Differentiating heart failure phenotypes using sex-specific transcriptomic and proteomic biomarker panels.

AIMS: Heart failure with preserved ejection fraction (HFpEF) accounts for 30-50% of patients with heart failure (HF). A major obstacle in HF management is the difficulty in differentiating between HFpEF and heart failure with reduced ejection fraction (HFrEF) using conventional clinical and laboratory investigations. The aim of this study is to develop robust transcriptomic and proteomic biomarker signatures that can differentiate HFpEF from HFrEF. METHODS AND RESULTS: A total of 210 HF patients were recruited in participating institutions from the Alberta HEART study. An expert clinical adjudicating panel differentiated between patients with HFpEF and HFrEF. The discovery cohort consisted of 61 patients, and the replication cohort consisted of 70 patients. Transcriptomic and proteomic data were analysed to find panels of differentiating HFpEF from HFrEF. In the discovery cohort, a 22-transcript panel was found to differentiate HFpEF from HFrEF in male patients with a cross-validation AUC of 0.74, as compared with 0.70 for N-terminal pro-B-type natriuretic peptide (NT-proBNP) in those same patients. An ensemble of the transcript panel and NT-pro-BNP yielded a cross-validation AUC of 0.80. This performance improvement was also observed in the replication cohort. An ensemble of the transcriptomic panel with NT-proBNP produced a replication AUC of 0.90, as compared with 0.74 for NT-proBNP alone and 0.73 for the transcriptomic panel. CONCLUSIONS: We have identified a male-specific transcriptomic biomarker panel that can differentiate between HFpEF and HFrEF. These biosignatures could be further replicated on other patients and potentially be developed into a blood test for better management of HF patients.

Three-Dimensional Echocardiography Compared With Computed Tomography to Determine Mitral Annulus Size Before Transcatheter Mitral Valve Implantation.

BACKGROUND: Previously, through the use of computed tomography (CT), it has been proposed that D-shaped versus saddle-shaped mitral annulus (MA) segmentation is more biomechanically appropriate to determine transcatheter mitral valve implantation size and eligibility. METHODS AND RESULTS: Forty-one patients with severe mitral regurgitation being considered for transcatheter mitral valve implantation who had undergone cardiac CT and 3-dimensional transesophageal echocardiography (3D-TEE) were retrospectively evaluated. A standardized segmentation protocol for the D-shaped MA was developed using Philips Q-Laboratory mitral valve quantification software. MA dimensions were compared using Spearman's rank correlation and Bland-Altman analysis. Inter- and intraobserver agreement was quantified by intraclass correlation coefficient and Bland-Altman analysis. Mean age was 77±14 years; 71% male (n=29); mitral regurgitation pathogenesis was functional in 54% (n=22) and myxomatous in 46% (n=19). Mean MA area and circumference by 3D-TEE and CT were 11.3±2.7 versus 11.4±3.0 (P=0.67) and 124.1±15.6 versus 123.9±15.5 (P=0.79), respectively, with excellent correlation between modalities (r=0.84 and r=0.86; P<0.0001) and no systematic bias (-0.20±1.8 cm(2) [-3.7 cm(2); 3.3 cm(2)], 0.37±9 mm [-18.0 mm; 17.27 mm]). Mean septal-to-lateral and inter-trigone distances by 3D-TEE and CT were 33.2±4.7 versus 32.5±4.4 (P=0.24) and 31.7±3.5 versus 32.6±3.6 (P=0.06), respectively, with good correlation (r=0.69 and r=0.71; P<0.0001) and no systematic bias (0.77±3.8 mm [-6.7 mm; 8.2 mm], -1.5±3.1 mm [-4.6 mm; 7.6 mm]). There was excellent intra- and interobserver agreement according to intraclass correlation coefficients >0.90 for all parameters. CONCLUSIONS: Similar to cardiac CT, 3D-TEE allows for D-shaped MA segmentation with no systematic difference in MA dimensions between modalities. This study supports the utilization of 3D-TEE as a complementary tool to CT assessment of the D-shaped MA to determine transcatheter mitral valve implantation size.

Natural history of markers of collagen turnover in patients with early diastolic dysfunction and impact of eplerenone.

OBJECTIVES: This study was designed to evaluate the impact of eplerenone on collagen turnover in preserved systolic function heart failure (HFPSF). BACKGROUND: Despite growing interest in abnormal collagen metabolism as a feature of HFPSF with diastolic dysfunction, the natural history of markers of collagen turnover and the impact of selective aldosterone antagonism on this natural history remains unknown. METHODS: We evaluated 44 patients with HFPSF, randomly assigned to control (n = 20) or eplerenone 25 mg daily (n = 24) for 6 months, increased to 50 mg daily from 6 to 12 months. Serum markers of collagen turnover and inflammation were analyzed at baseline and at 6 and 12 months and included pro-collagen type-I and -III aminoterminal peptides, matrix metalloproteinase type-2, interleukin-6 and -8, and tumor necrosis factor-alpha. Doppler-echocardiographic assessment of diastolic filling indexes and tissue Doppler analyses were also obtained. RESULTS: The mean age of the patients was 80 +/- 7.8 years; 46% were male; 64% were receiving an angiotensin-converting enzyme inhibitor, 34% an angiotensin-II receptor blocker, and 68% were receiving beta-blocker therapy. Pro-collagen type-III and -I aminoterminal peptides, matrix metalloproteinase type-2, interleukin-6 and -8, and tumor necrosis factor-alpha increased with time in the control group. Eplerenone treatment had no significant impact on any biomarker at 6 months but attenuated the increase in pro-collagen type-III aminoterminal peptide at 12 months (p = 0.006). Eplerenone therapy was associated with modest effects on diastolic function without any impact on clinical variables or brain natriuretic peptide. CONCLUSIONS: This study demonstrates progressive increases in markers of collagen turnover and inflammation in HFPSF with diastolic dysfunction. Despite high background utilization of renin-angiotensin-aldosterone modulators, eplerenone therapy prevents a progressive increase in pro-collagen type-III aminoterminal peptide and may have a role in management of this disease. (The Effect of Eplerenone and Atorvastatin on Markers of Collagen Turnover in Diastolic Heart Failure; NCT00505336).