Dataset Information

Salivary Protein Panel to Diagnose Systolic Heart Failure.

ABSTRACT: Screening for systolic heart failure (SHF) has been problematic. Heart failure management guidelines suggest screening for structural heart disease and SHF prevention strategies should be a top priority. We developed a multi-protein biomarker panel using saliva as a diagnostic medium to discriminate SHF patients and healthy controls. We collected saliva samples from healthy controls (n = 88) and from SHF patients (n = 100). We developed enzyme linked immunosorbent assays to quantify three specific proteins/peptide (Kallikrein-1, Protein S100-A7, and Cathelicidin antimicrobial peptide) in saliva samples. The analytical and clinical performances and predictive value of the proteins were evaluated. The analytical performances of the immunoassays were all within acceptable analytical ranges. The multi-protein panel was able to significantly (p < 0.001) discriminate saliva samples collected from patients with SHF from controls. The multi-protein panel demonstrated good performance with an overall diagnostic accuracy of 81.6% (sensitivity of 79.2% and specificity of 85.7%) when distinguishing SHF patients from healthy individuals. In conclusion, we have developed immunoassays to measure the salivary concentrations of three proteins combined as a panel to accurately distinguish SHF patients from healthy controls. While this requires confirmation in larger cohorts, our findings suggest that this three-protein panel has the potential to be used as a biomarker for early detection of SHF.

SUBMITTER: Zhang X

PROVIDER: S-EPMC6995570 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature

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Salivary Protein Panel to Diagnose Systolic Heart Failure.

Zhang Xi X Broszczak Daniel D Kostner Karam K Guppy-Coles Kristyan B KB Atherton John J JJ Punyadeera Chamindie C

Biomolecules 20191122 12

Screening for systolic heart failure (SHF) has been problematic. Heart failure management guidelines suggest screening for structural heart disease and SHF prevention strategies should be a top priority. We developed a multi-protein biomarker panel using saliva as a diagnostic medium to discriminate SHF patients and healthy controls. We collected saliva samples from healthy controls (n = 88) and from SHF patients (n = 100). We developed enzyme linked immunosorbent assays to quantify three specif ...[more]

PMID: 31766659

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Project description:ObjectivesThe purpose of the present study was to translate our laboratory investigations to establish safety and efficacy of 8 weeks of chronic SC B-type natriuretic peptide (BNP) administration in human Stage C heart failure (HF).BackgroundB-Type natriuretic peptide is a cardiac hormone with vasodilating, natriuretic, renin-angiotensin inhibiting, and lusitropic properties. We have previously demonstrated that chronic cardiac hormone replacement with subcutaneous (SC) administration of BNP in experimental HF resulted in improved cardiovascular function.MethodsWe performed a randomized double-blind placebo-controlled proof of concept study comparing 8 weeks of SC BNP (10 μg/kg bid) (n = 20) with placebo (n = 20) in patients with ejection fraction <35% and New York Heart Association functional class II to III HF. Primary outcomes were left ventricular (LV) volumes and LV mass determined by cardiac magnetic resonance imaging. Secondary outcomes include LV filling pressure by Doppler echo, humoral function, and renal function.ResultsEight weeks of chronic SC BNP resulted in a greater reduction of LV systolic and diastolic volume index and LV mass index as compared with placebo. There was a significantly greater improvement of Minnesota Living with Heart Failure score, LV filling pressure as demonstrated by the reductions of E/e' ratio, and decrease in left atrial volume index as compared with placebo. Glomerular filtration rate was preserved with SC BNP, as was the ability to activate plasma 3',5'-cyclic guanosine monophosphate (p < 0.05 vs. placebo).ConclusionsIn this pilot proof of concept study, chronic protein therapy with SC BNP improved LV remodeling, LV filling pressure, and Minnesota Living with Heart Failure score in patients with stable systolic HF on optimal therapy. Renin-angiotensin was suppressed, and glomerular filtration rate was preserved. Subcutaneous BNP represents a novel, safe, and efficacious protein therapeutic strategy in human HF. Further studies are warranted to determine whether these physiologic observations can be translated into improved clinical outcomes and ultimately delay the progression of HF. (Cardiac Hormone Replacement With BNP in Heart Failure: A Novel Therapeutic Strategy; NCT00252187).

Project description:Double-stranded RNA-dependent protein kinase (PKR) is a eukaryotic initiation factor 2? kinase that inhibits mRNA translation under stress conditions. PKR also mediates inflammatory and apoptotic signaling independently of translational regulation. Congestive heart failure is associated with cardiomyocyte hypertrophy, inflammation, and apoptosis, but the role of PKR in left ventricular hypertrophy and the development of congestive heart failure has not been examined.We observed increased myocardial PKR expression and translocation of PKR into the nucleus in humans and mice with congestive heart failure. To determine the impact of PKR on the development of congestive heart failure, PKR knockout and wild-type mice were exposed to pressure overload produced by transverse aortic constriction. Although heart size increased similarly in wild-type and PKR knockout mice after transverse aortic constriction, PKR knockout mice exhibited very little pulmonary congestion, well-preserved left ventricular ejection fraction and contractility, and significantly less myocardial fibrosis compared with wild-type mice. Bone marrow-derived cells from wild-type mice did not abolish the cardiac protective effect observed in PKR knockout mice, whereas bone marrow-derived cells from PKR knockout mice had no cardiac protective effect in wild-type mice. Mechanistically, PKR knockout attenuated transverse aortic constriction-induced tumor necrosis factor-? expression and leukocyte infiltration and lowered cardiac expression of proapoptotic factors (Bax and caspase-3), so that PKR knockout hearts were more resistant to transverse aortic constriction-induced cardiomyocyte apoptosis. PKR depletion in isolated cardiomyocytes also conferred protection against tumor necrosis factor-?- or lipopolysaccharide-induced apoptosis.PKR is a maladaptive factor upregulated in hemodynamic overload that contributes to myocardial inflammation, cardiomyocyte apoptosis, and the development of congestive heart failure.

Project description:Full Title: Transition from Compensated Hypertrophy to Systolic Heart Failure in the Spontaneously Hypertensive Rat: Structure, Function, and Transcript Analysis Gene expression changes and left ventricular remodeling associated with the transition to systolic heart failure (HF) were determined in the spontaneously hypertensive rat (SHR). By combining transcriptomics of left ventricles from six SHR with HF with changes in function and structure we aimed to better understand the molecular events underlying the onset of systolic HF compared to six age-matched, SHR with compensated hypertrophy. Left ventricle (LV) ejection fraction was depressed (82Â±4 to 52Â±3 %) in compensated vs. failing animals.Â Systolic blood pressure decreased and LV end-diastolic and systolic volume increased with HF.Â Failing SHR hearts also demonstrated increases in left and right ventricular mass relative to non-failing SHRs.Â Â LV papillary muscle force development and shortening velocity decreased, Î²-adrenergic responsiveness was depressed, myocardial stiffness and myocardial fibrosis increased with HF relative to non-failing animals. Initial micro-array analysis revealed that 1,431 transcripts were differentially expressed with HF compared to non-failing SHR (p<0.05). Of the identified transcripts, lipopolysaccharide binding protein, the most highly expressed transcript with HF, was negatively correlated to myocardial force while elevated expression of the collagen cross-linking enzyme lysyl oxidase correlated positively with muscle stiffness. Besides these individual transcripts, gene set enrichment analysis (GSEA) identified multiple enriched pathways with HF, most prominent of the altered signaling pathways involved TGF-Î² and insulin signaling. GESA analysis additionally identified altered gene sets involving inflammation, oxidative stress, cell degradation and cell death, among others (all p<0.01). In contrast to diastolic HF where few transcripts are reported to be altered, our data indicate multiple genes and pathways involved in a variety of biological processes characterize the onset of systolic HF, consistent with many functional and structural changes present in the failing hypertensive heart. Comprehensive gene expression profiling of heart failure Rat model vs control.

Project description:Full Title: Transition from Compensated Hypertrophy to Systolic Heart Failure in the Spontaneously Hypertensive Rat: Structure, Function, and Transcript Analysis Gene expression changes and left ventricular remodeling associated with the transition to systolic heart failure (HF) were determined in the spontaneously hypertensive rat (SHR). By combining transcriptomics of left ventricles from six SHR with HF with changes in function and structure we aimed to better understand the molecular events underlying the onset of systolic HF compared to six age-matched, SHR with compensated hypertrophy. Left ventricle (LV) ejection fraction was depressed (82±4 to 52±3 %) in compensated vs. failing animals. Systolic blood pressure decreased and LV end-diastolic and systolic volume increased with HF. Failing SHR hearts also demonstrated increases in left and right ventricular mass relative to non-failing SHRs. LV papillary muscle force development and shortening velocity decreased, β-adrenergic responsiveness was depressed, myocardial stiffness and myocardial fibrosis increased with HF relative to non-failing animals. Initial micro-array analysis revealed that 1,431 transcripts were differentially expressed with HF compared to non-failing SHR (p<0.05). Of the identified transcripts, lipopolysaccharide binding protein, the most highly expressed transcript with HF, was negatively correlated to myocardial force while elevated expression of the collagen cross-linking enzyme lysyl oxidase correlated positively with muscle stiffness. Besides these individual transcripts, gene set enrichment analysis (GSEA) identified multiple enriched pathways with HF, most prominent of the altered signaling pathways involved TGF-β and insulin signaling. GESA analysis additionally identified altered gene sets involving inflammation, oxidative stress, cell degradation and cell death, among others (all p<0.01). In contrast to diastolic HF where few transcripts are reported to be altered, our data indicate multiple genes and pathways involved in a variety of biological processes characterize the onset of systolic HF, consistent with many functional and structural changes present in the failing hypertensive heart.

Dataset Information

Salivary Protein Panel to Diagnose Systolic Heart Failure.

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Salivary Protein Panel to Diagnose Systolic Heart Failure.

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