Coronary flow reserve is predictive of the risk of cardiovascular death regardless of chronic kidney disease stage.

Microvascular rarefaction is found in experimental uremia, but data from patients with chronic kidney disease (CKD) are limited. We therefore quantified absolute myocardial blood flow and coronary flow reserve (the ratio of peak to resting flow) from myocardial perfusion positron emission tomography scans at a single institution. Individuals were classified into standard CKD categories based on the estimated glomerular filtration rate. Associations of coronary flow reserve with CKD stage and cardiovascular mortality were analyzed in models adjusted for cardiovascular risk factors. The coronary flow reserve was significantly associated with CKD stage, declining in early CKD, but it did not differ significantly among individuals with stage 4, 5, and dialysis-dependent CKD. Flow reserve with preserved kidney function was 2.01, 2.06 in stage 1 CKD, 1.91 in stage 2, 1.68 in stage 3, 1.54 in stage 4, 1.66 in stage 5, and 1.55 in dialysis-dependent CKD. Coronary flow reserve was significantly associated with cardiovascular mortality in adjusted models (hazard ratio 0.76, 95% confidence interval: 0.63-0.92 per tertile of coronary flow reserve) without evidence of effect modification by CKD. Thus, coronary flow reserve is strongly associated with cardiovascular risk regardless of CKD severity and is low in early stage CKD without further decrement in stage 5 or dialysis-dependent CKD. This suggests that CKD physiology rather than the effects of dialysis is the primary driver of microvascular disease. Our findings highlight the potential contribution of microvascular dysfunction to cardiovascular risk in CKD and the need to define mechanisms linking low coronary flow reserve to mortality.

Ranolazine in Symptomatic Diabetic Patients Without Obstructive Coronary Artery Disease: Impact on Microvascular and Diastolic Function.

BACKGROUND: Treatments for patients with myocardial ischemia in the absence of angiographic obstructive coronary artery disease are limited. In these patients, particularly those with diabetes mellitus, diffuse coronary atherosclerosis and microvascular dysfunction is a common phenotype and may be accompanied by diastolic dysfunction. Our primary aim was to determine whether ranolazine would quantitatively improve exercise-stimulated myocardial blood flow and cardiac function in symptomatic diabetic patients without obstructive coronary artery disease. METHODS AND RESULTS: We conducted a double-blinded crossover trial with 1:1 random allocation to the order of ranolazine and placebo. At baseline and after each 4-week treatment arm, left ventricular myocardial blood flow and coronary flow reserve (CFR; primary end point) were measured at rest and after supine bicycle exercise using 13N-ammonia myocardial perfusion positron emission tomography. Resting echocardiography was also performed. Multilevel mixed-effects linear regression was used to determine treatment effects. Thirty-five patients met criteria for inclusion. Ranolazine did not significantly alter rest or postexercise left ventricular myocardial blood flow or CFR. However, patients with lower baseline CFR were more likely to experience improvement in CFR with ranolazine (r=-0.401, P=0.02) than with placebo (r=-0.188, P=0.28). In addition, ranolazine was associated with an improvement in E/septal e' (P=0.001) and E/lateral e' (P=0.01). CONCLUSIONS: In symptomatic diabetic patients without obstructive coronary artery disease, ranolazine did not change exercise-stimulated myocardial blood flow or CFR but did modestly improve diastolic function. Patients with more severe baseline impairment in CFR may derive more benefit from ranolazine. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01754259.

Usefulness of the Mitral Regurgitation Severity Index to Assess the Severity of Chronic Mitral Regurgitation.

Existing metrics for grading mitral regurgitation (MR) are limited and fraught with high interobserver variability. We developed and evaluated a Doppler-based, semiquantitative novel index (Mitral Regurgitation Severity Index [MRSI]) of MR severity. In a total of 125 patients (70 in the derivation cohort and 55 in the validation cohort), MRSI was calculated as a ratio of time velocity integral of mitral inflow (continuous-wave Doppler-TVI MV) to the time velocity integral of the left ventricle outflow (pulse-wave Doppler-TVI LVOT). Inter-rater agreement for MRSI and predictive ability of the MRSI were then assessed. In the derivation cohort, MRSI differed significantly between patients with severe MR (2.6 ± 0.51) and mild-moderate (nonsevere) MR (1.4 ± 0.18) and a cutoff of ≥1.8 was associated with optimal diagnostic accuracy. In the validation cohort, MRSI exhibited excellent agreement between a level II and a level III reader with a mean difference of -0.14 (95% confidence limit of agreement: -0.80 to 0.53), correlation coefficient of 0.88 (p <0.001), and 16% CV; and using the cut point of 1.8, it exhibited good inter-rater reproducibility with a kappa coefficient of 0.72 (p <0.001). In conclusion, MRSI appears to be a simple, quantitative, practical, color-independent metric to differentiate severe MR from nonsevere MR.

Association between various anthropometric measures of obesity and markers of subclinical atherosclerosis.

Central obesity is a known cardiovascular risk factor and measures of visceral obesity are known to predict atherosclerosis. This study sought to explore the association between various anthropometric measures and markers of subclinical atherosclerosis (MoSCA) among low risk healthy individuals. Multi-Ethnic Study of Atherosclerosis (MESA) is a population-based study of Caucasian (38%), Afro-American (28%), Chinese (22%) and Hispanic (12%) subjects, aged 45-84 years, free from clinical cardiovascular disease. We performed a post hoc analysis of the limited access dataset of MESA subjects to evaluate the association between carotid intima media thickness and coronary artery calcium score (CACS), as MoSCA and various measures of obesity. Multivariable regression analyses adjusted for traditional cardiovascular risk factors, ethnicity and C-reactive protein were performed. Each unit increase in waist-hip ratio was strongly associated with increase in both common and internal carotid intima media thickness (beta: 0.12, 95% confidence interval (CI): 0.06 to 0.18, p < 0.001 and beta: 0.23, 95% CI: 0.03 to 0.43, p = 0.021, respectively). Measures of central obesity were superior to body mass index as demonstrated by their consistent association with each category of CACS when compared to the reference category (CACS = 0). Compared to body mass index, measures of visceral obesity were significantly associated with MoSCA in this multiethnic healthy population. Waist-hip ratio seems to be more consistent in its association with various MoSCA compared to other anthropometric measures.

Prognostic Value of Coronary Flow Reserve in Patients with Dialysis-Dependent ESRD.

Capillary rarefaction of the coronary microcirculation is a consistent phenotype in patients with dialysis-dependent ESRD (dd-ESRD) and may help explain their excess mortality. Global coronary flow reserve (CFR) assessed by positron emission tomography (PET) is a noninvasive, quantitative marker of myocardial perfusion and ischemia that integrates the hemodynamic effects of epicardial stenosis, diffuse atherosclerosis, and microvascular dysfunction. We tested whether global CFR provides risk stratification in patients with dd-ESRD. Consecutive patients with dd-ESRD clinically referred for myocardial perfusion PET imaging were retrospectively included, excluding patients with prior renal transplantation. Per-patient CFR was calculated as the ratio of stress to rest absolute myocardial blood flow. Multivariable Cox proportional hazards models, including age, overt cardiovascular disease, and myocardial scar/ischemia burden, were used to assess the independent association of global CFR with all-cause and cardiovascular mortality. The incremental value of global CFR was assessed with relative integrated discrimination index and net reclassification improvement. In 168 patients included, median global CFR was 1.4 (interquartile range, 1.2-1.8). During follow-up (median of 3 years), 36 patients died, including 21 cardiovascular deaths. Log-transformed global CFR independently associated with all-cause mortality (hazard ratio, 0.01 per 0.5-unit increase; 95% confidence interval, <0.01 to 0.14; P<0.001) and cardiovascular mortality (hazard ratio, 0.01 per 0.5-unit increase; 95% confidence interval, <0.01 to 0.15; P=0.002). For all-cause mortality, addition of global CFR resulted in risk reclassification in 27% of patients. Thus, global CFR may provide independent and incremental risk stratification for all-cause and cardiovascular mortality in patients with dd-ESRD.

18F-Florbetapir Binds Specifically to Myocardial Light Chain and Transthyretin Amyloid Deposits: Autoradiography Study.

BACKGROUND: (18)F-florbetapir is a promising imaging biomarker for cardiac light chain amyloidosis (AL) and transthyretin amyloidosis (ATTR). Our aim, using human autopsy myocardial specimens, was to test the hypothesis that (18)F-florbetapir binds specifically to myocardial AL and ATTR amyloid deposits. METHODS AND RESULTS: We studied myocardial sections from 30 subjects with autopsy-documented AL (n=10), ATTR (n=10), and nonamyloid controls (n=10) using (18)F-florbetapir and cold florbetapir compound and digital autoradiography. Total and nonspecific binding of (18)F-florbetapir was determined using the maximum signal intensity values. Specific binding of (18)F-florbetapir was calculated by subtracting nonspecific from total binding measurements (in decays per minute/mm(2), DPM mm(2)) and was compared with cardiac structure and function on echocardiography and the histological extent of amyloid deposits. Diffuse or focally increased (18)F-florbetapir uptake was noted in all AL and ATTR samples and in none of the control samples. Compared with control samples, mean (18)F-florbetapir-specific uptake was significantly higher in the amyloid samples (0.94±0.43 versus 2.00±0.58 DPM/mm(2); P<0.001), and in the AL compared with the ATTR samples (2.48±0.40 versus 1.52±0.22 DPM/mm(2); P<0.001). The samples from subjects with atypical echocardiographic features of amyloidosis showed quantitatively more intense (18)F-florbetapir-specific uptake compared with control samples (1.50±0.17 versus 0.94±0.43 DPM/mm(2); P=0.004), despite smaller amyloid extent than in subjects with typical echocardiograms. CONCLUSIONS: (18)F-florbetapir specifically binds to myocardial AL and ATTR deposits in humans and offers the potential to screen for the 2 most common types of myocardial amyloid.

Uric acid and cardiovascular disease risk reclassification: findings from NHANES III.

BACKGROUND: The studied associations between serum uric acid (sUA) and cardiovascular disease (CVD) events have been controversial. We sought to evaluate the association between sUA and CVD mortality, including its ability to reclassify risk in a multiethnic nationally representative population free of clinical CVD and diabetes at baseline. METHODS: The study cohort included 11,009 adults enrolled as a part of the National Health and Nutrition Examination Survey (NHANES) III. Multivariate Cox proportional hazard analysis was performed to evaluate sUA as a predictor of CVD and coronary heart disease (CHD) mortality. Discriminative and recalibrative properties of sUA for CHD deaths were also assessed over traditional CVD risk factors. Net reclassification index (NRI) was calculated by comparing regression models incorporating traditional CVD risk factors with and without sUA. RESULTS: sUA was not predictive of either CVD mortality [model 4: hazards ratio (HR) 1.06, 95% confidence interval (CI) 0.96-1.16, p = 0.27] or CHD mortality (model 4: HR 1.06, 95% CI 0.94-1.19, p = 0.32). Addition of sUA to traditional CVD risk factors resulted in no significant increment in c-statistic, receiver-operating characteristics-area under curve, absolute NRI (0.5%, 95% CI -1.9 to 2.9%, p = 0.68), or intermediate NRI (2.5%, 95% CI -1.6 to 6.6%, p = 0.24) for prediction of hard CHD deaths. CONCLUSIONS: sUA was not an independent predictor of both CVD and CHD mortality. Ethnicity did not influence the association of sUA with CVD mortality. Furthermore, sUA did not add to risk assessment beyond traditional CVD risk factors.

Left ventricular hypertrophy and risk reclassification for coronary events in multi-ethnic adults.

BACKGROUND: Left ventricular hypertrophy (LVH) has not been evaluated for reclassification improvement in the intermediate Framingham risk category for incident hard coronary events in a large multi ethnic population free of cardiovascular disease at baseline. DESIGN: A post-hoc analysis on the Multi Ethnic Study of Atherosclerosis (MESA) dataset (n = 4921) was performed. METHODS: LVH was defined as the upper 95 th percentile of cardiac magnetic resonance imaging derived left ventricular mass (LVM) indexed based on body surface area (BSA) and height. Multivariate Cox proportional hazards models were used to assess the independent association between LVH and composite outcomes like all cardiovascular disease (CVDa) and hard coronary heart disease (CHDh) events over a mean follow-up period of 4.5 years. To assess the incremental value of LVH over traditional CV risk factors for CHDh prediction, we compared the discrimination, calibration and net reclassification index (NRI) of models comprising of traditional CV risk factors with and without LVH. RESULTS: LVH derived from LVM indexed by BSA (LVH-BSA) and height(1.7)(LVH-height) showed an independent association with CVDa (LVH-BSA: hazard ratio (HR) 1.52, 95% confidence interval (CI) 1.05-2.20, p = 0.03; LVH-height(1.7): HR 1.58, 95% CI 1.14-2.18, p = 0.012) and CHDh (LVH-BSA: HR 2.36, 95% CI 1.37-4.04, p = 0.002; LVH-height(1.7): HR: 1.95, 95% CI: 1.17-3.26, p = 0.01). Addition of LVH to the model based on traditional CV risk factors demonstrated no significant improvement in NRI for CHDh in either the entire cohort (LVH-BSA: NRI 1.7%, 95% CI: -8.3% to 11.7%, p = 0.74; LVH-height(1.7): NRI 2.7%, 95% CI: -5.8% to 11.3%, p = 0.62) or the intermediate risk group (LVH-BSA: NRI 12.0%, 95% CI: -5.7% to 29.8%, p = 0.19; LVH-height(1.7): NRI 14.5%, 0.1% to 28.8%, p = 0.05). CONCLUSIONS: Although an independent predictor of cardiovascular events, LVH does not lead to clinically meaningful reclassification of the overall and intermediate risk population for CHDh.

Association of cystatin C with measures of obesity and its impact on cardiovascular events among healthy US adults.

BACKGROUND: This study sought to explore the relationship between cystatin C (CysC) and anthropometric measures of obesity and the influence of this association on mortality [cardiovascular disease (CVD), coronary heart disease, and all-cause] in a nationally representative population free of CVD, diabetes mellitus, and macroalbuminuria (MA). METHODS: The study cohort included 4577 adult participants of the Third National Health and Nutrition Examination Survey (NHANES). Spearman correlation analysis was performed to ascertain the association between various anthropometric measures and CysC. Formal statistical analyses of the interaction term between anthropometric measures and CysC for outcomes were performed followed by stratified multivariate Cox proportional hazard analyses. RESULTS: A moderate degree of association was seen between CysC and measures of visceral adiposity as represented by waist-to-height ratio (WHR) and waist circumference (WC) and only a weak association between CysC and body mass index (BMI). CysC was predictive of all study outcomes in individuals with normal anthropometric measurements only. CONCLUSIONS: CysC correlated better with measures of visceral adiposity (WC and WHR) compared to BMI and appears to be a better predictor of adverse cardiovascular outcomes among those with anthropometric measures not suggestive of obesity compared to those with abnormal measures of anthropometry.

Non-high-density lipoprotein cholesterol and coronary artery calcium progression in a multiethnic US population.

Non-high-density lipoprotein cholesterol (non-HDLc) is an independent predictor of cardiovascular disease risk, with elevated levels signifying an increased risk beyond low-density lipoprotein. Previous data have shown inconsistent association of lipid subfractions with progression of coronary artery calcium (CAC), a surrogate marker of incident cardiovascular disease. We sought to evaluate the association between non-HDLc and development (incident) and progression of CAC in a cohort of multiethnic asymptomatic subjects. The cohort (n = 5,705) was derived from the limited access data set of the Multi-Ethnic Study of Atherosclerosis obtained from the National Heart Lung and Blood Institute. Multivariable regression analysis was performed to derive the association between non-HDLc and incident CAC (n = 2,927) and non-HDLc and progression of CAC (n = 2,778). In the population without CAC at baseline, non-HDLc, especially >190 mg/dl, was independently associated with incident CAC (relative risk 1.40, 95% confidence interval 1.09 to 1.79, p = 0.008) after adjustments with age, gender, race, systolic blood pressure, antihypertension medication use, smoking, diabetes, lipid-lowering therapy use, follow-up duration, and waist-hip ratio. Similarly, among those with CAC at baseline, non-HDLc levels >190 mg/dl were associated with significant CAC progression in the overall population (ß 16.4, 95% confidence interval -5.63 to 27.2, p = 0.003) after adjustments. In conclusion, non-HDLc levels, especially >190 mg/dl, are consistently associated with increased risk of CAC progression. Our results suggest that among lipid fractions, non-HDLc may be best suited for the prediction of future CAC progression.

Comparative analysis of red cell distribution width and high sensitivity C-reactive protein for coronary heart disease mortality prediction in multi-ethnic population: findings from the 1999-2004 NHANES.

BACKGROUND: Red cell distribution width (RDW) has been shown to predict all-cause and cardiovascular (CVD) mortality. However, the predictive ability of RDW for future coronary heart disease (CHD) mortality in comparison to high sensitivity C-reactive protein (hs-CRP) has not been assessed in a population cohort free of CVD. METHODS: Analysis was performed on 8,513 adult participants (age > 20 years) free of CVD from the National Health and Nutrition Examination Surveys 1999-2004. Cox-proportional hazard analyses were used to assess the role of RDW and hs-CRP in CHD mortality and in subgroups based on high and low RDW and hs-CRP. RESULTS: On adjustment for traditional risk factors (age, sex, systolic blood pressure, anti-hypertensive medication use, total cholesterol, high density lipoprotein cholesterol, lipid lowering therapy, smoking, diabetes mellitus, anemia, mean corpuscular volume and nutritional deficiencies), RDW [hazard ratio (HR) 1.26 95% Confidence Interval (CI) [1.12-1.42] p < 0.001] remained an independent predictor, while hs-CRP [HR 1.18 95% CI [0.98-1.41] p = 0.077] did not. On comparative analysis, high RDW (> 12.6%) was predictive of CHD mortality irrespective of hs-CRP status [hs-CRP ≤ 3 mg/L (HR 1.17 95% CI [1.01-1.36] p = 0.031)] and hs-CRP > 3 mg/L (HR 1.44 95% CI [1.23-1.68] p < 0.001). Hs-CRP was not predictive in either high or low RDW subgroup. CONCLUSION: RDW but not hs-CRP was associated with CHD mortality independent of traditional risk factors in a cohort with no pre-existing CVD. RDW may be considered a stronger biomarker for CHD death than hs-CRP and needs further prospective evaluation in CVD risk assessment.