Antecedent hypertension and heart failure after myocardial infarction

AbstractObjectivesWe sought to assess the relationship of antecedent hypertension to neurohormones, ventricular remodeling and clinical heart failure (HF) after myocardial infarction (MI).BackgroundHeart failure is a probable contributor to the increased mortality observed after MI in those with antecedent hypertension. Hence, neurohormonal activation, adverse ventricular remodeling and a higher incidence of clinical HF may be expected in this group. However, no previous report has documented serial postinfarction neurohumoral status, serial left ventricular imaging and clinical outcomes over prolonged follow-up in a broad spectrum of patients with and without antecedent hypertension.MethodsInpatient events were documented in 1,093 consecutive patients (436 hypertensive and 657 normotensive) with acute MI. In 68% (282 hypertensive, 465 normotensive) serial neurohormonal sampling and radionuclide ventriculography were performed one to four days and three to five months after infarction. Clinical outcomes were recorded over a mean follow-up of two years.ResultsPlasma neurohormones were significantly higher in hypertensives than in normotensives one to four days and three to five months after infarction. From similar initial values, left ventricular volumes increased significantly in hypertensives, compared with normotensives. Left ventricular ejection fraction rose significantly in normotensive but not hypertensive patients. Together with higher inpatient (8.1% vs. 4.4%, p < 0.002) and post-discharge mortality (9.5% vs. 5.5%, p = 0.043), hypertensive patients incurred more inpatient HF (33% vs. 24%, p < 0.001) and more late HF requiring readmission to hospital (12.4% vs. 5.5%, p < 0.001). Antecedent hypertension predicted late HF in patients >64 years of age with neurohormonal activation and early left ventricular dilation.ConclusionsAntecedent hypertension interacts with age, neurohumoral activation and early ventricular remodeling to confer greater risk of HF after MI

Urocortin 2 Infusion in Healthy Humans Hemodynamic, Neurohormonal, and Renal Responses

ObjectivesWe sought to examine the effects of urocortin (UCN) 2 infusion on hemodynamic status, cardiovascular hormones, and renal function in healthy humans.BackgroundUrocortin 2 is a vasoactive and cardioprotective peptide belonging to the corticotrophin-releasing factor peptide family. Recent reports indicate the urocortins exert important effects beyond the hypothalamo-pituitary-adrenal axis upon cardiovascular and vasohumoral function in health and cardiac disease.MethodsWe studied 8 healthy unmedicated men on 3 separate occasions 2 to 5 weeks apart. Subjects received placebo, 25-μg low-dose (LD), and 100-μg high-dose (HD) of UCN 2 intravenously over the course of 1 h in a single-blind, placebo-controlled, dose-escalation design. Noninvasive hemodynamic indexes, neurohormones, and renal function were measured.ResultsThe administration of UCN 2 dose-dependently increased cardiac output (mean peak increments ± SEM) (placebo 0.5 ± 0.2 l/min; LD 2.1 ± 0.6 l/min; HD 5.0 ± 0.8 l/min; p < 0.001), heart rate (placebo 3.3 ± 1.0 beats/min; LD 8.8 ± 1.8 beats/min; HD 17.8 ± 2.1 beats/min; p < 0.001), and left ventricular ejection fraction (placebo 0.6 ± 1.4%; LD 6.6 ± 1.5%; HD 14.1 ± 0.8%; p < 0.001) while decreasing systemic vascular resistance (placebo −128 ± 50 dynes·s/cm5; LD −407 ± 49 dynes·s/cm5; HD −774 ± 133 dynes·s/cm5; p < 0.001). Activation of plasma renin activity (p = 0.002), angiotensin II (p = 0.001), and norepinephrine (p < 0.001) occurred only with the higher 100-μg dose. Subtle decreases in urine volume (p = 0.012) and natriuresis (p = 0.001) were observed.ConclusionsBrief intravenous infusions of UCN 2 in healthy humans induced pronounced dose-related increases in cardiac output, heart rate, and left ventricular ejection fraction while decreasing systemic vascular resistance. Subtle renal effects and activation of plasma renin, angiotensin II, and norepinephrine (at high-dose only) were observed. These findings warrant further investigation of the role of UCN 2 in circulatory regulation and its potential therapeutic application in heart disease

Influence of natriuretic peptide receptor-1 on survival and cardiac hypertrophy during development

The heart adapts to an increased workload through the activation of a hypertrophic response within the cardiac ventricles. This response is characterized by both an increase in the size of the individual cardiomyocytes and an induction of a panel of genes normally expressed in the embryonic and neonatal ventricle, such as atrial natriuretic peptide (ANP). ANP and brain natriuretic peptide (BNP) exert their biological actions through activation of the natriuretic peptide receptor-1 (Npr1). The current study examined mice lacking Npr1 (Npr1−/−) activity and investigated the effects of the absence of Npr1 signaling during cardiac development on embryo viability, cardiac structure and gene and protein expression. Npr1−/−embryos were collected at embryonic day (ED) 12.5, 15.5 and neonatal day 1 (ND 1). Npr1−/−embryos occurred at the expected Mendelian frequency at ED 12.5, but knockout numbers were significantly decreased at ED 15.5 and ND 1. There was no indication of cardiac structural abnormalities in surviving embryos. However, Npr1−/−embryos exhibited cardiac enlargement (without fibrosis) from ED 15.5 as well as significantly increased ANP mRNA and protein expression compared to wild-type (WT) mice, but no concomitant increase in expression of the hypertrophy-related transcription factors, Mef2A, Mef2C, GATA-4, GATA-6 or serum response factor (SRF). However, there was a significant decrease in Connexin-43 (Cx43) gene and protein expression at mid-gestation in Npr1−/−embryos. Our findings suggest that the mechanism by which natriuretic peptide signaling influences cardiac development in Npr1−/− mice is distinct from that seen during the development of pathological cardiac hypertrophy and fibrosis. The decreased viability of Npr1−/−embryos may result from a combination of cardiomegaly and dysregulated Cx43 protein affecting cardiac contractility

Influence of natriuretic peptide receptor-1 on survival and cardiac hypertrophy during development

The heart adapts to an increased workload through the activation of a hypertrophic response within the cardiac ventricles. This response is characterized by both an increase in the size of the individual cardiomyocytes and an induction of a panel of genes normally expressed in the embryonic and neonatal ventricle, such as atrial natriuretic peptide (ANP). ANP and brain natriuretic peptide (BNP) exert their biological actions through activation of the natriuretic peptide receptor-1 (Npr1). The current study examined mice lacking Npr1 (Npr1−/−) activity and investigated the effects of the absence of Npr1 signaling during cardiac development on embryo viability, cardiac structure and gene and protein expression. Npr1−/−embryos were collected at embryonic day (ED) 12.5, 15.5 and neonatal day 1 (ND 1). Npr1−/−embryos occurred at the expected Mendelian frequency at ED 12.5, but knockout numbers were significantly decreased at ED 15.5 and ND 1. There was no indication of cardiac structural abnormalities in surviving embryos. However, Npr1−/−embryos exhibited cardiac enlargement (without fibrosis) from ED 15.5 as well as significantly increased ANP mRNA and protein expression compared to wild-type (WT) mice, but no concomitant increase in expression of the hypertrophy-related transcription factors, Mef2A, Mef2C, GATA-4, GATA-6 or serum response factor (SRF). However, there was a significant decrease in Connexin-43 (Cx43) gene and protein expression at mid-gestation in Npr1−/−embryos. Our findings suggest that the mechanism by which natriuretic peptide signaling influences cardiac development in Npr1−/− mice is distinct from that seen during the development of pathological cardiac hypertrophy and fibrosis. The decreased viability of Npr1−/−embryos may result from a combination of cardiomegaly and dysregulated Cx43 protein affecting cardiac contractility

Cardiac Dysfunction, Congestion and Loop Diuretics: their Relationship to Prognosis in Heart Failure

Background: Diuretics are the mainstay of treatment for congestion but concerns exist that they adversely affect prognosis. We explored whether the relationship between loop diuretic use and outcome is explained by the underlying severity of congestion amongst patients referred with suspected heart failure. Method and Results: Of 1190 patients, 712 had a left ventricular ejection fraction (LVEF) ≤50 %, 267 had LVEF >50 % with raised plasma NTproBNP (>400 ng/L) and 211 had LVEF >50 % with NTproBNP ≤400 ng/L; respectively, 72 %, 68 % and 37 % of these groups were treated with loop diuretics including 28 %, 29 % and 10 % in doses ≥80 mg furosemide equivalent/day. Compared to patients with cardiac dysfunction (either LVEF ≤50 % or NT-proBNP >400 ng/L) but not taking a loop diuretic, those taking a loop diuretic were older and had more clinical evidence of congestion, renal dysfunction, anaemia and hyponatraemia. During a median follow-up of 934 (IQR: 513–1425) days, 450 patients were hospitalized for HF or died. Patients prescribed loop diuretics had a worse outcome. However, in multi-variable models, clinical, echocardiographic (inferior vena cava diameter), and biochemical (NTproBNP) measures of congestion were strongly associated with an adverse outcome but not the use, or dose, of loop diuretics. Conclusions: Prescription of loop diuretics identifies patients with more advanced features of heart failure and congestion, which may account for their worse prognosis. Further research is needed to clarify the relationship between loop diuretic agents and outcome; imaging and biochemical measures of congestion might be better guides to diuretic dose than symptoms or clinical signs

Multiparameter Lead Optimization to Give an Oral Checkpoint Kinase 1 (CHK1) Inhibitor Clinical Candidate: (R)-5-((4-((Morpholin-2-ylmethyl)amino)-5-(trifluoromethyl)pyridin-2-yl)amino)pyrazine-2-carbonitrile (CCT245737)

Multiparameter optimization of a series of 5-((4-aminopyridin-2-yl)amino)pyrazine-2-carbonitriles resulted in the identification of a potent and selective oral CHK1 preclinical development candidate with in vivo efficacy as a potentiator of deoxyribonucleic acid (DNA) damaging chemotherapy and as a single agent. Cellular mechanism of action assays were used to give an integrated assessment of compound selectivity during optimization resulting in a highly CHK1 selective adenosine triphosphate (ATP) competitive inhibitor. A single substituent vector directed away from the CHK1 kinase active site was unexpectedly found to drive the selective cellular efficacy of the compounds. Both CHK1 potency and off-target human ether-a-go-go-related gene (hERG) ion channel inhibition were dependent on lipophilicity and basicity in this series. Optimization of CHK1 cellular potency and in vivo pharmacokinetic–pharmacodynamic (PK–PD) properties gave a compound with low predicted doses and exposures in humans which mitigated the residual weak in vitro hERG inhibition

Natriuretic peptide receptors and neutral endopeptidase in mediating the renal actions of a new therapeutic synthetic natriuretic peptide dendroaspis natriuretic peptide

AbstractObjectivesThe objectives of the current study were to define for the first time the roles of the natriuretic peptide (NP) receptors and neutral endopeptidase (NEP) in mediating and modulating the renal actions of Dendroaspis natriuretic peptide (DNP), a new therapeutic synthetic NP.BackgroundRecent reports have advanced the therapeutic potential of a newly described synthetic NP called DNP. Dendroaspis natriuretic peptide is a 38-amino acid peptide recently isolated from the venom of Dendroaspis augusticeps (the green mamba snake).MethodsSynthetic DNP was administered intra-renally at 5 ng/kg/min to 11 normal anesthetized dogs, 5 of which received the NP receptor antagonist HS-142-1 (3 mg/kg intravenous bolus) while the remaining 6 dogs received an infusion of the NEP inhibitor, candoxatrilat (8 and 80 μg/kg/min) (Pfizer, Sandwich United Kingdom).ResultsIntra-renal DNP resulted in marked natriuresis associated with increased urinary cyclic guanosine monophosphate excretion (UcGMPV), glomerular filtration rate (GFR), and renal blood flow (RBF) and decreased distal fractional sodium reabsorption (FNaR) compared with baseline. HS-142-1 attenuated the natriuretic response to DNP, resulting in decreased UcGMPV, GFR, and RBF and increased distal FNaR. In contrast, low and high doses of NEP inhibitor did not potentiate the renal actions of DNP.ConclusionsWe report that the NP receptor blockade attenuated the renal actions of synthetic DNP and that the NEP inhibitor did not alter the renal response to DNP. This latter finding is a unique property of synthetic DNP, as distinguished from other known NPs, supporting its potential as a therapeutic agent