Machine Learned Cellular Phenotypes in Cardiomyopathy Predict Sudden Death.

RATIONALE: Susceptibility to VT/VF (ventricular tachycardia/fibrillation) is difficult to predict in patients with ischemic cardiomyopathy either by clinical tools or by attempting to translate cellular mechanisms to the bedside. OBJECTIVE: To develop computational phenotypes of patients with ischemic cardiomyopathy, by training then interpreting machine learning of ventricular monophasic action potentials (MAPs) to reveal phenotypes that predict long-term outcomes. METHODS AND RESULTS: We recorded 5706 ventricular MAPs in 42 patients with coronary artery disease and left ventricular ejection fraction ≤40% during steady-state pacing. Patients were randomly allocated to independent training and testing cohorts in a 70:30 ratio, repeated K=10-fold. Support vector machines and convolutional neural networks were trained to 2 end points: (1) sustained VT/VF or (2) mortality at 3 years. Support vector machines provided superior classification. For patient-level predictions, we computed personalized MAP scores as the proportion of MAP beats predicting each end point. Patient-level predictions in independent test cohorts yielded c-statistics of 0.90 for sustained VT/VF (95% CI, 0.76-1.00) and 0.91 for mortality (95% CI, 0.83-1.00) and were the most significant multivariate predictors. Interpreting trained support vector machine revealed MAP morphologies that, using in silico modeling, revealed higher L-type calcium current or sodium-calcium exchanger as predominant phenotypes for VT/VF. CONCLUSIONS: Machine learning of action potential recordings in patients revealed novel phenotypes for long-term outcomes in ischemic cardiomyopathy. Such computational phenotypes provide an approach which may reveal cellular mechanisms for clinical outcomes and could be applied to other conditions.

Developing an integrated strategy to reduce ethnic and racial disparities in the delivery of clinical preventive services for older Americans.

OBJECTIVES: To determine the optimum strategy for increasing up-to-date (UTD) levels in older Americans, while reducing disparities between White, Black, and Hispanic adults, aged 65 years and older. METHODS: Data were analyzed from the 2008 Behavioral Risk Factor Surveillance System, quantifying the proportion of older Americans UTD with influenza and pneumococcal vaccinations, mammograms, Papanicolaou tests, and colorectal cancer screening. A comparison of projected changes in UTD levels and disparities was ascertained by numerically accounting for UTD adults lacking 1 or more clinical preventive services (CPS). Analyses were performed by gender and race/ethnicity. RESULTS: Expanded provision of specific vaccinations and screenings each increased UTD levels. When those needing only vaccinations were immunized, there was a projected decrease in racial/ethnic disparities in UTD levels (2.3%-12.2%). When those needing only colorectal cancer screening, mammography, or Papanicolaou test were screened, there was an increase in UTD disparities (1.6%-4.5%). CONCLUSIONS: A primary care and public health focus on adult immunizations, in addition to other CPS, offers an effective strategy to reduce disparities while improving UTD levels.

Experimental and theoretical ventricular electrograms and their relation to electrophysiological gradients in the adult rat heart.

The electrical activity of adult mouse and rat hearts has been analyzed extensively, often as a prerequisite for genetic engineering studies or for the development of rodent models of human diseases. Some aspects of the initiation and conduction of the cardiac action potential in rodents closely resemble those in large mammals. However, rodents have a much higher heart rate and their ventricular action potential is triangular and very short. As a consequence, an interpretation of the electrocardiogram in the mouse and rat remains difficult and controversial. In this study, optical mapping techniques have been applied to an in vitro left ventricular adult rat preparation to obtain patterns of conduction and action potential duration measurements from the epicardial surface. This information has been combined with previously published mathematical models of the rat ventricular myocyte to develop a bidomain model for action potential propagation and electrogram formation in the rat left ventricle. Important insights into the basis for the repolarization waveform in the ventricular electrogram of the adult rat have been obtained. Notably, our model demonstrated that the biphasic shape of the rat ventricular repolarization wave can be explained in terms of the transmural and apex-to-base gradients in action potential duration that exist in the rat left ventricle.

Plasma membrane KATP channel-mediated cardioprotection involves posthypoxic reductions in calcium overload and contractile dysfunction: mechanistic insights into cardioplegia.

Our recent data demonstrate that activation of pmKATP channels polarizes the membrane of cardiomyocytes and reduces Na+/Ca2+ exchange-mediated Ca2+ overload. However, it is important that these findings be extended into contractile models of hypoxia/reoxygenation injury to further test the notion that pmKATP channel activation affords protection against contractile dysfunction and calcium overload. Single rat heart right ventricular myocytes were enzymatically isolated, and cell contractility and Ca2+ transients in field-stimulated myocytes were measured in a cellular model of metabolic inhibition and reoxygenation. Activation of pmKATP with P-1075 (5 microM) or inhibition of the Na+/Ca2+ exchanger with KB-R7943 (5 microM)reduced reoxygenation-induced diastolic Ca2+ overload and improved the rate and magnitude of posthypoxic contractile recovery during the first few minutes of reoxygenation. Moreover,diastolic Ca2+ overload and posthypoxic contractile dysfunction were aggravated in ventricular myocytes either subjected to specific blockade of pmKATP with HMR1098 (20 microM) or expressing the dominant-negative pmKATP construct Kir6.2(AAA) in the presence of P-1075. Our results suggest that a common mechanism, involving resting membrane potential-modulated increases in diastolic [Ca2+]i, is responsible for the development of contractile dysfunction during reoxygenation following metabolic inhibition. This novel and highly plausible cellular mechanism for pmKATP-mediated cardioprotection may have direct clinical relevance as evidenced by the following findings: a hypokalemic polarizing cardioplegia solution supplemented with the pmKATP opener P-1075 improved Ca2+ homeostasis and recovery of function compared with hyperkalemic depolarizing St. Thomas' cardioplegia following contractile arrest in single ventricular myocytes and working rat hearts. We therefore propose that activation of pmKATP channels improves posthypoxic cardiac function via reductions in abnormal diastolic Ca2+ homeostasis mediated by reverse-mode Na+/Ca2+ exchange.

Microalbuminuria and concentrations of antioxidants among US adults.

BACKGROUND: Microalbuminuria may increase the risk for cardiovascular disease. Increased oxidative stress, which may be important in the pathophysiological process of cardiovascular disease, occurs frequently in people with microalbuminuria and could depress their antioxidant concentrations, which then could contribute to end-organ damage associated with microalbuminuria. METHODS: We examined associations between microalbuminuria and circulating concentrations of vitamins A, C, and E and carotenoids in 9,575 US adults aged 20 years or older who participated in the Third National Health and Nutrition Examination Survey (1988 to 1994). RESULTS: After adjustment for age, sex, race or ethnicity, education, smoking status, cotinine concentration, physical activity, alcohol use, fruit and vegetable intake, vitamin or mineral use during the past 24 hours, body mass index, systolic blood pressure, and total cholesterol, triglyceride, glucose, insulin, and C-reactive protein concentrations, concentrations of beta-cryptoxanthin (odds ratio for quartile of highest concentration compared with quartile of lowest concentration, 0.56; 95% confidence interval, 0.38 to 0.82), lutein/zeaxanthin (odds ratio, 0.59; 95% confidence interval, 0.37 to 0.94), lycopene (odds ratio, 0.64; 95% confidence interval, 0.46 to 0.89), and total carotenoids (odds ratio, 0.54; 95% confidence interval, 0.38 to 0.75) were associated inversely with microalbuminuria. Vitamin C, vitamin E, and selenium concentrations were not significantly associated with microalbuminuria. CONCLUSION: People with microalbuminuria may have reduced concentrations of selected antioxidants. Additional research is needed to examine the relationships between microalbuminuria and antioxidant status, mechanisms for depletion of antioxidants, and possible benefits from increased intake of antioxidants through dietary change or the use of supplements in people with microalbuminuria.

Two arginines in the cytoplasmic C-terminal domain are essential for voltage-dependent regulation of A-type K+ current in the Kv4 channel subfamily.

Contributions of the C-terminal domain of Kv4.3 to the voltage-dependent gating of A-type K+ current (IA) were examined by (i) making mutations in this region, (ii) heterologous expression in HEK293 cells, and (iii) detailed voltage clamp analyses. Progressive deletions of the C terminus of rat Kv4.3M (to amino acid 429 from the N terminus) did not markedly change the inactivation time course of IA but shifted the voltage dependence of steady state inactivation in the negative direction to a maximum of -17 mV. Further deletions (to amino acid 420) shifted this parameter in the positive direction, suggesting a critical role for the domain 429-420 in the voltage-dependent regulation of IA. There are four positively charged amino acids in this domain: Lys423, Lys424, Arg426, and Arg429. The replacement of the two arginines with alanines (R2A) resulted in -23 and -13 mV shifts of inactivation and activation, respectively. Additional replacement of the two lysines with alanines did not result in further shifts. Single replacements of R426A or R429A induced -15 and -10 mV shifts of inactivation, respectively. R2A did not significantly change the inactivation rate but did markedly change the voltage dependence of recovery from inactivation. These two arginines are conserved in Kv4 subfamily, and alanine replacement of Arg429 and Arg432 in Kv4.2 gave essentially the same results. These effects of R2A were not modulated by co-expression of the K+ channel beta subunit, KChIPs. In conclusion, the two arginines in the cytosolic C-terminal domain of alpha-subunits of Kv4 subfamily strongly regulate the voltage dependence of channel activation, inactivation, and recovery.

Serum total cholesterol concentrations and awareness, treatment, and control of hypercholesterolemia among US adults: findings from the National Health and Nutrition Examination Survey, 1999 to 2000.

BACKGROUND: Serum cholesterol concentrations have decreased in the US population. Whether the decline continued during the 1990s is unknown. METHODS AND RESULTS: We used data from 4148 men and women aged > or =20 years who had a total cholesterol determination or reported using cholesterol-lowering medications and who participated in the National Health and Nutrition Examination Survey (NHANES) from 1999 to 2000 (this is a cross-sectional health examination survey of the US population), and we compared the results with data from 15 719 participants in NHANES III (1988 to 1994). For all adults, the age-adjusted mean total cholesterol concentration decreased from 5.31 mmol/L (205 mg/dL) in NHANES III to 5.27 mmol/L (203 mg/dL) in NHANES 1999 to 2000 (P=0.159). The age-adjusted mean total cholesterol concentration decreased by 0.02 mmol/L (0.7 mg/dL) among men (P=0.605) and 0.06 mmol/L (2.3 mg/dL) among women (P=0.130). Significant decreases were observed among men aged > or =75 years, black men, and Mexican-American women. Among participants who had a total cholesterol concentration > or =5.2 mmol/L (200 mg/dL) or who reported using cholesterol-lowering medications, 69.5% reported having had their cholesterol checked, 35.0% were aware that they had hypercholesterolemia, 12.0% were on treatment, and 5.4% had a total cholesterol concentration <5.2 mmol/L (200 mg/dL) after age adjustment. CONCLUSIONS: The mean serum total cholesterol concentration of the adult US population in 1999 to 2000 has changed little since 1988 to 1994. The low percentage of adults with controlled blood cholesterol concentration suggests the need for a renewed commitment to the prevention, treatment, and control of hypercholesterolemia.