Inheritance plays a significant role in defining drug response and toxicity. Advances in molecular pharmacology and modern genomics emphasize genetic variation in dictating inter-individual pharmacokinetics and pharmacodynamics. A case in point is the homeostatic ATP-sensitive potassium (K ATP ) channel, an established drug target that adjusts membrane excitability to match cellular energetic demand. There is an increased recognition that genetic variability of the K ATP channel impacts therapeutic decision-making in human disease.Genetic variations account for 15-30% of inter-individual differences in drug metabolism and as much as 95% of variability in individual drug response. 1 Individualization of therapy is aimed at achieving the best therapeutic outcome using patient-stratified genomic information. Integrated pharmacology with genetics provides an attractive strategy poised to decipher the heterogeneity of disease phenotypes and dissect variations in drug response, leading to therapeutic optimization. The information gained through pharmacogenomics holds particular promise in improving drug efficacy while minimizing toxicity, with subgrouping of patients based on genetic variations fostering early and personalized treatment. 2 Pharmacogenomics has established genetic variations in drug-metabolizing pathways, transporters, receptors, and signaling cascades as critical in defining pharmacokinetic and/or pharmacodynamic outcomes. 3 A therapeutic target that has recently received attention is the K ATP channel, widely distributed in tissue beds of high metabolic activity. 4 K ATP channels exhibit unique energetic decoding capabilities based on a heteromultimeric structure comprised of an inwardly rectifying K + -conducting (Kir) pore and a larger regulatory subunit, an ATPaseharboring ATP-binding cassette protein-the sulfonylurea receptor (SUR). By matching membrane excitability with fluctuations in cellular metabolic demand, K ATP channels link energetic flux and cell homeostasis. K ATP channels play cytoprotective roles throughout the body, including in the myocardium, vasculature, brain, skeletal muscle, and pancreas. 5 Indeed, in the pancreas, antagonism of K ATP channel activity with sulfonylurea agents facilitates insulin release and is a first-line treatment in adult-onset diabetes mellitus. K ATP channel openers display protective properties, although their clinical use is less common. 5 Here, we highlight how the K ATP genetic variability influences disease susceptibility, and delineate how this knowledge translates into advances in therapeutic management.Correspondence: A Terzic (E-mail: terzic.andre@mayo.edu). CONFLICT OF INTERESTThe authors declared no conflict of interest. 6,7 Nucleotide fluxes in the submembrane space influence channel function, which sets membrane excitability to ultimately control insulin release (Figure 1). In response to hyperglycemia and high intracellular glucose, channel closure permits membrane depolarization and associated calcium influx, facilitating insulin r...

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We have investigated the effect of varying sodium intake on the renin-angiotensin system, ADP-induced platelet aggregation in vitro, and blood 5-HT concentrations in 9 male volunteers. Systolic blood pressure was slightly reduced during a low sodium diet, whereas the diastolic pressure remained unchanged. Plasma renin activity and aldosterone concentration both fell significantly when sodium intake was increased; plasma angiotensin II concentration also fell, but not significantly. There was a significant fall in haematocrit after an increased sodium intake, but there was no change in the whole-blood platelet count after correcting for this. There were no significant changes in either total (i.e. PRP) or platelet 5-HT concentrations. The extent of platelet aggregation induced by 5 and 20 mumol.l-1 of ADP increased significantly when dietary sodium intake was increased. When compared with low or normal sodium intakes, lower concentrations of ADP were required to produce 50% of maximum aggregation after a high sodium intake. The 5-HT2 receptor antagonist ketanserin (1 mumol.l-1 in vitro) reduced the extent of aggregation induced by 5 mumol.l-1 ADP after the volunteers had taken a high sodium diet, whereas the angiotensin II receptor antagonist saralasin (1 nmol.l-1) increased the rate of aggregation after the low sodium diet. Thus, during a high sodium intake, human platelets become more sensitive to the aggregating agent ADP. It is possible that this effect is mediated via platelet 5-HT2 receptors, since ketanserin abolished the increase in salt-induced aggregation seen with 5 mumol.l-1 ADP.

Background Cardiac power output-to-mass (CPOM) ratio is a measure of myocardial performance that incorporates both pressure and flow output, normalized to left ventricular (LV) mass generating that cardiac work. Prior small studies have shown that CPOM predicts outcomes in patients with ischemic cardiomyopathy and reduced LV ejection fraction (EF). We sought to evaluate the prognostic significance of peak exercise CPOM and power reserve (increase from rest to peak exercise) in patients with normal EF. Methods and results Retrospective study in 24,783 patients (age 59±13 years, 45% females) with EF≥50% and no significant valve disease or right ventricular (RV) dysfunction, undergoing exercise stress echocardiography between 2004–2018. CPOM was calculated as previously described (0.222 x cardiac output x mean blood pressure / LV mass) and expressed in Watts/100g myocardium. Power reserve was calculated as difference in CPOM between peak stress and rest. All-cause mortality was the primary endpoint. Patients were divided into quartiles of power reserve. Patients with higher power reserve were younger, had higher blood pressure and heart rate, lower LV mass, and lower prevalence of prior myocardial infarction. (Table). During follow-up (median (IQR) 3.9 (0.6–8.3) years), 931 (3.8%) patients died. Progressively lower power reserve was associated with increasing mortality (Figure A). Compared to patients with abnormal stress test, patients with the lowest power reserve but otherwise normal stress test had the same survival as those with infarction/cardiomyopathy or ischemia on stress test (Figure B). Resting CPOM had lower predictive value. After adjusting for age, sex, METs achieved, ischemia/infarction on stress test results, and diastolic function grade, both peak exercise CPOM and power reserve were independent predictors of mortality (p<0.0001), incremental to conventional measures. Conclusion Cardiac power output and reserve measured during exercise stress echo provides independent prognostic information in patients with normal resting EF and no significant valve disease or RV dysfunction. The survival of patients with low power reserve but normal stress test was similar to patients with prior infarction/ cardiomyopathy or ischemia on stress test.