Background Anaemia is common in patients with HFrEF and is associated with poor clinical outcomes. Although they reduce rates of mortality and heart failure hospitalization, renin-angiotensin (RAS) blockers lower haemoglobin and may induce anaemia. Concomitant neprilysin inhibition might ameliorate this effect of RAS blockers. Purpose We investigated the effect of sacubitril/valsartan compared with enalapril on clinical outcomes, according to anaemia status, and on haemoglobin levels in PARADIGM-HF. Methods Patient characteristics and clinical outcomes were compared between patients with and without anaemia (defined as haemoglobin <120 g/L in women and <130 g/L in men) at baseline. We investigated the effect of randomized treatment (sacubitril/valsartan or enalapril) on clinical outcomes according to anaemia status at screening. We also examined the effect of treatment on change in haemoglobin from baseline and on the incidence of anaemia. The primary endpoint in PARADIGM-HF was the composite of heart failure hospitalization or cardiovascular death. Results Of 8239 participants with a baseline haemoglobin measurement, 1677 (20.4%) were anaemic. Compared to those without anaemia, patients with anaemia had a more severe heart failure profile, worse kidney function, greater neurohormonal derangement and worse clinical outcomes. Sacubitril/valsartan, compared to enalapril, reduced the risk of the primary endpoint similarly in patients with anaemia (HR 0.84, 95% CI 0.71–1.00) and without anaemia (HR 0.78, 95% CI 0.71–0.87), p-value for interaction=0.478. Between baseline and 12 months, haemoglobin decreased by 1.5 (95% CI 1.7 to 1.2) g/L with sacubitril/valsartan compared with 2.3 (2.6 to 2.0) g/L with enalapril group: mean difference 0.8 (95% CI 0.5 to 1.2) g/L, p<0.001. The between-treatment difference apparent by 12 months, persisted up to 36 months. Patients assigned to sacubitril/valsartan were less likely to develop new anaemia at 12 months [321 of 2806 (11.4%)] compared to patients randomized to enalapril [440 of 2384 (15.6%)], odds ratio 0.70 (95% CI 0.60–0.81), p<0.001. Conclusions Compared to enalapril, sacubitril/valsartan reduced mortality and hospitalization in HFrEF patients with and without anaemia. Haemoglobin decreased less with sacubitril/valsartan and the incidence of new anaemia was lower in the sacubitril/valsartan group compared with the enalapril group. Funding Acknowledgement Type of funding sources: Private company. Main funding source(s): PARADIGM-HF was funded by Novartis.

We demonstrate that familial hypertrophic cardiomyopathy (FHC), an autosomal dominant disorder of heart muscle, is a genetically heterogeneous disease. The locus responsible for FHC in members of one large kindred was recently mapped to chromosome 14q11-12 (FHC-1). We have characterized three additional unrelated families in which the gene for FHC segregates as an autosomal dominant trait to determine if these disease loci also map to FHC-1. All family members were clinically studied by physical examination, electrocardiogram, and two-dimensional echocardiography. Genetic studies were performed using DNA probes which are derived from loci that are closely linked to FHC-1. In one family the genetic defect maps to the previously identified FHC-1 locus. However, the loci responsible for FHC in two other families were not linked to FHC-1. We conclude that FHC can be caused by defects in at least two loci and is a genetically heterogeneous disorder. (J. Clin. Invest. 1990. 86:993-999.)

Background/Introduction N-terminal pro-B-type natriuretic peptide (NT-proBNP) is a marker of ventricular wall stress and a potent predictor of death and heart failure (HF) across multiple populations (from healthy insurance applicants to various disease entities). Purpose To evaluate the prognostic importance of NT-proBNP in patients with acute myocardial infarction (AMI) complicated by left ventricular systolic dysfunction, pulmonary congestion, or both and ≥1 of 8 predefined risk-augmenting factors (age ≥70 years, diabetes, previous MI, eGFR <60 ml/min/1.73 m2, atrial fibrillation, LVEF <30%, Killip class III/IV, or ST elevation MI without reperfusion) enrolled in PARADISE-MI. Methods Patients were randomized to sacubitril/valsartan 200mg or ramipril 5mg twice daily within 0.5 to 7 days of presenting with an AMI. Patients with prior HF were excluded. NT-proBNP and high-sensitivity troponin T (hsTnT) were collected at randomization in a prespecified sub-study of 1129 patients. The primary endpoint of PARADISE-MI was a time-to-first composite of cardiovascular (CV) death or incident HF (hospitalization or outpatient symptomatic HF); secondary endpoints included all-cause death and the composite of fatal or non-fatal MI or stroke. Results Median NT-proBNP was 1757 pg/ml [interquartile range, 896–3462 pg/ml] at randomization (4.0±1.8 days after presentation with the index MI). Patients with higher NT-proBNP levels at baseline were older, more commonly women and more frequently had hypertension, atrial fibrillation, renal dysfunction, and pulmonary congestion at randomization (all p<0.001). NT-proBNP concentrations were only weakly correlated with levels of hsTnT at randomization (r=0.38, p<0.001). NT-proBNP at baseline was strongly associated with the primary composite endpoint (adjusted HR 1.45 per doubling NT-proBNP; 95% CI, 1.23–1.70), independent of clinical variables as well as hsTnT (Figure). NT-proBNP was also independently associated with all-cause death (aHR 1.74; 95% CI, 1.38–2.21) and fatal or non-fatal MI or stroke (aHR 1.24; 95% CI, 1.05–1.45). The relative effect of sacubitril/valsartan versus ramipril on the primary composite endpoint was not statistically different across the spectrum of NT-proBNP (p-interaction = 0.46). Conclusions When assessed within the first week of a high risk AMI NT-proBNP is not only associated with incident HF and death but also with atherosclerotic events and provides prognostic information that is independent of hsTnT in this post AMI population. Funding Acknowledgement Type of funding sources: None.

SUMMARY Four babies with complete heart block associated with maternal systemic lupus erythematosus (SLE) are described, together with a 5th baby whose mother had serological abnormalities only. One baby had a rapidly fatal outcome, one has required digoxin for heart failure, and the remaining 3 are asymptomatic but remain in complete heart block. Additional manifestations were present in 2 of them. The spectrum of neonatal abnormalities that may occur in association with maternal SLE and related connective tissue disorders is discussed, together with the possible causes and the prognosis. We conclude that congenital heart block is more common than had previously been appreciated.

The D/I (deletion, D, insertion, I) polymorphism of the angiotensin-converting enzyme (ACE) gene has been extensively studied for its association with a number of cardiovascular and other disease states. However, its potential association with differential clinical efficacy of ACE inhibitors (ACE-I) administered to patients who had suffered a myocardial infarction (MI), i.e. the prevention of left ventricular (LV) remodeling, has so far not been specifically studied. The aim of the study was to investigate whether the D/I polymorphism of the ACE gene is associated with the incidence of post-MI LV remodeling in patients drawn from the 'Healing and Early Afterload Reducing Therapy' (HEART) Study. The ACE D/I polymorphism was characterized by the polymerase chain reaction (PCR) in 265 subjects from the 'Healing and Early Afterload Reducing Therapy' Study, a double-blind, placebo-controlled trial with the objective of determining whether early or delayed administration of the ACE-I, ramipril, in patients with acute anterior wall MI would be optimal in reducing LV enlargement. Selected frequencies for the ACE D and I alleles were 0.59 and 0.41 (placebo-high dose group), 0.56 and 0.44 (low dose-low dose group), and, 0.60 and 0.40 (high dose-high dose group), respectively. All observed genotype frequencies were in Hardy-Weinberg equilibrium. There was no evidence for an association between genotype and outcome regarding LV size or function, nor with the initial blood pressure response after ACE-I administration (adjusted for covariates). Our data provide no evidence for an association of the ACE D/I polymorphism with the risk of LV remodeling post-MI in the presence of ACE-I therapy, and therefore do not suggest that differential clinical efficacy of ACE-inhibitors is related to this genetic marker.