Abstract-Brachial blood pressure is predictive of cardiovascular outcome; however central pressure may better represent the load imposed on the coronary and cerebral arteries and thereby bear a stronger relationship to vascular damage and prognosis. Relations of brachial and central pressures to carotid artery hypertrophy (intimal-medial thickness and vascular mass), extent of atherosclerosis (plaque score), and incident cardiovascular events were examined in the Strong Heart Study. Central pressures were calculated using radial applanation tonometry. Among 3520 participants, central and brachial pulse pressures were more strongly related to vascular hypertrophy and extent of atherosclerosis than were systolic pressures. Central pulse pressure was more strongly related to all 3 arterial measures than was brachial pulse pressure (rϭ0.

Drug dosage adjustment for patients with acute or chronic kidney disease is an accepted standard of practice. The challenge is how to accurately estimate a patient's kidney function in both acute and chronic kidney disease and determine the influence of renal replacement therapies on drug disposition. Kidney Disease: Improving Global Outcomes (KDIGO) held a conference to investigate these issues and propose recommendations for practitioners, researchers, and those involved in the drug development and regulatory arenas. The conference attendees discussed the major challenges facing drug dosage adjustment for patients with kidney disease. In particular, although glomerular filtration rate is the metric used to guide dose adjustment, kidney disease does affect nonrenal clearances, and this is not adequately considered in most pharmacokinetic studies. There are also inadequate studies in patients receiving all forms of renal replacement therapy and in the pediatric population. The conference generated 37 recommendations for clinical practice, 32 recommendations for future research directions, and 24 recommendations for regulatory agencies (US Food and Drug Administration and European Medicines Agency) to enhance the quality of pharmacokinetic and pharmacodynamic information available to clinicians. The KDIGO Conference highlighted the gaps and focused on crafting paths to the future that will stimulate research and improve the global outcomes of patients with acute and chronic kidney disease.

Background Inorganic arsenic exposure in water and food is a global public health problem. Chronic exposure to high levels of arsenicis consistently associated with increased risk of cardiovascular disease, whereas prospective data on low to moderate chronic arsenic exposure (<100μg/L in drinking water) are lacking. Objective To evaluate the association between chronic low to moderate arsenic exposure and incident cardiovascular disease. Design Prospective cohort study. Setting The Strong Heart Study baseline visit in 1989-1991, with follow-up through 2008. Patients 3,575 American Indian men and women aged 45-74 years living in Arizona, Oklahoma, and North and South Dakota. Measurements The sum of inorganic and methylated arsenic species in urine at baseline was used as a biomarker of chronic arsenic exposure. Participants were followed for incident fatal and non-fatal cardiovascular disease, including coronary heart disease and stroke. Results 1,184 participants developed fatal and non-fatal cardiovascular disease and 439 participants developed fatal cardiovascular disease. Comparing the highest to lowest quartile arsenic concentrations (>15.7 vs. <5.8 μg/g creatinine), the hazard ratios (95% confidence interval) for cardiovascular disease, coronary heart disease, and stroke mortality after adjustment for socio-demographic factors, smoking, body mass index, and lipids were 1.65 (1.20, 2.27; p-trend<0.001), 1.71 (1.19, 2.44; p-trend<0.001) and 3.03 (1.08, 8.50; p-trend=0.061), respectively. The corresponding hazard ratios for incident cardiovascular disease, coronary heart disease, and stroke were 1.32 (1.09, 1.59; p-trend=0.002), 1.30 (1.04, 1.62; p-trend=0.006), and 1.47 (0.97, 2.21; p-trend=0.032), respectively. These associations varied by study region and were attenuated following further adjustment for diabetes, hypertension, and measures of kidney disease. Limitations Direct measurement of individual arsenic in drinking water was unavailable. Residual confounding and differences in potential confounders across study regions may exist. Conclusions Low to moderate chronic arsenic exposure, as measured in urine, was prospectively associated with cardiovascular disease incidence and mortality.

Background Cadmium is a widespread toxic metal with potential cardiovascular effects, but no studies have evaluated cadmium and incident cardiovascular disease. We evaluated the association of urine cadmium concentration with cardiovascular disease incidence and mortality in a large population-based cohort. Methods We conducted a prospective cohort study of 3,348 American Indian adults aged 45–74 years from Arizona, Oklahoma and North and South Dakota who participated in the Strong Heart Study in 1989–1991. Urine cadmium was measured using inductively coupled plasma mass spectrometry. Follow-up extended through 31 December 2008. Results The geometric mean cadmium level in the study population was 0.94 μg/g (95% confidence interval= 0.92 – 0.93). We identified 1,084 cardiovascular events, including 400 deaths. After adjustment for sociodemographic and cardiovascular risk factors, the hazard ratios (comparing the 80th to the 20th percentile of urine cadmium concentrations) was 1.43 for cardiovascular mortality (95% confidence interval=1.21 – 1.70), and 1.34 for coronary heart disease mortality (1.10 – 1.63). The corresponding hazard ratios for incident cardiovascular disease, coronary heart disease, stroke, and heart failure were 1.24 (1.11 – 1.38), 1.22 (1.08 – 1.38), 1.75 (1.17 – 2.59) and 1.39 (1.01 – 1.94), respectively. The associations were similar in most study subgroups including never-smokers. Conclusions Urine cadmium, a biomarker of long-term exposure, was associated with increased cardiovascular mortality and with increased incidence of cardiovascular disease. These findings support that cadmium exposure is a cardiovascular risk factor.

Objective To facilitate clinical use of central PP, we sought to determine a value that might predict adverse outcome and thereby provide a target for assessment of intervention strategies. Background We previously documented that central pulse pressure (PP) more strongly relates to carotid hypertrophy and extent of atherosclerosis and, more importantly, better predicts incident cardiovascular disease (CVD) than brachial PP. Methods Radial applanation tonometry was performed in the 3rd Strong Heart Study exam to determine central blood pressure. Cox regression analyses were performed using pre-specified covariates and quartiles of central and brachial PP. Results Among 2,405 participants without prevalent CVD, 344 suffered CVD events during 5.6±1.7 years. Quartiles of central PP (p<0.001) predicted outcome more strongly than quartiles of brachial PP (p=0.052). With adjustment for covariates, only the event rate in the 4th quartile of central PP (≥50 mmHg) was significantly higher than that in the first quartile (HR 1.69, 95% CI: 1.20–2.39, p=0.003). Central PP ≥50 mmHg was related to outcome in both men (HR 2.06, 95% CI: 1.39–3.04, p<0.001) and women (HR 2.03, 95% CI: 1.55–2.65, p<0.001); in participants with (HR 1.84, 95% CI: 1.41–2.39, p<0.001) and without diabetes (HR 1.91, 95% CI: 1.29–2.83, p=0.001); and in individuals below (HR 2.51, 95% CI: 1.59–3.95, p<0.001) and above (HR 1.53, 95% CI: 1.19–1.97, p=0.001) the age of 60. Conclusions Central PP ≥50 mmHg predicts adverse CVD outcome and may serve as a target in intervention strategies, if confirmed in other populations and in prospective studies.

ABSTRACT:Our objective was to evaluate the pharmacokinetics of metformin during pregnancy. Serial blood and urine samples were collected over one steady-state dosing interval in women treated with metformin during early to late pregnancy (n ‫؍‬ 35) and postpartum (n ‫؍‬ 16). Maternal and umbilical cord blood samples were obtained at delivery from 12 women. Metformin concentrations were also determined in breast milk samples obtained over one dosing interval in 6 women. Metformin renal clearance increased significantly in mid (723 ؎ 243 ml/min, P < 0.01) and late pregnancy (625 ؎ 130 ml/min, P < 0.01) compared with postpartum (477 ؎ 132 ml/min). These changes reflected significant increases in creatinine clearance (240 ؎ 70 ml/min, P < 0.01 and 207 ؎ 56 ml/min, P < 0.05 versus 165 ؎ 44 ml/min) and in metformin net secretion clearance (480 ؎ 190 ml/min, P < 0.01 and 419 ؎ 78 ml/min, P < 0.01 versus 313 ؎ 98 ml/min) in mid and late pregnancy versus postpartum, respectively. Metformin concentrations at the time of delivery in umbilical cord plasma ranged between nondetectable (<5 ng/ml) and 1263 ng/ml. The daily infant intake of metformin through breast milk was 0.13 to 0.28 mg, and the relative infant dose was <0.5% of the mother's weight-adjusted dose. Our results indicate that metformin pharmacokinetics are affected by pregnancy-related changes in renal filtration and net tubular transport and can be roughly estimated by the use of creatinine clearance. At the time of delivery, the fetus is exposed to metformin concentrations from negligible to as high as maternal concentrations. In contrast, infant exposure to metformin through the breast milk is low.

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IMPORTANCE The value of measuring levels of glycated hemoglobin (HbA1c) for the prediction of first cardiovascular events is uncertain. OBJECTIVE To determine whether adding information on HbA1c values to conventional cardiovascular risk factors is associated with improvement in prediction of cardiovascular disease (CVD) risk. DESIGN, SETTING, AND PARTICIPANTS Analysis of individual-participant data available from 73 prospective studies involving 294 998 participants without a known history of diabetes mellitus or CVD at the baseline assessment. MAIN OUTCOMES AND MEASURES Measures of risk discrimination for CVD outcomes (eg, C-index) and reclassification (eg, net reclassification improvement) of participants across predicted 10-year risk categories of low (<5%), intermediate (5%to <7.5%), and high (≥7.5%) risk. RESULTS During a median follow-up of 9.9 (interquartile range, 7.6-13.2) years, 20 840 incident fatal and nonfatal CVD outcomes (13 237 coronary heart disease and 7603 stroke outcomes) were recorded. In analyses adjusted for several conventional cardiovascular risk factors, there was an approximately J-shaped association between HbA1c values and CVD risk. The association between HbA1c values and CVD risk changed only slightly after adjustment for total cholesterol and triglyceride concentrations or estimated glomerular filtration rate, but this association attenuated somewhat after adjustment for concentrations of high-density lipoprotein cholesterol and C-reactive protein. The C-index for a CVD risk prediction model containing conventional cardiovascular risk factors alone was 0.7434 (95% CI, 0.7350 to 0.7517). The addition of information on HbA1c was associated with a C-index change of 0.0018 (0.0003 to 0.0033) and a net reclassification improvement of 0.42 (−0.63 to 1.48) for the categories of predicted 10-year CVD risk. The improvement provided by HbA1c assessment in prediction of CVD risk was equal to or better than estimated improvements for measurement of fasting, random, or postload plasma glucose levels. CONCLUSIONS AND RELEVANCE In a study of individuals without known CVD or diabetes, additional assessment of HbA1c values in the context of CVD risk assessment provided little incremental benefit for prediction of CVD risk.