RESUMEN
Hypertension and metabolic syndrome frequently coexist to increase the risk for adverse cardiometabolic outcomes. To date, no drug has been proven to be effective in treating hypertension with metabolic syndrome. M-atrial natriuretic peptide is a novel atrial natriuretic peptide analog that activates the particulate guanylyl cyclase A receptor. This study conducted a double-blind, placebo-controlled trial in 22 patients and demonstrated that a single subcutaneous injection of M-atrial natriuretic peptide was safe, well-tolerated, and exerted pleiotropic properties including blood pressure-lowering, lipolytic, and insulin resistance-improving effects. (MANP in Hypertension and Metabolic Syndrome [MANP-HTN-MS]; NCT03781739).
RESUMEN
Background Phosphodiesterase V (PDEV) is upregulated in heart failure, leading to increased degradation of cGMP and impaired natriuresis. PDEV inhibition improves the renal response to B-type natriuretic peptide in animal models. We tested the hypothesis that long-term PDEV inhibition would improve renal function and cardiorenal response after short-term volume load in subjects with pre-heart failure. Methods and Results A total of 20 subjects with pre-heart failure (defined as an ejection fraction ≤45% without previous diagnosis of heart failure) and renal impairment were randomized in a 2:1 manner to tadalafil or placebo. Baseline echocardiography and renal clearance study were performed, followed by a short-term saline load and repeated echocardiography and renal clearance study. Subjects then received either tadalafil at a goal dose of 20 mg daily or placebo, and the study day was repeated after 12 weeks. Long-term tadalafil did not improve glomerular filtration rate (median increase of 2.0 mL/min in the tadalafil group versus 13.5 mL/min in the placebo group; P=0.54). There was no difference in urinary sodium or cGMP excretion with PDEV inhibition following short-term saline loading. Conclusions Glomerular filtration rate and urinary sodium/cGMP excretion were not significantly different after 12 weeks of tadalafil compared with placebo. These results do not support the use of PDEV inhibition to improve renal response in patients with pre-heart failure. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT01970176.
Asunto(s)
Insuficiencia Cardíaca , Animales , GMP Cíclico , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 5 , Tasa de Filtración Glomerular , Insuficiencia Cardíaca/tratamiento farmacológico , Humanos , Péptido Natriurético Encefálico , Sodio , Tadalafilo/uso terapéuticoRESUMEN
Cenderitide is a novel designer natriuretic peptide (NP) composed of C-type natriuretic peptide (CNP) fused to the C-terminus of Dendroaspis natriuretic peptide (DNP). Cenderitide was engineered to coactivate the two NP receptors, particulate guanylyl cyclase (pGC)-A and -B. The rationale for its design was to achieve the renal-enhancing and antifibrotic properties of dual receptor activation, but without clinically significant hypotension. Here we report the first clinical trial on the safety, tolerability, and cyclic guanosine monophosphate (cGMP) activating properties of Cenderitide in subjects with stable heart failure (HF). Four-hour infusion of Cenderitide was safe, well-tolerated, and significantly increased plasma cGMP levels and urinary cGMP excretion without adverse effects with no change in blood pressure. Thus, Cenderitide has a favorable safety profile and expected pharmacological effects in stable human HF. Our results support further investigations of Cenderitide in HF as a potential future cGMP-enhancing therapeutic strategy.
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Fármacos Cardiovasculares/uso terapéutico , AMP Cíclico/sangre , Insuficiencia Cardíaca/tratamiento farmacológico , Péptidos Natriuréticos/uso terapéutico , Venenos de Serpiente/uso terapéutico , Anciano , Biomarcadores/sangre , Biomarcadores/orina , Fármacos Cardiovasculares/efectos adversos , Enfermedad Crónica , AMP Cíclico/orina , Método Doble Ciego , Esquema de Medicación , Femenino , Tasa de Filtración Glomerular/efectos de los fármacos , Insuficiencia Cardíaca/sangre , Insuficiencia Cardíaca/fisiopatología , Insuficiencia Cardíaca/orina , Humanos , Infusiones Intravenosas , Riñón/efectos de los fármacos , Riñón/fisiopatología , Masculino , Persona de Mediana Edad , Minnesota , Péptidos Natriuréticos/efectos adversos , Estudios Prospectivos , Eliminación Renal , Venenos de Serpiente/efectos adversos , Factores de Tiempo , Resultado del TratamientoRESUMEN
AIMS: We have previously reported that asymptomatic systolic heart failure (HF) is characterized by an impaired renal response to volume expansion due to lack of activation of urinary cGMP which is corrected by subcutaneous (SQ) BNP. In the current study, we sought to define the cardiorenal response to intravascular volume expansion after 12 weeks of SQ BNP therapy. METHODS AND RESULTS: We utilized a double-blinded, placebo-controlled study to compare 12 weeks of twice-daily SQ BNP 10 µg/kg (n = 22) or placebo (n = 12) in asymptomatic systolic HF. Subjects underwent two study visits: baseline and after 12 weeks of therapy. At each study visit, echocardiography, renal, and neurohumoral assessments were performed before and after intravascular volume expansion. The primary endpoint was change in urinary sodium excretion in response to volume expansion at 12 weeks, and we observed a greater increase in urinary sodium excretion [166 (77, 290) vs. 15 (-39, 72) mEq/min; P = 0.02] with SQ BNP treatment vs. placebo. Secondary endpoints included change in urine flow and glomerular filtration rate (GFR) in response to volume expansion at 12 weeks. We observed a significant increase in urine flow (P < 0.01) and trend for differential response in GFR (P = 0.08) with SQ BNP treatment vs. placebo. CONCLUSION: Among patients with asymptomatic systolic HF, twice-daily SQ BNP therapy improved the cardiorenal response to volume expansion at 12-week follow-up. Further studies are warranted to determine if these beneficial physiological observations with chronic natriuretic peptide administration translate into a delay in the progression to symptomatic HF.
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Insuficiencia Cardíaca Sistólica/tratamiento farmacológico , Natriuréticos/uso terapéutico , Péptido Natriurético Encefálico/uso terapéutico , Sodio/orina , Anciano , Enfermedades Asintomáticas , Factor Natriurético Atrial/metabolismo , GMP Cíclico/sangre , GMP Cíclico/orina , Método Doble Ciego , Ecocardiografía , Femenino , Fluidoterapia , Tasa de Filtración Glomerular , Insuficiencia Cardíaca Sistólica/diagnóstico por imagen , Insuficiencia Cardíaca Sistólica/metabolismo , Insuficiencia Cardíaca Sistólica/fisiopatología , Humanos , Infusiones Subcutáneas , Riñón/metabolismo , Masculino , Persona de Mediana EdadAsunto(s)
Diuréticos/administración & dosificación , Furosemida/administración & dosificación , Tasa de Filtración Glomerular/efectos de los fármacos , Insuficiencia Cardíaca Sistólica/tratamiento farmacológico , Anciano , Relación Dosis-Respuesta a Droga , Femenino , Insuficiencia Cardíaca Sistólica/fisiopatología , Humanos , Masculino , Resultado del TratamientoRESUMEN
OBJECTIVES: We hypothesized an impaired renal endocrine and natriuretic response to volume expansion (VE) in humans with pre-clinical systolic dysfunction (PSD) and pre-clinical diastolic dysfunction (PDD). We further hypothesized that exogenous B-type natriuretic peptide (BNP) could rescue an impaired natriuretic response in PSD and PDD. BACKGROUND: Recent reports suggest that in early systolic heart failure (HF), there is an impaired natriuretic response to acute VE. METHODS: PSD was defined as left ventricular ejection fraction <40% without HF symptoms. PDD was defined as ejection fraction >50%, moderate to severe diastolic dysfunction by Doppler criteria, and no HF symptoms. A double-blinded, placebo-controlled, crossover study was employed to determine the renal response to VE (0.25 ml/kg/min of normal saline for 60 min) in the presence and absence of exogenous BNP. Twenty healthy control subjects, 20 PSD subjects, and 18 PDD subjects participated. RESULTS: In healthy control subjects, urinary cyclic guanosine monophosphate (cGMP) and natriuresis increased after VE. In contrast, among PSD and PDD subjects, there was a paradoxical decrease in urinary cGMP and attenuated natriuresis. Pre-treatment with subcutaneous BNP resulted in similar increases in both urinary cGMP and natriuresis among healthy normal, PSD, and PDD subjects. CONCLUSIONS: In PSD and PDD, there is impaired renal cGMP activation, which contributes to impaired natriuresis in response to VE. Impaired activation of urinary cGMP and reduced natriuresis may contribute to volume overload and the progression of HF among PSD and PDD subjects. Importantly, the impaired renal excretory response to VE is rescued by exogenous BNP in PSD and PDD.