identified HFpEF (Framingham HF criteria, ejection fraction ≥50%) patients (n=562) from Olmsted County, Minnesota, underwent echocardiography at HF diagnosis and follow-up for cause-specific mortality and HF hospitalization. RV function was categorized by tertiles of tricuspid annular plane systolic excursion and by semiquantitative (normal, mild RVD, or moderate to severe RVD) 2-dimensional assessment. Whether RVD was defined by semiquantitative assessment or tricuspid annular plane systolic excursion ≤15 mm, HFpEF patients with RVD were more likely to have atrial fibrillation, pacemakers, and chronic diuretic therapy. At echocardiography, patients with RVD had slightly lower left ventricular ejection fraction, worse diastolic dysfunction, lower blood pressure and cardiac output, higher pulmonary artery systolic pressure, and more severe RV enlargement and tricuspid valve regurgitation. After adjustment for age, sex, pulmonary artery systolic pressure, and comorbidities, the presence of any RVD by semiquantitative assessment was associated with higher all-cause (hazard ratio=1.35; 95% confidence interval, 1.03–1.77; P =0.03) and cardiovascular (hazard ratio=1.85; 95% confidence interval, 1.20–2.80; P =0.006) mortality and higher first (hazard ratio=1.99; 95% confidence interval, 1.35–2.90; P =0.0006) and multiple (hazard ratio=1.81; 95% confidence interval, 1.18–2.78; P =0.007) HF hospitalization rates. RVD defined by tricuspid annular plane systolic excursion values showed similar but weaker associations with mortality and HF hospitalizations. Conclusions— In the community, RVD is common in HFpEF patients, is associated with clinical and echocardiographic evidence of more advanced HF, and is predictive of poorer outcomes.