Urinary Peptidomic Biomarker for Personalized Prevention and Treatment of Diastolic Left Ventricular Dysfunction.

Diastolic heart failure (DHF) is characterized by slow left ventricular (LV) relaxation, increased LV stiffness, interstitial deposition of collagen, and a modified extracellular matrix proteins. Among Europeans, the frequency of asymptomatic diastolic LV dysfunction (DD) is 25%. This constitutes a large pool of people at high risk of DHF. The goal of this review was to describe the discovery and the initial validation of new multidimensional urinary peptidomic biomarkers (UPB) indicative of DD, mainly consisting of collagen fragments, and to describe a roadmap for their introduction into clinical practice. The availability of new drugs creates a window of opportunity for mounting a randomized clinical trial consolidating the clinical applicability of UPB to screen for DD. If successfully completed, such trial will benefit ≈25% of all people older than 50 years and open a large market for a UPB diagnostic tool and the drug tested. Moreover, sequenced peptides making up UPB will generate novel insights in the pathophysiology of DD and facilitate personalized treatment of patients with DHF for whom prevention came too late. If proven cost-effective, the clinical application of UPB will contribute to the sustainability of health care in aging population in epidemiologic transition.

Chronic Peptide Therapy With B-Type Natriuretic Peptide in Patients With Pre-Clinical Diastolic Dysfunction (Stage B Heart Failure).

OBJECTIVES: This study determined whether there is development of tachyphylaxis to enhancement of cardiorenal response to acute volume loading (AVL) with B-type natriuretic peptide (BNP) after 12-week, twice-daily subcutaneous BNP administration in patients with preclinical diastolic dysfunction (PDD). BACKGROUND: PDD is characterized by normal systolic function and moderate or severe diastolic dysfunction but no symptoms of heart failure (HF). Impairment in cardiorenal endocrine response to stress by AVL exists in PDD and is corrected by acute administration of subcutaneous BNP. METHODS: A double-blinded, placebo-controlled proof-of-concept study was conducted to compare 12 weeks of twice daily subcutaneous BNP, 10 µg/kg (n = 24), versus placebo (n = 12) in PDD. Subjects underwent 2 study visits, at baseline and after 12 weeks. At each study visit, echocardiography, renal, and neurohumoral assessments were performed before and after intravascular AVL. RESULTS: Among those with PDD, there was a statistically significant improvement in diastolic function after 12 weeks of BNP, as measured by a decrease in the Doppler E/e' ratio (where E is early mitral inflow velocity and e' is mitral annulus early diastolic motion) (p = 0.004) and improvement of diastolic dysfunction grade (p = 0.008). After 12 weeks, there was statistically significantly greater sodium excretion, urine flow, and urinary cyclic guanosine monophosphate excretion to AVL (all p < 0.001), as well as a trend toward greater glomerular filtration rate (p = 0.050) in the BNP group as compared to the placebo group. CONCLUSIONS: In subjects with PDD, chronic BNP administration resulted in sustained improvement in diastolic function without development of tachyphylaxis to the enhancement of cardiorenal response to volume expansion with BNP. (Human Brain Natriuretic Peptide [BNP] [or Nesiritide] to Help Heart, Kidney and Humoral Function; NCT00405548).

Impaired natriuretic and renal endocrine response to acute volume expansion in pre-clinical systolic and diastolic dysfunction.

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.

Microalbuminuria in systolic and diastolic chronic heart failure patients.

BACKGROUND: Microalbuminuria is considered a major risk factor predisposing to cardiovascular morbidity and mortality. Microalbuminuria levels in patients with or without diabetes have been associated with a higher risk of chronic heart failure (HF). However, there are limited data regarding prevalence of microalbuminuria in chronic heart failure and its prognostic value. The aim of this study was to assess the occurrence of microalbuminuria in chronic heart failure patients as well as its association with clinical, echocardiographic, and body composition markers. METHODS: In a cross-sectional study, we included 72 chronic heart failure patients (NYHA I-III) on standard HF therapy. All patients had an echocardiogram and body composition by vector bioelectric impedance analysis (measured by Body Stat Quad Scan). RESULTS: The studied population consisted of 64% men at mean age of 62.6 +/- 15.1 years. Patients were divided into systolic and diastolic HF groups. Microalbuminuria was observed in 40% of diastolic and 24% systolic HF patients (p = 0.04). Microalbuminuria was present in more patients with volume overload (80 vs. 21.9%, p = 0.002), with a worse phase angle and lower serum albumin (4.7 vs. 5.9 degrees and 3.5 vs. 4.0 mg/dl, p = 0.02) and higher pulmonary arterial pressure compared with patients without microalbuminuria in systolic HF patients. There was no significant association between frequency of microalbuminuria and ejection fraction. In the diastolic HF group, the presence of microalbuminuria was not associated with any known risk factor. CONCLUSIONS: Microalbuminuria was more frequent in diastolic than systolic HF patients. In systolic HF patients microalbuminuria was associated with factors known to be markers of worse prognosis.