Non-invasive intraventricular pressure differences estimated with cardiac MRI in subjects without heart failure and with heart failure with reduced and preserved ejection fraction.

Objective: Non-invasive assessment of left ventricular (LV) diastolic and systolic function is important to better understand physiological abnormalities in heart failure (HF). The spatiotemporal pattern of LV blood flow velocities during systole and diastole can be used to estimate intraventricular pressure differences (IVPDs). We aimed to demonstrate the feasibility of an MRI-based method to calculate systolic and diastolic IVPDs in subjects without heart failure (No-HF), and with HF with reduced ejection fraction (HFrEF) and HF with preserved ejection fraction (HFpEF). Methods: We studied 159 subjects without HF, 47 subjects with HFrEF and 32 subjects with HFpEF. Diastolic and systolic intraventricular flow was measured using two-dimensional in-plane phase-contrast MRI. The Euler equation was solved to compute IVPDs in diastole (mitral base to apex) and systole (apex to LV outflow tract). Results: Subjects with HFpEF demonstrated a higher magnitude of the early diastolic reversal of IVPDs (-1.30 mm Hg) compared with the No-HF group (-0.78 mm Hg) and the HFrEF group (-0.75 mm Hg; analysis of variance p=0.01). These differences persisted after adjustment for clinical variables, Doppler-echocardiographic parameters of diastolic filling and measures of LV structure (No-HF=-0.72; HFrEF=-0.87; HFpEF=-1.52 mm Hg; p=0.006). No significant differences in systolic IVPDs were found in adjusted models. IVPD parameters demonstrated only weak correlations with standard Doppler-echocardiographic parameters. Conclusions: Our findings suggest distinct patterns of systolic and diastolic IVPDs in HFpEF and HFrEF, implying differences in the nature of diastolic dysfunction between the HF subtypes.

Right Atrial Phasic Function in Heart Failure With Preserved and Reduced Ejection Fraction.

OBJECTIVES: This study researched right atrial (RA) deformation indexes and their association with all-cause mortality among subjects with or without heart failure (HF). BACKGROUND: Although left atrial dysfunction is well described in HF, patterns of RA dysfunction and their prognostic implications are unclear. Cardiac magnetic resonance (CMR) imaging can provide excellent visualization of the RA. We used CMR to characterize RA phasic function in HF and to assess its prognostic implications. METHODS: This study prospectively examined 608 adults without HF (n = 407), as well as adults with HF with a reduced ejection fraction (HFrEF) (n = 105) or with HF with a preserved ejection fraction (HFpEF) (n = 96). Phasic RA function was measured via volume measurements and feature-tracking methods to derive longitudinal strain. All-cause death was ascertained over a median follow-up of 38.9 months. Standardized hazard ratios (HRs) were computed via Cox regression. RESULTS: Measures of RA phasic function were more prominently impaired in subjects with HFrEF than those in subjects with HFpEF. In analyses that adjusted for demographic factors, HF status, left ventricular ejection fraction, right ventricular end-diastolic volume index, and right ventricular ejection fraction, RA reservoir strain (HR: 0.66; 95% confidence interval [CI]: 0.47 to 0.92; p = 0.0154), RA expansion index (HR: 0.53; 95% CI: 0.31 to 0.91; p = 0.0116), RA conduit strain (HR: 0.58; 95% CI: 0.40 to 0.84; p = 0.0039), and RA conduit strain rate (HR: 1.51; 95% CI: 1.02 to 2.220; p = 0.0373) independently predicted all-cause mortality. In contrast, RA booster pump function and RA volume index did not independently predict the risk of death. CONCLUSIONS: Phasic RA function is predictive of the risk of all-cause death in a diverse group of subjects with and without HF. RA conduit and reservoir function are independent predictors of mortality.

Vitamin K Status, Warfarin Use, and Arterial Stiffness in Heart Failure.

Large artery stiffening contributes to the pathophysiology of heart failure (HF) and associated comorbidities. MGP (matrix Gla-protein) is a potent inhibitor of vascular calcification. MGP activation is vitamin K-dependent. We aimed (1) to compare dp-ucMGP (dephospho-uncarboxylated MGP) levels between subjects with HF with preserved ejection fraction (HFpEF) and HF with reduced ejection fraction (HFrEF) and subjects without HF; (2) to assess the relationship between dp-ucMGP levels and arterial stiffness; and (3) to assess the relationship between warfarin use, dp-ucMGP levels, and arterial stiffness in HF. We enrolled 348 subjects with HFpEF (n=96), HFrEF (n=53), or no HF (n=199). Carotid-femoral pulse wave velocity, a measure of large artery stiffness, was measured with arterial tonometry. Dp-ucMGP was measured with ELISA. Dp-ucMGP levels were greater in both HFrEF (582 pmol/L; 95% CI, 444-721 pmol/L) and HFpEF (549 pmol/L; 95% CI, 455-643 pmol/L) compared with controls (426 pmol/L; 95% CI, 377-475 pmol/L; ANCOVA P=0.0067). Levels of dp-ucMGP were positively associated with carotid-femoral pulse wave velocity (standardized ß, 0.31; 95% CI, 0.19-0.42; P<0.0001), which was also true in analyses restricted to patients with HF (standardized ß, 0.34; 95% CI, 0.16-0.52; P=0.0002). Warfarin use was significantly associated with carotid-femoral pulse wave velocity (standardized ß, 0.13; 95% CI, 0.004-0.26; P=0.043), but this relationship was eliminated after adjustment for dp-ucMGP. In conclusion, levels of dp-ucMGP are increased in HFpEF and HFrEF and are independently associated with arterial stiffness. Future studies should investigate whether vitamin K supplementation represents a suitable therapeutic strategy to prevent or reduce arterial stiffness in HFpEF and HFrEF.

Poor Glycemic Control Is Associated With Increased Extracellular Volume Fraction in Diabetes.

OBJECTIVE: We assessed whether poor glycemic control is associated with an increase in myocardial fibrosis among adults with diabetes. RESEARCH DESIGN AND METHODS: We studied 47 adults with type 2 diabetes and stratified them into three groups according to their hemoglobin A1c (HbA1c) level: <6.5% (group 1; n = 12), 6.5-7.5% (group 2; n = 20), and >7.5% (group 3; n = 15). Left ventricular (LV) mass was assessed using cardiac MRI. The extracellular volume fraction (ECVF), an index of myocardial fibrosis, was measured by using myocardial T1 mapping before and after the administration of a gadolinium-based contrast agent. RESULTS: Mean HbA1c was 5.84 ± 0.16%, 6.89 ± 0.14%, and 8.57 ± 0.2% in groups 1, 2, and 3, respectively. LV mass was not significantly different between the groups. The myocardial ECVF was significantly greater in groups 2 (mean 27.6% [95% CI 24.8-30.3]) and 3 (27.6% [24.4-30.8]) than in group 1 (21.1% [17.5-24.7]; P = 0.015). After adjusting for age, sex, BMI, blood pressure, and estimated glomerular filtration rate, the myocardial ECVF was significantly greater in groups 2 (27.4% [24.4-30.4]) and 3 (28% [24.5-31.5]) than in group 1 (20.9% [17.1-24.6]; P = 0.0156, ANCOVA). CONCLUSIONS: An increased myocardial ECVF, suggesting myocardial fibrosis, is independently associated with poor glycemic control among adults with diabetes. Further research should assess whether tight glycemic control can revert fibrosis to healthy myocardium or ameliorate it and its adverse clinical consequences.

Circulating Dephospho-Uncarboxylated Matrix Gla-Protein Is Associated With Kidney Dysfunction and Arterial Stiffness.

BACKGROUND: Large artery stiffening is increased in advanced chronic kidney disease (CKD) but likely develops progressively in earlier stages of CKD. Active matrix Gla-protein (MGP) is a potent vitamin K-dependent inhibitor of vascular calcification. A recent animal model demonstrated intrinsic abnormalities in vitamin K metabolism even in early CKD, but whether early human CKD is associated with vascular vitamin K deficiency is unknown. METHODS: We enrolled 137 adults without HF with varying degrees of renal function: normal estimated glomerular filtration rate (eGFR; >90 ml/min; n = 59), mildly reduced eGFR (stage 2 CKD: eGFR = 60-89 ml/min; n = 53) or at least moderately reduced eGFR (stage 3-5 CKD; eGFR < 60 ml/min; n = 25). Carotid-femoral pulse wave velocity (CF-PWV) was measured with carotid and femoral tonometry. Dephospho-uncarboxylated matrix gla-protein (dp-ucMGP) was measured with enzyme-linked immunosorbent assay (ELISA) (VitaK; Maastricht University; The Netherlands). RESULT: Dp-ucMGP levels were progressively increased with decreasing renal function (eGFR ≥ 90: 247 pmol/l; eGFR 60-89: 488 pmol/l; eGFR < 60: 953 pmol/l; P < 0.0001). These differences persisted after adjustment for multiple potential confounders (eGFR ≥ 90: 314 pmol/l; eGFR 60-89: 414 pmol/l; eGFR < 60: 770 pmol/l; P < 0.0001). In a multivariable model adjusted for various confounders, dp-ucMGP was a significant independent predictor of CF-PWV (ß = 0.21; P = 0.019). In formal mediation analyses, dp-ucMGP mediated a significant relationship between eGFR and higher CF-PWV (ß = -0.16; P = 0.005), whereas no significant dp-ucMGP-independent relationship was present (ß = -0.02; P = 0.80). CONCLUSIONS: CKD is associated with increased (inactive) dp-ucMGP, a vitamin K-dependent inhibitor of vascular calcification, which correlates with large artery stiffness. Further studies are needed to assess whether vitamin K2 supplementation represents a suitable therapeutic strategy to prevent or reduce arterial stiffening in CKD.

Late Systolic Myocardial Loading Is Associated With Left Atrial Dysfunction in Hypertension.

BACKGROUND: Late systolic load has been shown to cause diastolic dysfunction in animal models. Although the systolic loading sequence of the ventricular myocardium likely affects its coupling with the left atrium (LA), this issue has not been investigated in humans. We aimed to assess the relationship between the myocardial loading sequence and LA function in human hypertension. METHODS AND RESULTS: We studied 260 subjects with hypertension and 19 normotensive age- and sex-matched controls. Time-resolved central pressure and left ventricular geometry were measured with carotid tonometry and cardiac magnetic resonance imaging, respectively, for computation of time-resolved ejection-phase myocardial wall stress (MWS). The ratio of late/early ejection-phase MWS time integrals was computed as an index of late systolic myocardial load. Atrial mechanics were measured with cine-steady-state free-precession magnetic resonance imaging using feature-tracking algorithms. Compared with normotensive controls, hypertensive participants demonstrated increased late/early ejection-phase MWS and reduced LA function. Greater levels of late/early ejection-phase MWS were associated with reduced LA conduit, reservoir, and booster pump LA function. In models that included early and late ejection-phase MWS as independent correlates of LA function, late systolic MWS was associated with lower, whereas early systolic MWS was associated with greater LA function, indicating an effect of the relative loading sequence (late versus early MWS) on LA function. These relationships persisted after adjustment for multiple potential confounders. CONCLUSIONS: A myocardial loading sequence characterized by prominent late systolic MWS was independently associated with atrial dysfunction. In the context of available experimental data, our findings support the deleterious effects of late systolic loading on ventricular-atrial coupling.