Redfield, Margaret M.

Abstract Aims In heart failure (HF), pulmonary venous hypertension (PVH) produces pulmonary hypertension (PH) with remodeling of pulmonary veins (PV) and arteries (PA). In a porcine PVH model, we performed proteomic-based bioinformatics to investigate unique pathophysiologic mechanisms mediating PA and PV remodeling. Methods and results Large PV were banded (PVH, n = 10) or not (Sham, n = 9) in piglets. At sacrifice, PV and PA were perfusion labelled for vessel-specific histology and proteomics. The PA and PV were separately sampled with laser-capture micro-dissection for mass spectrometry. Pulmonary vascular resistance [Wood Units; 8.6 (95% confidence interval: 6.3, 12.3) vs. 2.0 (1.7, 2.3)] and PA [19.9 (standard error of mean, 1.1) vs. 10.3 (1.1)] and PV [14.2 (1.2) vs. 7.6 (1.1)] wall thickness/external diameter (%) were increased in PVH (P < 0.05 for all). Similar numbers of proteins were identified in PA (2093) and PV (2085) with 94% overlap, but biological processes differed. There were more differentially expressed proteins (287 vs. 161), altered canonical pathways (17 vs. 3), and predicted upstream regulators (PUSR; 22 vs. 6) in PV than PA. In PA and PV, bioinformatics indicated activation of the integrated stress response and mammalian target of rapamycin signalling with dysregulated growth. In PV, there was also activation of Rho/Rho-kinase signalling with decreased actin cytoskeletal signalling and altered tight and adherens junctions, ephrin B, and caveolae-mediated endocytosis signalling; all indicating disrupted endothelial barrier function. Indeed, protein biomarkers and the top PUSR in PV (transforming growth factor-beta) suggested endothelial to mesenchymal transition in PV. Findings were similar in human autopsy specimens. Conclusion These findings provide new therapeutic targets to oppose pulmonary vascular remodeling in HF-related PH.

Aim There is an association between heart failure with preserved ejection fraction (HFpEF) and insulin resistance, but less is known about the diabetic continuum, and in particular about pre‐diabetes, in HFpEF. We examined characteristics and outcomes of participants with diabetes or pre‐diabetes in PARAGON‐HF. Methods and results Patients aged ≥50 years with left ventricular ejection fraction ≥45%, structural heart disease and elevated N‐terminal pro‐B‐type natriuretic peptide (NT‐proBNP) were eligible. Patients were classified according to glycated haemoglobin (HbA1c): (i) normal HbA1c, <6.0%; (ii) pre‐diabetes, 6.0%–6.4%; (iii) diabetes, ≥6.5% or history of diabetes. The primary outcome was a composite of cardiovascular (CV) death and total heart failure hospitalizations (HFH). Of 4796 patients, 50% had diabetes and 18% had pre‐diabetes. Compared to patients with normal HbA1c, patients with pre‐diabetes and diabetes more often were obese, had a history of myocardial infarction and had lower Kansas City Cardiomyopathy Questionnaire scores, while patients with diabetes had more clinical evidence of congestion, but similar NT‐proBNP concentrations. The risks of the primary composite outcome (rate ratio [RR] 1.59, 95% confidence interval [CI] 1.35–1.88), total HFH (RR 1.67, 95% CI 1.39–2.02) and CV death (hazard ratio [HR] 1.35, 95% CI 1.07–1.71) were higher among patients with diabetes, compared to those with normal HbA1c. Patients with pre‐diabetes had a higher risk (which was intermediate between that of patients with diabetes and those with normal HbA1c) of the primary outcome (HR 1.27, 95% CI 1.00–1.60) and HFH (HR 1.35, 95% CI 1.03–1.77), but not of CV death (HR 1.02, 95% CI 0.75–1.40). Patients with diabetes treated with insulin had worse outcomes than those not, and those with ‘lean diabetes’ had similar mortality rates to those with a higher body mass index, but lower rates of HFH. Conclusion Pre‐diabetes is common in patients with HFpEF and is associated with worse clinical status and greater risk of HFH. Clinical Trial Registration: ClinicalTrials.gov Identifier NCT01920711.

Background Little is known about the impact of chronic obstructive pulmonary disease (COPD) in patients with heart failure with preserved ejection fraction (HFpEF). Methods and Results We examined outcomes in patients with heart failure with preserved ejection fraction, according to COPD status, in the PARAGON‐HF (Prospective Comparison of Angiotensin Receptor Neprilysin Inhibitor With Angiotensin Receptor Blocker Global Outcomes in Heart Failure With Preserved Ejection Fraction) trial. The primary outcome was a composite of first and recurrent hospitalizations for heart failure and cardiovascular death. Of 4791 patients, 670 (14%) had COPD. Patients with COPD were more likely to be men (58% versus 47%; P <0.001) and had worse New York Heart Association functional class (class III/IV 24% versus 19%), worse Kansas City Cardiomyopathy Questionnaire Clinical Summary Scores (69 versus 76; P <0.001) and more frequent history of heart failure hospitalization (54% versus 47%; P <0.001). The decrement in Kansas City Cardiomyopathy Questionnaire Clinical Summary Scores with COPD was greater than for other common comorbidities. Patients with COPD had echocardiographic right ventricular enlargement, higher serum creatinine (100 μmol/L versus 96 μmol/L) and neutrophil‐to‐lymphocyte ratio (2.7 versus 2.5), than those without COPD. After multivariable adjustment, COPD was associated with worse outcomes: adjusted rate ratio for the primary outcome 1.51 (95% CI, 1.25–1.83), total heart failure hospitalization 1.54 (95% CI, 1.24–1.90), cardiovascular death (adjusted hazard ratio [HR], 1.42; 95% CI, 1.10–1.82), and all‐cause death (adjusted HR, 1.52; 95% CI, 1.25–1.84). COPD was associated with worse outcomes than other comorbidities and Kansas City Cardiomyopathy Questionnaire Clinical Summary Scores declined more in patients with COPD than in those without. Conclusions Approximately 1 in 7 patients with heart failure with preserved ejection fraction had concomitant COPD, which was associated with greater functional limitation and a higher risk of heart failure hospitalization and death. Registration URL: https://www.clinicaltrials.gov ; Unique identifier: NCT01920711 .

In contrast to the wide application of zebrafish embryos in developmental genetic studies, the value of an adult zebrafish to dissect signaling pathways in human diseases such as cardiomyopathy remains largely elusive. Previously, we have established anemic tr265/tr265 fish as the first adult zebrafish model of cardiomyopathy. Here, we generate the second adult zebrafish cardiomyopathy model induced by injection of a single bolus of doxorubicin (DOX). Despite their different pathogenesis, cardiac enlargement induced by either anemia or DOX can be effectively attenuated by inhibition of target of rapamycin (TOR) signaling via rapamycin treatment. However, along the progression of both models, we have also detected dynamic TOR activity and distinct effects of TOR signaling inhibition at different stages of pathogenesis. To assess the long term effects of TOR haploinsufficiency, we utilized a zebrafish target of rapamycin (ztor) mutant that was identified from a mutagenesis screen. We show that sustained TOR inhibition in ztor/+ improved cardiac function, prevented pathological remodeling events, and ultimately reduced mortality in both adult fish models of cardiomyopathy. Mechanistically, these cardioprotective effects are conveyed by the anti-hypertrophy, anti-apoptosis, and pro-autophagy function of TOR signaling inhibition. Together, our results prove adult zebrafish as a novel vertebrate model for human cardiomyopathies and provide genetic evidences for a cardioprotective function of TOR signaling inhibition in different forms of cardiomyopathies.

Objective: To determine among community heart failure (HF) patients whether frailty is associated with an increased risk of hospitalization, emergency department (ED) visits and death, independently of comorbidities. Background: Frailty is associated with adverse outcomes in some populations; however the prognostic value of frailty among HF patients is not fully documented, particularly for healthcare utilization. Methods: Olmsted, Dodge and Fillmore County residents with HF between 10/2007 and 12/2010 were prospectively recruited to undergo frailty assessment. Frailty was defined as 3 or more of the following: unintentional weight loss >10 lbs. in 1 year, physical exhaustion, weak grip strength, and slowness and low activity measured by the SF-12 physical component score. Intermediate frailty was defined as having 1-2 components. To account for repeated events, Anderson-Gill modeling was used to determine if frailty predicted hospitalization or ED visits. Cox proportional hazards regression examined associations between frailty and death. Results: Among 409 patients (mean age 73±13, 58% male), 19% were frail and 55% had intermediate frailty. Within one year, 449 hospitalizations, 523 ED visits and 34 deaths occurred. There was a positive graded association between frailty and hospitalization and ED visits (Table). After adjustment for age, sex, ejection fraction and comorbidity, frailty was associated with an 80% increased risk of hospitalization and a 60% increased risk of ED visits. Frailty was also associated with more than a 2-fold increased risk of death after adjustment. Conclusion: In the community, frailty is prevalent and is a strong and independent predictor of hospitalizations, ED visits and death among HF patients. As it is independent from coexisting comorbidities, frailty defines new avenues for intervention and should be formally assessed clinically. Hazard Ratios (95% CI) for Hospitalizations, Emergency Department Visits and Death by Frailty Status Not Frail Intermediate Frail Frail P for trend Hospitalization Crude 1.00 1.46 (1.05-2.02) 2.15 (1.45-3.19) <0.001 Fully-adjusted 1.00 1.29 (0.94-1.77) 1.82 (1.22-2.73) 0.005 Emergency Department Visits Crude 1.00 1.59 (1.14-2.21) 1.88 (1.22-2.90) 0.002 Fully-adjusted 1.00 1.46 (1.05-2.05) 1.58 (1.01-2.48) 0.034 Death Crude 1.00 1.40 (0.73-2.69) 3.98 (2.01-7.90) <0.001 Fully-adjusted 1.00 0.87 (0.44-1.73) 2.42 (1.19-4.95) 0.003

Background: Preclinical diastolic dysfunction (PDD) is defined as subjects with normal systolic function, moderate or severe diastolic dysfunction determined by Doppler criteria but with no symptoms of heart failure (HF). We have previously demonstrated that an impaired cardiorenal endocrine response to stress by acute volume loading (AVL) exists in PDD and that is corrected by acute administration of sq B-type natriuretic peptide (BNP). Type V phosphodiesterase (PDEV) metabolizes cGMP, second messenger of BNP. The objective of the current study is to determine if the combination of PDEV inhibitor (PDEVI) and BNP will result in a greater enhancement of the cardiorenal response to AVL as compared to PDEVI alone in PDD. Methods: Randomized double-blind single placebo-controlled cross-over study in 20 PSD subjects. We determined cardiorenal effects of PDEVI with Tadalafil (T) 5 mg alone and in combination with acute sq BNP (Nesiritide 10 μg/Kg), in response to AVL (normal saline 0.25 ml/kg/min for 1 hour). Each subject had 2 study visits, separated by at least 1 week. At each visit, echocardiogram and renal clearance studies with iothalmate and PAH to measure GFR and renal plasma flow (RPF) were done before and after AVL. Each patient was randomized to receive T at both visits and either placebo or sq-BNP one visit and crossover to the other on the next visit. Results: T+BNP resulted in smaller LA volume index (-4±10 vs 3±7 ml/m 2 , p< 0.05) and lower right ventricular systolic pressure (-4±3 vs 2±6 mmHg, p< 0.05) in response to AVL as compared to T alone. Moreover, T+ BNP resulted in a significant reduction of plasma ANP and LV end-systolic volume in response to AVL while T alone did not. However, the combination to T+BNP did not enhance the renal response to AVL as compared to T alone. Both the change in urine flow (1.7±5 vs 2.4±5 ml/min, p> 0.05) and sodium excretion (129±200 vs 124±270 mEq/min, p>0.05) in response to AVL were similar between T+BNP and T alone. Conclusion: In PDD, the combination of PDEVI and BNP reduced LV filling pressure in response to AVL as compared to PDEVI alone. However, it did not enhance the renal response to AVL. This suggests a differential cardiac versus renal response to the maximization of cGMP system with PDEVI and BNP.

Background: In heart failure with preserved ejection fraction (HFpEF), left ventricular (LV) systolic elastance (Ees) increases in tandem with increases in arterial elastance (Ea), which maintains ejection fraction but limits systolic reserve and precipitates volume sensitivity. The left atrium (LA) lies in series with the LV and contributes to LV stroke volume. We hypothesized that HFpEF is associated with increased LA systolic elastance (E LA ) and deranged atrioventricular (AV) coupling which may additionally compromise cardiac performance. Methods: HFpEF was modeled by experimental hypertension (bilateral renal wrap + DOCA) in elderly dogs (n=9). LA and LV structure, function (echo, MRI) and invasively assessed pressure-volume relationships (PVR, open-chest; pericardiotomy; admittance catheter) were compared to sham-operated young dogs (control; n=13). Results: As compared to controls, HFpEF dogs displayed concentric remodeling, with increased diastolic stiffness, Ea and Ees (p<0.05 for all) and reduced Ea/Ees (p=0.03). LA maximum volume (28±3 vs 23±3mL, p=0.007), LA stroke volume (4±1 vs2±1mL, p=0.006), LA active emptying fraction (18±6 vs 12±2%, p=0.03) and LA ejection rate (51±14 vs 30±16mL/s) were higher in HFpEF versus controls, suggesting increased LA stroke work and inotropy. At matched heart rate and LA pressure, E LA was steeper in HFpEF than control (2.7±0.9 vs 1.5±0.6mmHg/mL, p=0.01) and positively correlated with Ees (r=0.6, p=0.005) and Ea (r=0.66, p=0.002). However AV mismatch occurred as increases in E LA were not proportionate to increases in Ees (Ees/E LA 1.3±0.4 HFpEF vs 0.8±0.4 control, p<0.05). On linear regression, worse AV coupling (i.e. higher Ees/E LA ) was associated with lower LV stroke volume ( Figure ). Conclusion: In experimental HFpEF, despite enhanced LA contractility, AV coupling was deranged. Worse AV coupling may further contribute to reserve dysfunction, LA pressure rise, and susceptibility to pulmonary edema in HFpEF.