Izzah Vasim

Effects of organic and inorganic nitrate on aortic and carotid haemodynamics in heart failure with preserved ejection fraction

To assess the haemodynamic effects of organic vs. inorganic nitrate administration among patients with heart failure with preserved ejection fraction (HFpEF).

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.

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.

Effect of organic and inorganic nitrates on cerebrovascular pulsatile power transmission in patients with heart failure and preserved ejection fraction

OBJECTIVE Increased penetration of pulsatile power to the brain has been implicated in the pathogenesis of age-related cognitive dysfunction and dementia, a common comorbidity in patients with heart failure and preserved ejection fraction (HFpEF). However, there is a lack of knowledge on the effects of organic and inorganic nitrates administration in this population on the power carried by pressure and flow waves traveling through the proximal aorta and penetrating the carotid artery into the brain microvasculature. APPROACH We assessed aortic and carotid hemodynamics non-invasively in two sub-studies: (1) at baseline and after administration of 0.4 mg of sublingual nitroglycerine (an organic nitrate; n  =  26); and (2) in a randomized controlled trial of placebo (PB) versus inorganic nitrate administration (beetroot-juice (BR), 12.9 mmol NO3; n  =  16). MAIN RESULTS Wave and hydraulic power analysis demonstrated that NTG increased total hydraulic power (from 5.68% at baseline to 8.62%, P  =  0.001) and energy penetration (from 8.69% to 11.63%; P  =  0.01) from the aorta to the carotid, while inorganic nitrate administration did not induce significant changes in aortic and carotid wave power (power: 5.49%PB versus 6.25%BR, P  =  0.49; energy: 8.89%PB versus 10.65%BR, P  =  0.27). SIGNIFICANCE Organic nitrates, but not inorganic nitrates, increase the amount of hydraulic energy transmitted into the carotid artery in subjects with HFpEF. These findings may have implications for the adverse effect profiles of these agents (such as the differential incidence of headaches) and for the pulsatile hemodynamic stress of the brain microvasculature in this patient population.

ANTICOAGULATION DECISIONS FOR TREATMENT OF INTRA-CARDIAC THROMBUS

Intracardiac thrombus is challenging as the risk of embolization dictates ideal management. We present a case highlighting the clinical rationale behind anticoagulation decisions for a large intracardiac thrombus. A 52 year old lady with metastatic gastroesophageal adenocarcinoma & recurrent DVTs,

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

CARDIO-FEMORAL VASCULAR INDEX: A NEW MARKER OF ARTERIAL AGING

Background: Aortic stiffness (AS) is an important mediator of CVD risk with aging. Operator-independent methods to assess AS are needed. Cardio-ankle vascular index (CAVI) is a noninvasive estimate of AS that can be automatically measured with cuff-based systems. Its specificity to AS as a marker of