Caroline Tufaro

Acute Hemodynamic Effects of Riociguat in Patients With Pulmonary Hypertension Associated With Diastolic Heart Failure (DILATE-1): A Randomized, Double-Blind, Placebo-Controlled, Single-Dose Study

BACKGROUND: Deficient nitric oxide-soluble guanylate cyclase-cyclic guanosine monophosphate signaling results from endothelial dysfunction and may underlie impaired cardiac relaxation in patients with heart failure with preserved left ventricular ejection fraction (HFpEF) and pulmonary hypertension (PH). The acute hemodynamic effects of riociguat, a novel soluble guanylate cyclase stimulator, were characterized in patients with PH and HFpEF. METHODS: Clinically stable patients receiving standard HF therapy with a left ventricular ejection fraction > 50%, mean pulmonary artery pressure (mPAP) ≥ 25 mm Hg, and pulmonary arterial wedge pressure (PAWP) > 15 mm Hg at rest were randomized to single oral doses of placebo or riociguat (0.5, 1, or 2 mg). The primary efficacy variable was the peak decrease in mPAP from baseline up to 6 h. Secondary outcomes included hemodynamic and echocardiographic parameters, safety, and pharmacokinetics. RESULTS: There was no significant change in peak decrease in mPAP with riociguat 2 mg (n = 10) vs placebo (n = 11, P = .6). However, riociguat 2 mg significantly increased stroke volume (+9 mL [95% CI, 0.4-17]; P = .04) and decreased systolic BP (−12 mm Hg [95% CI, −22 to −1]; P = .03) and right ventricular end-diastolic area (−5.6 cm2 [95% CI, −11 to −0.3]; P = .04), without significantly changing heart rate, PAWP, transpulmonary pressure gradient, or pulmonary vascular resistance. Riociguat was well tolerated. CONCLUSIONS: In patients with HFpEF and PH, riociguat was well tolerated, had no significant effect on mPAP, and improved exploratory hemodynamic and echocardiographic parameters. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT01172756; URL: www.clinicaltrials.gov

Cardiac Magnetic Resonance Postcontrast T1 Time Is Associated With Outcome in Patients With Heart Failure and Preserved Ejection Fraction

Background—The underlying pathophysiology of heart failure with preserved ejection fraction (HFPEF) is incompletely understood, but myocardial extracellular matrix accumulation is thought to play a major role. Our aims were to estimate myocardial extracellular matrix using cardiac magnetic resonance T1 mapping and to assess the relationship between pathobiology/pathophysiology and prognosis. Methods and Results—Patients with suspected HFPEF (n=100) were enrolled in this prospective, observational study. Confirmatory diagnostic tests, cardiac magnetic resonance imaging including T1 mapping, and invasive hemodynamic assessments were performed at baseline. Sixty-one patients with confirmed HFPEF entered a longitudinal outcome-monitoring phase (mean, 22.9±5.0 months), during which 16 had a cardiac event. Cardiac magnetic resonance T1 time (hazard ratio, 0.99; 95% confidence interval, 0.98–0.99; P=0.046), left atrial area (hazard ratio, 1.08; 95% confidence interval, 1.03–1.13; P<0.01), and pulmonary vascular resistance (hazard ratio, 1.01; 95% confidence interval, 1.00–1.01; P=0.03) were significantly associated with cardiac events. Patients with T1 times below the median (<388.3 ms) were at greater risk of cardiac events than the rest of the group (P<0.01). Extracellular matrix of left ventricular biopsies (n=9), quantified by TissueFAXS technology correlated with T1 time (R=0.98; P<0.01). T1 time also correlated with right ventricular–pulmonary arterial coupling (pulmonary vascular resistance: R=−0.36; P<0.01; right ventricular ejection fraction: R=0.28; P=0.01). Conclusions—In the present preliminary study, cardiac magnetic resonance postcontrast T1 time is associated with prognosis in HFPEF, suggesting postcontrast T1 as possible biomarker for HFPEF.

Extracellular matrix expansion by cardiac magnetic resonance T1 mapping- validation with myocardial biopsy

Background Accumulation of diffuse myocardial fibrosis / extracellular volume (ECV) in the myocardium is common to various cardiac diseases and is associated with an unfavorable prognosis. Various cardiac magnetic resonance (CMR) T1 mapping techniques have recently been proposed for the quantification of ECV, including: 1. Modified Look-Locker Inversion recovery (MOLLI) T1 mapping including calculation of ECV, 2. Post-contrast multiple-breath-hold T1 mapping. 3. Native (precontrast) T1 mapping. T1 mapping is a promising technique, however, validation data based on myocardial biopsy are sparse. Methods 36 heart failure patients underwent CMR T1 mapping and left-ventricular biopsy within 4 weeks. CMR protocols (1.5-T scanner, (Magnetom Avanto, Siemens Healthcare, Erlangen, Germany) included non-product MOLLI and multiple-breath-hold T1 mapping. The population consisted of 22 patients with HFpEF (heart failure with preserved ejection fraction), 7 with cardiac amyloidosis, 3 with HFrEF (heart failure with reduced ejection fraction) and 4 with organic mitral regurgitation (MR). Specimens were stained using modified Trichrome. TissueFAXS and dedicated software were used to quantify ECV. Results ECV by TissueFAXS was 32±17% and 35±13% by CMR MOLLI. Post-contrast T1 times by the multiple-breathhold sequence were 411±79ms, native T1 times were 1009±73ms. Patients with amyloidosis had significantly more ECV by TissueFAXS (59±13%, p<0.001) and with CMR MOLLI (56±12%, p<0.001) compared with the other pathologies. The amount of TissueFAXS ECV correlated significantly with native T1 times (r=0.657, p<0.001), MOLLI ECV (r=0.907, p<0.001) and with multiple-breath-hold post-contrast T1 times (r=-0.683, p<0.001). When excluding patients with amyloidosis, only MOLLI ECV significantly correlated with histology (r=0.491, p=0.015), whereas multiple-breath-hold post-contrast T1 times just missed the level of significance (r=-0.413, p=0.056).

EXTENT OF DIFFUSE MYOCARDIAL FIBROSIS DETERMINES OUTCOME IN PATIENTS WITH HEART FAILURE AND PRESERVED EJECTION FRACTION

The underlying pathophysiology of heart failure with preserved ejection fraction (HFPEF) is incompletely understood, but myocardial fibrosis is believed to play a major role. Our aims were to use cardiac magnetic resonance (CMR) T1 mapping to quantify diffuse myocardial fibrosis, and to identify

Epicardial fat volume is inversely correlated with the degree of diastolic dysfunction and outcome in patients with heart failure with preserved ejection fraction

Methods HFPEF was defined as serum NT-proBNP levels >220 pg/ml, E/e by echocardiography ≥8, signs or symptoms of heart failure and preserved left ventricular ejection fraction (EF≥50%). 58 HFPEF patients and 34 controls were prospectively evaluated. All patients underwent right heart catheterization. CMR studies included the assessment of cardiac function and dimensions by standard cine sequences. Epicardial fat volume was quantified offline, using dedicated software (cmr42).

Diffuse myocardial fibrosis by post-contrast T1-time predicts outcome in heart failure with preserved ejection fraction

Background Diffuse myocardial fibrosis plays a key role in disease progression of heart failure with preserved ejection fraction (HFPEF). Recently it was shown that diffuse myocardial fibrosis is strongly related to post-contrast longitudinal relaxation (T1) time by cardiac magnetic resonance imaging (CMR). The aim of our study was to assess diffuse myocardial fibrosis by CMR T1-mapping in HFPEF patients and test its predictive value.

Prevalence and prognostic significance of right ventricular systolic dysfunction in heart failure with preserved ejection fraction. Insights from a cardiac magnetic resonance imaging study

Background Cardiac magnetic resonance imaging (CMR) is the goldstandard technique for the assessment of right ventricular function. Recent data indicate that right ventricular ejection fraction (RVEF) <45% by CMR is a strong predictor of outcome in patients with dilated cardiomyopathy. However, the prognostic significance of RVEF in heart failure with preserved ejection fraction (HFpEF) is unknown.