Whether prevalence and mortality of patients with heart failure with preserved or mid-range (40–49%) ejection fraction (HFpEF and HFmREF) are similar to those of heart failure with reduced ejection fraction (HFrEF), as reported in some epidemiologic studies, remains highly controversial. We determined and compared characteristics and outcomes for patients with HFpEF, HFmREF, and HFrEF in a prospective, international, multi-ethnic population. Prospective multi-centre longitudinal study in New Zealand (NZ) and Singapore. Patients with HF were assessed at baseline and followed over 2 years. The primary outcome was death from any cause. Secondary outcome was death and HF hospitalization. Cox proportional hazards models were used to compare outcomes for patients with HFpEF, HFmrEF, and HFrEF. Of 2039 patients enrolled, 28% had HFpEF, 13% HFmrEF, and 59% HFrEF. Compared with HFrEF, patients with HFpEF were older (62 vs. 72 years), more commonly female (17% vs. 48%), and more likely to have a history of hypertension (61% vs. 78%) but less likely to have coronary artery disease (55% vs. 41%). During 2 years of follow-up, 343 (17%) patients died. Adjusting for age, sex, and clinical risk factors, patients with HFpEF had a lower risk of death compared with those with HFrEF (hazard ratio 0.62, 95% confidence interval 0.46–0.85). Plasma (NT-proBNP) was similarly related to mortality in both HFpEF, HFmrEF, and HFrEF independent of the co-variates listed and of ejection fraction. Results were similar for the composite endpoint of death or HF and were consistent between Singapore and NZ. These prospective multinational data showed that the prevalence of HFpEF within the HF population was lower than HFrEF. Death rate was comparable in HFpEF and HFmrEF and lower than in HFrEF. Plasma levels of NT-proBNP were independently and similarly predictive of death in the three HF phenotypes. Australian New Zealand Clinical Trial Registry (ACTRN12610000374066).

Aims: Since their identification in the circulation, microRNAs have received considerable interest as putative biomarkers of cardiovascular disease. We have investigated the diagnostic utility of microRNAs in differentiating between patients with heart failure (HF) and non-HF-related breathlessness, and between HF with reduced (HF-REF) and preserved (HF-PEF) EF. Methods and results: MicroRNA profiling was performed on plasma from 32 HF and 15 COPD patients, as well as 14 healthy controls. Seventeen microRNAs were selected for validation in 44 HF, 32 COPD, 59 other breathless, and 15 controls. Cases of HF were split evenly between HF-REF and HF-PEF. Diagnostic utility was compared with NT-proBNP and high sensitivity troponin T (hs-troponin T). MiR-103 [area under the curve (AUC) = 0.642, P = 0.007], miR-142-3p (AUC = 0.668, P = 0.002), miR-199a-3p (AUC = 0.668, P = 0.002), miR-23a (AUC = 0.637, P = 0.010), miR-27b (AUC = 0.642, P = 0.008), miR-324-5p (AUC = 0.621, P = 0.023), and miR-342-3p (AUC = 0.644, P = 0.007) were associated with HF diagnosis in regression and receiver operating characteristic (ROC) analyses. Individually, NT-proBNP (AUC = 0.896, P = 9.68 × 10−14) and hs-troponin T (AUC = 0.750, P = 2.50 × 10−6) exhibited greater sensitivity and specificity. However, combining significantly associated microRNAs with NT-proBNP improved the AUC of NT-proBNP by 4.6% (P = 0.013). Four microRNAs, miR-103, miR-142-3p, miR-30b, and miR-342-3p, were differentially expressed between HF and controls, COPD, and other breathless patients (P = 0.002–0.030). Eight microRNAs that distinguished between HF-REF and HF-PEF in screening (P = 0.017–0.049) were not replicated in the validation. Conclusions: Four microRNAs distinguished between HF and exacerbation of COPD, other causes of dyspnoea, and controls. Seven were associated with HF diagnosis in regression and ROC analysis. Although individually NT-proBNP was far superior in predicting HF, combining microRNA levels with NT-proBNP may add diagnostic value.

CRF is released in response to various stressors and regulates ACTH secretion and glucocorticoid production. CRF overproduction has been implicated in affective disorders, such as depression and anorexia nervosa, and may lead to Cushing's syndrome. To test whether CRF overproduction leads to Cushing's syndrome and to develop an animal model of chronic pituitary-adrenal activation, the CRF gene was expressed under control of the metallothionein promoter in transgenic mice. CRF transgenic animals exhibit endocrine abnormalities involving the hypothalamic-pituitary-adrenal axis, such as elevated plasma levels of ACTH and glucocorticoids. These animals display physical changes similar to those of patients with Cushing's syndrome, such as excess fat accumulation, muscle atrophy, thin skin, and alopecia. These findings indicate that chronic production of excess CRF results in sustained stimulation of pituitary corticotrope cells, resulting in elevated ACTH and consequent glucocorticoid overproduction, a condition that leads to the development of Cushing's syndrome. Analysis of CRF mRNA distribution revealed that transgene expression is primarily restricted to cells that express the endogenous CRF gene and does not follow the pattern predicted of a metallothionein-regulated gene. These results suggest that DNA elements located outside of the CRF promoter but present within the CRF intron, coding, or 3'-flanking regions may contribute to the cell type specificity of CRF gene expression.

Atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) are cardiac hormones, secreted by the atria and ventricles, respectively, in the normal adult heart. They participate in the regulation of blood pressure and body fluid homeostasis and modify growth and development of cardiovascular tissues and bone. Levels of ANP are higher in the fetal circulation than in adults, and fetal ventricles express higher levels of ANP and BNP than adult ventricles. The reappearance of ventricular ANP expression in adults is recognized as a marker of the induction of the embryonic gene program in ventricular hypertrophy. The natriuretic peptide system appears to be functional by midgestation, to respond to volume stimuli, and to regulate blood pressure and salt and water balance in the developing embryo. In addition, the natriuretic peptides may help regulate the blood supply to the fetus, acting as vasodilators in the placental vasculature. Peaks of ANP and BNP expression during gestation coincide with significant events in cardiac organogenesis, suggesting a role for ANP/BNP in the formation of the heart. In knockout mice lacking the natriuretic peptide receptor (NPR)-A gene (Npr1(-/-)), survival is reduced, with hearts enlarged at birth and possible cardiac developmental abnormalities. Surviving adult Npr1(-/-) mice have elevated blood pressure and marked cardiac hypertrophy and fibrosis, indicating that the ANP/BNP system is an important regulator of myocyte growth during development.