Redfield, Margaret M.

Abstract Background Mild asymptomatic left ventricular systolic dysfunction (ALVSD) may be associated with incident heart failure (HF). However, this gray zone group needs incremental risk refinement. We hypothesized that diastolic dysfunction (DD) may refine HF and death risk prediction in mild ALVSD. Methods and results Among 4047 subjects aged ≥55/≤80 years followed by 10 general practitioners in northern Italy, the DAVID-Berg study prospectively enrolled 623 asymptomatic outpatients at increased risk for HF. Baseline evaluation included clinical visit, N-terminal pro B-type natriuretic peptide, and echocardiogram. Based on left ventricular ejection fraction (LVEF) and DD, subjects were classified as: control group (normal LVEF, n = 459, 76%), mild ALVSD (LVEF ≥40%/<53%) without DD (n = 89, 15%) and with DD (n = 54, 9%). Subjects with LVEF <40% or without full echocardiographic data were excluded from the analysis (n = 21). Mean age of the population was 69 ±7 years, 56% were men, mostly hypertensive, mean LVEF was 61%. During a median follow-up of 5.7 years, 88 subjects (15%) experienced HF/death events (59 HF events and 29 deaths). Compared to the control group, mild ALVSD was associated with a higher risk of incident HF/death (hazard ratio 1.80, 95% confidence interval 1.10–2.93, adjusted P = 0.019) according to the Cox proportional hazards model. However, this higher risk was present only in subjects with combined DD (P = 0.005) and not in those without it (P = 0.30). Results were consistent even considering the individual components of the primary outcome. Conclusion In a high-risk population, an echocardiographic exam is normally performed to assess systolic dysfunction. Our data underline the importance of also relying on DD to risk stratify mild ALVSD. Mild ALVSD might be a predictor of adverse events mainly in subjects with combined DD, though further studies are needed to confirm these results.

Background: To describe the baseline characteristics of patients with heart failure and preserved left ventricular ejection fraction enrolled in the PARAGON-HF trial (Prospective Comparison of Angiotensin Receptor Neprilysin Inhibitor With Angiotensin Receptor Blocker Global Outcomes in HFpEF) comparing sacubitril/valsartan to valsartan in reducing morbidity and mortality. Methods and Results: We report key demographic, clinical, and laboratory findings, and baseline therapies, of 4822 patients randomized in PARAGON-HF, grouped by factors that influence criteria for study inclusion. We further compared baseline characteristics of patients enrolled in PARAGON-HF with those patients enrolled in other recent trials of heart failure with preserved ejection fraction (HFpEF). Among patients enrolled from various regions (16% Asia-Pacific, 37% Central Europe, 7% Latin America, 12% North America, 28% Western Europe), the mean age of patients enrolled in PARAGON-HF was 72.7±8.4 years, 52% of patients were female, and mean left ventricular ejection fraction was 57.5%, similar to other trials of HFpEF. Most patients were in New York Heart Association class II, and 38% had ≥1 hospitalizations for heart failure within the previous 9 months. Diabetes mellitus (43%) and chronic kidney disease (47%) were more prevalent than in previous trials of HFpEF. Many patients were prescribed angiotensin-converting enzyme inhibitors or angiotensin receptor blockers (85%), β-blockers (80%), calcium channel blockers (36%), and mineralocorticoid receptor antagonists (24%). As specified in the protocol, virtually all patients were on diuretics, had elevated plasma concentrations of N-terminal pro-B-type natriuretic peptide (median, 911 pg/mL; interquartile range, 464–1610), and structural heart disease. Conclusions: PARAGON-HF represents a contemporary group of patients with HFpEF with similar age and sex distribution compared with prior HFpEF trials but higher prevalence of comorbidities. These findings provide insights into the impact of inclusion criteria on, and regional variation in, HFpEF patient characteristics. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov . Unique identifier: NCT01920711.

Background: Diagnosis of heart failure with preserved ejection fraction (HFpEF) is challenging in euvolemic patients with dyspnea, and no evidence-based criteria are available. We sought to develop and then validate noninvasive diagnostic criteria that could be used to estimate the likelihood that HFpEF is present among patients with unexplained dyspnea to guide further testing. Methods: Consecutive patients with unexplained dyspnea referred for invasive hemodynamic exercise testing were retrospectively evaluated. Diagnosis of HFpEF (case) or noncardiac dyspnea (control) was ascertained by invasive hemodynamic exercise testing. Logistic regression was performed to evaluate the ability of clinical findings to discriminate cases from controls. A scoring system was developed and then validated in a separate test cohort. Results: The derivation cohort included 414 consecutive patients (267 cases with HFpEF and 147 controls; HFpEF prevalence, 64%). The test cohort included 100 consecutive patients (61 with HFpEF; prevalence, 61%). Obesity, atrial fibrillation, age >60 years, treatment with ≥2 antihypertensives, echocardiographic E/e’ ratio >9, and echocardiographic pulmonary artery systolic pressure >35 mm Hg were selected as the final set of predictive variables. A weighted score based on these 6 variables was used to create a composite score (H 2 FPEF score) ranging from 0 to 9. The odds of HFpEF doubled for each 1-unit score increase (odds ratio, 1.98; 95% CI, 1.74–2.30; P <0.0001), with an area under the curve of 0.841 ( P <0.0001). The H 2 FPEF score was superior to a currently used algorithm based on expert consensus (increase in area under the curve of 0.169; 95% CI, 0.120–0.217; P <0.0001). Performance in the independent test cohort was maintained (area under the curve, 0.886; P <0.0001). Conclusions: The H 2 FPEF score, which relies on simple clinical characteristics and echocardiography, enables discrimination of HFpEF from noncardiac causes of dyspnea and can assist in determination of the need for further diagnostic testing in the evaluation of patients with unexplained exertional dyspnea.

Heart failure (HF) is a clinical syndrome of diverse etiologies and can be associated with preserved, reduced, or mid-range ejection fraction (EF). In the community, heart failure with preserved ejection fraction (HFpEF) is emerging as the most common form of HF. There remains considerable uncertainty regarding its pathogenesis, diagnosis, and optimal therapeutic approach. Hypotheses have been advanced to explain the underlying pathophysiology responsible for HFpEF, but to date, no specific therapy based on these hypotheses has been proven to improve outcomes in HFpEF. We provide a clinically focused review of the epidemiology, clinical presentation, diagnostic approach, pathophysiology, and treatment of HFpEF.

Endothelin-1 (ET-1) is a peptide that has been implicated in congestive heart failure (CHF). Although increased concentrations of circulating ET-1 have been repeatedly demonstrated, the activation of local ET-1 in target tissues of CHF remains poorly defined. Our objective was to characterize ET-1 tissue concentrations and gene expression of prepro ET-1 in myocardial, renal, and pulmonary tissue in rapid ventricular pacing-induced canine CHF. Progressive rapid ventricular pacing (38 days) resulted in impaired cardiovascular hemodynamics, increased atrial and left ventricular mass, decreased renal sodium excretion, and increased ET-1 plasma concentrations (all P < 0.05). Tissue analysis revealed significant increases in local ET-1 during CHF in left ventricular, renal, and pulmonary tissue, whereas a moderate increase in left atrial ET-1 did not reach statistical significance. In contrast, prepro-ET-1 gene expression was increased more than threefold in pulmonary tissue and more than twofold in left atrial myocardium with no increase in left ventricular or renal gene expression. The present studies demonstrate a differential pattern of ET-1 activation in cardiorenal and pulmonary tissue with a strong accumulation of ET-1 in kidney and lung during CHF. Although the observed increase in left ventricular and renal ET-1 in association with unaltered gene expression is consistent with increased uptake, pulmonary and atrial tissue may contribute to increased circulating and local ET-1 in CHF.

Circulating atrial natriuretic factor (ANF) is regulated by clearance receptors (ANFR-C). C-ANF-(4-23) is a ring-deleted analogue of ANF, which binds specifically to ANFR-C. The present studies were undertaken to determine total metabolic (TMCR), pulmonary (PCR), and renal clearance rates (RCR) of ANF in a group of seven mongrel dogs in chronic congestive heart failure (CHF) in comparison with a control group (n = 6). TMCR was not altered in CHF [1,534 +/- 319 vs. control: 1,735 +/- 208 ml/min; P = not significant (NS)] in association with an elevation of circulating endogenous ANF (206 +/- 44 vs. control: 36 +/- 10 pg/ml; P < 0.01). Infusion of C-ANF-(4-23) reduced TMCR in both groups similarly (CHF: 753 +/- 134 vs. control: 972 +/- 156 ml/min; P = NS). PCR was lower in CHF (286 +/- 431 vs. 1,672 +/- 407 ml/min; P < 0.05), whereas RCR was not different (10 +/- 24 vs. control: 15 +/- 25 ml/min; P = NS). ANFR-C blockade did not facilitate urinary sodium excretion in CHF. These studies demonstrate that 1) TMCR does not contribute to elevated endogenous ANF in CHF; 2) total functional activity of the clearance receptor pathway is preserved in CHF; and 3) renal ANF metabolism and the clearance receptor pathway are not linked to the avid sodium retention and renal ANF resistance observed in chronic CHF.

his study was designed to characterize left ventricular (LV) function and mass in a modified cardiomyopathy model in the dog in which right ventricular pacing rates are gradually increased throughout 38 days. On the last day of the pacing protocol, ejection fraction was reduced (25 +/- 3 vs. 60 +/- 1%) and LV end-diastolic diameter index (a ratio of LV end-diastolic diameter to body weight, 2.09 +/- 0.02 vs. 1.79 +/- 0.08 mm/kg) and LV mass index (a ratio of LV mass to body weight, 5.2 +/- 0.3 vs. 4.3 +/- 0.2 g/kg) were greater than in the normal dogs (P < 0.05, respectively). Cardiac filling pressures increased, and LV diastolic function and coronary blood flow were impaired. After 4 wk of recovery from the progressive pacing protocol, LV end-diastolic diameter index (2.12 +/- 0.06 mm/kg) and LV mass index (5.6 +/- 0.2 g/kg) remained increased. Ejection fraction was improved (38 +/- 4%) but still depressed. LV diastolic function, coronary blood flow, and cardiac filling pressures returned to levels seen in the normal dogs. This modified cardiomyopathy model associated with LV hypertrophy complements the conventional tachycardia-induced cardiomyopathy model without LV hypertrophy.

Adrenomedullin (ADM) is a new member of a family of vasodilating and natriuretic peptides that plays an important role in cardiorenal regulation. This study was designed to establish the plasma, urinary, cardiac, and renal tissue concentrations and immunohistochemical localizations of ADM in normal dogs and dogs with experimental congestive heart failure (CHF) produced by rapid ventricular pacing. Plasma ADM concentration was 5.6 ± 0.4 pg/ml in normal dogs and significantly increased to 14.5 ± 2.5 pg/ml in CHF dogs ( P < 0.05). Ventricular and renal tissue ADM were significantly increased in CHF dogs compared with normals. Immunohistochemical examination revealed positive ADM immunostaining within the myocytes, and ventricular ADM immunoreactivity was significantly more intense in CHF dogs than in normals. ADM immunoreactivity was also observed in the glomerulus, distal tubules, and medullary collecting duct cells in the kidney, and the intensities of ADM immunoreactivity in these sites were increased in CHF dogs compared with normals. In addition, ventricular ADM was a powerful marker for left ventricular mass, and circulating ADM correlated positively with left ventricular end-diastolic pressure and inversely with cardiac output and ejection fraction. Despite an increase in renal tissue ADM, urinary ADM did not increase in CHF dogs. The current study demonstrates that plasma concentration of ADM is increased in experimental CHF and that ventricular and renal ADM is activated in the progression of CHF. Tissue and circulating ADM also are markers for the alterations in myocardial structure and function. This study supports a potential role for ADM in the neurohumoral activation in experimental CHF.