Amer Ahmed Syed

Heart Failure, Left Ventricular Remodeling, and Circulating Nitric Oxide Metabolites.

Background Stable plasma nitric oxide (NO) metabolites (NOM), composed predominantly of nitrate and nitrite, are attractive biomarkers of NO bioavailability. NOM levels integrate the influence of NO‐synthase‐derived NO production/metabolism, dietary intake of inorganic nitrate/nitrite, and clearance of NOM. Furthermore, nitrate and nitrite, the most abundant NOM, can be reduced to NO via the nitrate‐nitrite‐NO pathway. Methods and Results We compared serum NOM among subjects without heart failure (n=126), subjects with heart failure and preserved ejection fraction (HFpEF; n=43), and subjects with heart failure and reduced ejection fraction (HFrEF; n=32). LV mass and extracellular volume fraction were measured with cardiac MRI. Plasma NOM levels were measured after reduction to NO via reaction with vanadium (III)/hydrochloric acid. Subjects with HFpEF demonstrated significantly lower unadjusted levels of NOM (8.0 μmol/L; 95% CI 6.2–10.4 μmol/L; ANOVA P=0.013) than subjects without HF (12.0 μmol/L; 95% CI 10.4–13.9 μmol/L) or those with HFrEF (13.5 μmol/L; 95% CI 9.7–18.9 μmol/L). There were no significant differences in NOM between subjects with HFrEF and subjects without HF. In a multivariable model that adjusted for age, sex, race, diabetes mellitus, body mass index, current smoking, systolic blood pressure, and glomerular filtration rate, HFpEF remained a predictor of lower NOM (β=−0.43; P=0.013). NOM did not correlate with LV mass, or LV diffuse fibrosis. Conclusions HFpEF, but not HFrEF, is associated with reduced plasma NOM, suggesting greater endothelial dysfunction, enhanced clearance, or deficient dietary ingestion of inorganic nitrate. Our findings may underlie the salutary effects of inorganic nitrate supplementation demonstrated in recent clinical trials in HFpEF.

Late Systolic Myocardial Loading Is Associated With Left Atrial Dysfunction in HypertensionCLINICAL PERSPECTIVE

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.

Inactive Matrix Gla-Protein and Arterial Stiffness in Type 2 Diabetes Mellitus

BACKGROUND Large artery stiffness is increased in diabetes mellitus and causes an excessive pulsatile load to the heart and to the microvasculature. The identification of pathways related to arterial stiffness may provide novel therapeutic targets to ameliorate arterial stiffness in diabetes. Matrix Gla-Protein (MGP) is an inhibitor of vascular calcification. Activation of MGP is vitamin K dependent. We hypothesized that levels of inactive MGP (dephospho-uncarboxylated MGP; dp-ucMGP) are related to arterial stiffness in type 2 diabetes. METHODS We enrolled a multiethnic cohort of 66 participants with type 2 diabetes. Carotid-femoral pulse wave velocity (CF-PWV) was measured with high-fidelity arterial tonometry (Sphygmocor Device). Dp-ucMGP was measured with ELISA (VitaK; The Netherlands). RESULTS The majority of the participants were middle-aged (62 ± 12 years), male (91%), and had a history of hypertension (82%). Average hemoglobin A1C was 7.2% (55 mmol/mol). Mean dp-ucMGP was 624 ± 638 pmol/l and mean CF-PWV was 11 ± 4 m/sec. In multivariable analyses, dp-ucMGP was independently related to African American ethnicity (&bgr; = −0.24, P = 0.005), warfarin use (&bgr; = 0.56, P < 0.001), and estimated glomerular filtration rate (eGFR, &bgr; = −0.32, P < 0.001). Dp-ucMGP predicted CF-PWV (&bgr; = 0.40, P = 0.011), even after adjustment for age, gender, ethnicity, mean arterial pressure, eGFR, and warfarin use. CONCLUSIONS In our cross-sectional analysis, circulating dp-ucMGP was independently associated with CF-PWV in type 2 diabetes. This suggests that deficient vitamin K-dependent activation of MGP may lead to large artery stiffening and could be targeted with vitamin K supplementation in the patients with diabetes.

Beta‐Blocker Use Is Associated With Impaired Left Atrial Function in Hypertension

Background Impaired left atrial (LA) mechanical function is present in hypertension and likely contributes to various complications, including atrial arrhythmias, stroke, and heart failure. Various antihypertensive drug classes exert differential effects on central hemodynamics and left ventricular function. However, little is known about their effects on LA function. Methods and Results We studied 212 subjects with hypertension and without heart failure or atrial fibrillation. LA strain was measured from cine steady‐state free‐precession cardiac MRI images using feature‐tracking algorithms. In multivariable models adjusted for age, sex, race, body mass index, blood pressure, diabetes mellitus, LA volume, left ventricular mass, and left ventricular ejection fraction, beta‐blocker use was associated with a lower total longitudinal strain (standardized β=−0.21; P=0.008), and lower LA expansion index (standardized β=−0.30; P<0.001), indicating impaired LA reservoir function. Beta‐blocker use was also associated with a lower positive strain (standardized β=−0.19; P=0.012) and early diastolic strain rate (standardized β=0.15; P=0.039), indicating impaired LA conduit function. Finally, beta‐blocker use was associated with a lower (less negative) late‐diastolic strain (standardized β=0.15; P=0.049), strain rate (standardized β=0.18; P=0.019), and a lower active LA emptying fraction (standardized β=−0.27; P<0.001), indicating impaired booster pump function. Use of other antihypertensive agents was not associated with LA function. Conclusions Beta‐blocker use is significantly associated with impaired LA function in hypertension. This association could underlie the increased risk of atrial fibrillation and stroke seen with the use of beta‐blockers (as opposed to other antihypertensive agents) demonstrated in recent trials.

ACQUISITION OF TIME-RESOLVED BRACHIAL PRESSURE WAVEFORMS FROM CUFF-BASED PULSE VOLUME RECORDINGS

Background: Time-resolved brachial pressure (BP) waveforms are informative regarding pulsatile arterial hemodynamics. In contrast to technically-demanding arterial tonometry (AT), noninvasive cuff-based pulse waveforms recordings (PVR) can be acquired without special training. Although similar in

HEART-FEMORAL PULSE WAVE VELOCITY IS A STRONGER MARKER OF ARTERIAL AGING THAN CAROTID-FEMORAL PULSE WAVE VELOCITY

Background: Carotid-femoral pulse wave velocity (cfPWV) is considered one of the standard methods to estimate aortic stiffness. Its requirement of a technically-skilled operator has motivated development of automated systems to measure PWV. Heart-femoral PWV (hfPWV) can be automatically measured in