The Polygenic and Monogenic Basis of Blood Traits and Diseases.

Blood cells play essential roles in human health, underpinning physiological processes such as immunity, oxygen transport, and clotting, which when perturbed cause a significant global health burden. Here we integrate data from UK Biobank and a large-scale international collaborative effort, including data for 563,085 European ancestry participants, and discover 5,106 new genetic variants independently associated with 29 blood cell phenotypes covering a range of variation impacting hematopoiesis. We holistically characterize the genetic architecture of hematopoiesis, assess the relevance of the omnigenic model to blood cell phenotypes, delineate relevant hematopoietic cell states influenced by regulatory genetic variants and gene networks, identify novel splice-altering variants mediating the associations, and assess the polygenic prediction potential for blood traits and clinical disorders at the interface of complex and Mendelian genetics. These results show the power of large-scale blood cell trait GWAS to interrogate clinically meaningful variants across a wide allelic spectrum of human variation.

KCND3 potassium channel gene variant confers susceptibility to electrocardiographic early repolarization pattern.

BACKGROUNDThe presence of an early repolarization pattern (ERP) on the surface ECG is associated with risk of ventricular fibrillation and sudden cardiac death. Family studies have shown that ERP is a highly heritable trait, but molecular genetic determinants are unknown.METHODSTo identify genetic susceptibility loci for ERP, we performed a GWAS and meta-analysis in 2,181 cases and 23,641 controls of European ancestry.RESULTSWe identified a genome-wide significant (P < 5 × 10-8) locus in the potassium voltage-gated channel subfamily D member 3 (KCND3) gene that was successfully replicated in additional 1,124 cases and 12,510 controls. A subsequent joint meta-analysis of the discovery and replication cohorts identified rs1545300 as the lead SNP at the KCND3 locus (OR 0.82 per minor T allele, P = 7.7 × 10-12) but did not reveal additional loci. Colocalization analyses indicate causal effects of KCND3 gene expression levels on ERP in both cardiac left ventricle and tibial artery.CONCLUSIONSIn this study, we identified for the first time to our knowledge a genome-wide significant association of a genetic variant with ERP. Our findings of a locus in the KCND3 gene provide insights not only into the genetic determinants but also into the pathophysiological mechanism of ERP, discovering a promising candidate for functional studies.FUNDINGThis project was funded by the German Center for Cardiovascular Research (DZHK Shared Expertise SE081 - STATS). For detailed funding information per study, see the Supplemental Acknowledgments.

Left ventricular systolic dysfunction associated with pulmonary hypertension riociguat trial (LEPHT): rationale and design.

AIMS: Pulmonary hypertension (PH) due to systolic left ventricular dysfunction (PH-sLVD) frequently complicates heart failure (HF), and greatly worsens the prognosis of patients with sLVD, but as yet has no approved treatment. The LEPHT study aims to characterize the haemodynamic profile, safety, tolerability, and pharmacokinetic profile of riociguat (BAY 63-2521), an oral stimulator of soluble guanylate cyclase, in patients with PH-sLVD. METHODS AND RESULTS: This 16-week, phase IIb, randomized, placebo-controlled, double-blind study enrols patients with PH-sLVD, defined as left ventricular ejection fraction (LVEF) ≤40% and mean pulmonary arterial pressure (PAP(mean)) ≥25 mmHg at rest. Patients using optimized HF medication will receive placebo or riociguat 0.5 mg, 1 mg, or up to 2 mg three times daily. The dose will be titrated for 8 weeks, based on systolic blood pressure and well-being, followed by 8 weeks of treatment at a stable dose. The primary efficacy variable is PAP(mean), while secondary efficacy endpoints include LVEF, exercise capacity, quality of life, and other haemodynamic and echocardiographic measurements. Safety and pharmacokinetics will also be assessed. After the 16-week study, patients will have the opportunity to be treated with riociguat in a long-term extension phase. CONCLUSION: The LEPHT study will provide valuable information on the haemodynamic, echocardiographic, and preliminary clinical effects of riociguat in patients with PH-sLVD. Trial registration NCT01065454.

Low serum magnesium concentrations predict cardiovascular and all-cause mortality.

BACKGROUND: Low serum magnesium (Mg(++)) levels are associated with future development of left ventricular hypertrophy independently of common cardiovascular risk factors, as recently demonstrated in the five-year follow-up of the population-based Study of Health in Pomerania (SHIP). As left ventricular hypertrophy has significant prognostic implications, we hypothesized that serum Mg(++) levels are associated with cardiovascular mortality. METHOD AND RESULTS: All-cause mortality and cardiovascular mortality were analyzed in relationship to serum Mg(++) concentrations at baseline by Cox proportional hazard model in SHIP (n=4203, exclusion of subjects with Mg(++) supplementation). The median duration of mortality follow-up was 10.1 years (25th percentile: 9.4 years, 75th percentile: 10.8 years; 38,075 person-years). During the follow-up, 417 deaths occurred. Mortality in subjects with Mg(++)≤0.73 mmol/l was significantly higher for all-cause deaths (10.95 death per 1000 person years), and cardiovascular deaths (3.44 deaths per 1000 person years) in comparison to higher Mg(++) concentrations (1.45 deaths from all-cause per 1000 person years, 1.53 deaths from cardiovascular cause per 1000 person years). This association remained statistically significant after adjustment for multiple cardiovascular risk factors, including arterial hypertension, and antihypertensive therapy including diuretics (log-rank-test p=0.0001 for all-cause mortality, and p=0.0174 for cardiovascular mortality). CONCLUSIONS: Low serum Mg(++) levels are associated with higher all-cause mortality and cardiovascular mortality. This corresponds well with recent findings that hypomagnesemia is associated with the increase of left ventricular mass over the following years.

Quinaprilat: a review of its pharmacokinetics, pharmacodynamics, toxicological data and clinical application.

BACKGROUND: Quinaprilat is an ACE inhibitor for intravenous use especially in patients with arterial hypertension or chronic heart failure. In contrast to the oral prodrug quinapril, it has not been approved for clinical application. OBJECTIVE: In this review, the pharmacokinetic and pharmacodynamic profile of quinaprilat as well as toxicological data and results of preclinical and clinical studies are summarized. METHODS: In a PubMed search for the terms "quinaprilat" and "quinapril", literature relevant for this review was selected. RESULTS: Quinaprilat is a potent nonsulfhydryl selective ACE inhibitor with a short elimination half-life of 2 - 3 h, but due to slow dissociation from tissue ACE, once daily dosing is sufficient for effective ACE inhibition. Quinaprilat is excreted mainly in urine. In long-term animal studies, quinaprilat was not teratogenic, mutagenic or carcinogenic. However, due to the risk of fetal and neonatal morbidity and death, it should not be administrated in pregnancy. Quinaprilat is characterized by an excellent safety profile; adverse events occur infrequently and are rarely serious. CONCLUSION: Quinaprilat is an attractive ACE inhibitor, which potently inhibits tissue ACE.

BAY 58-2667, a nitric oxide-independent guanylyl cyclase activator, pharmacologically post-conditions rabbit and rat hearts.

AIMS: BAY 58-2667 (BAY-58) directly activates soluble guanylyl cyclase without tolerance in a nitric oxide (NO)-independent manner, and its haemodynamic effect is similar to that of nitroglycerin. We tested whether BAY-58 could make both rabbit and rat hearts resistant to infarction when given at the end of an ischaemic insult. METHODS AND RESULTS: All hearts were exposed to 30 min regional ischaemia followed by 120-(isolated hearts) or 180-(in situ hearts) min reperfusion. BAY-58 (1-50 nM) infused for 60 min starting 5 min before reperfusion significantly reduced infarction from 33.0 +/- 3.2% in control isolated rabbit hearts to 9.5-12.7% (P < 0.05). In a more clinically relevant in situ rabbit model, infarct size was similarly reduced with a loading dose of 53.6 microg/kg followed by a 60 min infusion of 1.25 microg/kg/min (41.1 +/- 3.1% infarction in control hearts to 16.0 +/- 4.4% in treated hearts, P < 0.05). BAY-58 similarly decreased infarction in the isolated rat heart, and protection was abolished by co-treatment with a protein kinase G (PKG) antagonist, or a mitochondrial K(ATP) channel antagonist. Conversely, N(omega)-nitro-L-arginine-methyl-ester-hydrochloride, a NO-synthase inhibitor, failed to block BAY-58's ability to decrease infarction, consistent with the latter's putative NO-independent activation of PKG. Finally, BAY-58 increased myocardial cGMP content in reperfused hearts while cAMP was unchanged. CONCLUSION: When applied at reperfusion, BAY-58 is an effective cardioprotective agent with a mechanism similar to that of ischaemic pre-conditioning and, hence, should be a candidate for treatment of acute myocardial infarction in man.

Fish oil supplementation in the parenteral nutrition of critically ill medical patients: a randomised controlled trial.

OBJECTIVE: To test whether supplementation of parenteral nutrition with fish oil - aimed at increasing the n-3:n-6 ratio of polyunsaturated fatty acids (PUFA) to 1:2 - affects systemic inflammation and clinical outcome compared to standard parenteral nutrition with an n-3/n-6 ratio of 1:7 in medical intensive care unit (ICU) patients. DESIGN: Single-centre, placebo-controlled, double-blind, randomised clinical trial. SETTING: Twelve-bed medical ICU of a university hospital. PATIENTS: A total of 166 consecutive patients anticipated to need parenteral nutrition for more than 6 days. Patients were stratified for the presence of systemic inflammatory response syndrome (SIRS) at baseline (115 SIRS, 51 non-SIRS). INTERVENTION: Patients were randomly assigned to receive either a 1:1-mixture of medium-chain triglycerides (MCT) and long-chain triglycerides (LCT) with an n-3/n-6 PUFA ratio of 1:7, or the same MCT/LCT emulsion supplemented with fish oil (resulting in an n-3/n-6 ratio of 1:2). MEASUREMENTS AND RESULTS: Primary endpoints were changes in interleukin 6 (IL-6) and monocyte HLA-DR expression relative to baseline. Secondary endpoints were incidence of nosocomial infections, duration of mechanical ventilation, length of ICU stay, and 28-day mortality. Bleeding complications were recorded as a possible side effect of fish oil. Between standard and intervention groups, overall as well as stratified for SIRS or non-SIRS, no significant difference was detected in any of the endpoints or frequency and severity of bleeding events. CONCLUSIONS: In unselected critically ill medical patients, fish oil supplementation that increased the n-3/n-6 PUFA ratio to 1:2 did not affect inflammation or clinical outcome, compared to parenteral lipid nutrition with an MCT/LCT emulsion.