Clinical features and outcomes in patients with cardiogenic shock complicating acute myocardial infarction: early vs recent experience with impella.

OBJECTIVES: To compare clinical features and outcomes in patients with acute myocardial infarction complicated by cardiogenic shock (AMICS) treated in the early experience with Impella percutaneous ventricular assist device and patients treated recently. BACKGROUND: Since pre-market approval (PMA) of Impella device as treatment for AMICS, use of the device has grown considerably. METHODS: We retrospectively analyzed 649 AMICS patients treated with perioperative Impella, with 291 patients treated from 2008 to 2014 comprising the early experience cohort and 358 patients treated from 2017 to 2019 comprising the recent experience cohort. The primary end point was risk adjusted in-hospital mortality. RESULTS: Mean age and gender distribution of patients was similar in the two cohorts. The recent cohort had more invasive hemodynamic monitoring (64% vs 46%; P < .001) and less use of an intra-aortic balloon pump prior to Impella (15% vs 41%; P < .001). Recently treated patients were significantly more likely to receive Impella support prior to PCI (58% vs 44%; P = .005). In-hospital mortality was lower in the recent cohort (48% vs 56%; P = .043). This difference was however no longer significant after risk adjustment (adjusted OR 0.89, 95% CI 0.59-1.34, P = .59). Rates of acute kidney injury, major bleeding, and vascular complications requiring surgery were also significantly lower in the recent cohort. CONCLUSIONS: Use of Impella for AMICS during recent years is associated with lower unadjusted in-hospital mortality, which may reflect better patient selection, earlier device implantation, and improved management algorithms. In-depth understanding of these factors may inform the development of future treatment protocols.

Impella support and acute kidney injury during high-risk percutaneous coronary intervention: The Global cVAD Renal Protection Study.

BACKGROUND: Protection against acute kidney injury (AKI) has been reported with the use of Impella during high-risk percutaneous coronary intervention (HR-PCI). We sought to evaluate this finding by determining the occurrence of AKI during Impella-supported HR-PCI in patients from the Global cVAD Study and compare this incidence with their calculated AKI risk at baseline. METHODS AND RESULTS: In this prospective, multicenter study, we enrolled 314 consecutive patients. We included 223 patients that underwent nonemergent HR-PCI supported with Impella 2.5 or Impella CP and excluded those requiring hemodialysis prior to HR-PCI (19) and those with insufficient data (72). The primary outcome was AKI postprocedurally at 48 hr versus the predicted risk of AKI according to Mehran risk score. Logistic regression analysis determined predictors of AKI. Overall, 4.9% (11) of Impella-supported patients developed AKI (exclusively stage 1) at 48 hr versus a predicted rate of 21.9%, representing a 77.6% lower AKI rate (p < .0001). In this study, no Impella-supported patients required renal replacement therapy. Estimated glomerular filtration rate (ml/min/1.73 m2 ) alone predicted AKI (adjusted odds ratio [AOR]: 4.915; 95% confidence intervals [CI]: 1.02-23.53, p = .046), and increasing contrast had insignificant effects on AKI during high-risk PCI (AOR: 1.15; 95% CI: 0.87-1.51, p = .332). In patients not protected from AKI, the postprocedure incidence of AKI was not significantly greater and did not correlate with chronic kidney disease severity. CONCLUSION: The incidence of AKI was lower during HR-PCI than expected from current risk models. Although further exploration of this finding is warranted, these data support a new protective strategy against AKI during HR-PCI.

Transgenic expression of a dominant negative K(ATP) channel subunit in the mouse endothelium: effects on coronary flow and endothelin-1 secretion.

K(ATP) channels are involved in regulating coronary function, but the contribution of endothelial K(ATP) channels remains largely uncharacterized. We generated a transgenic mouse model to specifically target endothelial K(ATP) channels by expressing a dominant negative Kir6.1 subunit only in the endothelium. These animals had no obvious overt phenotype and no early mortality. Histologically, the coronary endothelium in these animals was preserved. There was no evidence of increased susceptibility to ergonovine-induced coronary vasospasm. However, isolated hearts from these animals had a substantially elevated basal coronary perfusion pressure. The K(ATP) channel openers, adenosine and levcromakalim, decreased the perfusion pressure whereas the K(ATP) channel blocker glibenclamide failed to produce a vasoconstrictive response. The inducible endothelial nitric oxide pathway was intact, as evidenced by vasodilation caused by bradykinin. In contrast, basal endothelin-1 release was significantly elevated in the coronary effluent from these hearts. Treatment of mice with bosentan (endothelin-1 receptor antagonist) normalized the coronary perfusion pressure, demonstrating that the elevated endothelin-1 release was sufficient to account for the increased coronary perfusion pressure. Pharmacological blockade of K(ATP) channels led to elevated endothelin-1 levels in the coronary effluent of isolated mouse and rat hearts as well as enhanced endothelin-1 secretion from isolated human coronary endothelial cells. These data are consistent with a role for endothelial K(ATP) channels to control the coronary blood flow by modulating the release of the vasoconstrictor, endothelin-1.

FABP2 Ala54Thr genotype is associated with glucoregulatory function and lipid oxidation after a high-fat meal in sedentary nondiabetic men and women.

BACKGROUND: A common functional missense mutation [Ala54Thr of the fatty acid-binding protein 2 gene (FABP2)] has previously been studied for associations with glucoregulation, postprandial lipemia, and lipid oxidation rates. However, most of those studies have not accounted for the interactive and potentially confounding effects of habitual physical activity and diet. OBJECTIVE: We tested the hypothesis that, in sedentary nondiabetic subjects following a low-fat diet, Thr54 FABP2 carriers have lower glucoregulatory function, greater postprandial lipemia, and greater lipid oxidation rates than do their Ala54 FABP2-homozygous counterparts. DESIGN: Men and women (n = 122) aged 50-75 y who were following a low-fat diet were genotyped and underwent oral-glucose-tolerance tests. A subgroup (n = 36) also underwent postprandial lipemia tests with lipid oxidation rate measurements. RESULTS: Thr54 carriers were less likely to have normal glucose tolerance (P = 0.05) and had higher fasting glucose concentrations (P = 0.003) than did Ala54 homozygotes. In Thr54 carriers, the insulin sensitivity index was lower (P = 0.02), and the fasting insulin and the oral-glucose-tolerance test insulin area under the curve were higher (P = 0.05 and 0.03, respectively) than in Ala54 homozygotes. FABP2 genotype was not associated with fasting or postprandial lipemia test triacylglycerol or free fatty acids (P > or = 0.22 for all), but postprandial lipid oxidation rates were higher (P = 0.01), which suggests that fat absorption is higher in Thr54 carriers than in Ala54 homozygotes. CONCLUSIONS: In sedentary nondiabetic persons following a low-fat diet, FABP2 Thr54 carriers have lower glucose tolerance and lower insulin action than do Ala54-homozygous persons. Furthermore, FABP Thr54 carriers have higher lipid oxidation rates, which may be the mechanism of glucoregulatory dysfunction.

Endurance training-induced changes in the insulin response to oral glucose are associated with the peroxisome proliferator-activated receptor-gamma2 Pro12Ala genotype in men but not in women.

The present study sought to investigate, in sedentary men and women, (a) whether a common functional gene variant (peroxisome proliferator-activated receptor-gamma2 [PPARgamma2] Pro12Ala) predicts insulin action and (b) whether improvements in insulin action in response to endurance exercise training are associated with PPARgamma2 Pro12Ala. Sedentary, 50- to 75-year-old men and women (N = 73) were genotyped and underwent oral glucose tolerance tests (OGTTs) before and after 6 months of endurance training. At baseline, men heterozygous for the Pro12Ala variant had a greater OGTT insulin area under the curve (AUC) as compared with Pro12 homozygous men (P = .009). Endurance training resulted in a significantly greater improvement in insulin AUC in Pro12Ala heterozygous men as compared with Pro12 homozygous men (P = .003) despite no genotype-specific differences with respect to training-induced changes in body weight, body mass index, and percent body fat. No differences between genotype groups were present at baseline or in response to training in women. Training did not alter the OGTT glucose AUC for the group as a whole, and the baseline, final, and change in glucose AUC were not dependent on PPARgamma2 genotype and/or sex. In conclusion, these findings suggest that sedentary men with the PPARgamma2 Pro12Ala variant have lower insulin action on glucose disposal as compared with their counterparts. However, these men are particularly responsive with respect to the magnitude of endurance training-induced improvement in insulin action.

Selected genetic polymorphisms and plasma coagulation factor VII changes with exercise training.

We assessed the effects of coagulation factor VII (FVII) gene polymorphisms, lipid-related polymorphisms, and exercise training-induced plasma lipoprotein lipid changes on FVII level changes with exercise training in middle- to older-aged men and women. Forty-six healthy sedentary men and women were stabilized on a low-fat diet and then underwent baseline testing, 6 mo of endurance exercise training, and final testing. Plasma FVII-Ag levels decreased with exercise training (106.7 +/- 1.4 vs. 104.2 +/- 1.6%, P = 0.005). There were no significant differences in FVII-Ag changes with exercise training between -323 (0/10 bp)/-401 (G/T) haplotype or -402 (G/A) genotype groups. FVII-Ag changes with training were not correlated with changes in plasma lipoprotein lipids. In linear regression analyses, FVII-Ag changes with training remained significant after adjusting for training-induced plasma lipoprotein lipid changes (P = 0.01). FVII changes with training were associated with apolipoprotein E genotype (P = 0.012); this relationship was still evident after adjusting for training-induced plasma lipoprotein lipid changes (P = 0.047). FVII changes with training also were significantly associated with human ATPase binding cassette-1 genotype (P = 0.018); this relationship persisted after accounting for the effect of the training-induced plasma lipoprotein lipid changes (P = 0.045). We conclude that plasma FVII-Ag changes with exercise training are more closely related to selected lipid-related genotypes than FVII gene promoter variants.

Influence of the interleukin-6 -174 G/C gene polymorphism on exercise training-induced changes in glucose tolerance indexes.

A polymorphism in the IL-6 gene, a G-to-C substitution 176 bp upstream of the ATG translation initiation site, has been associated with diabetes prevalence and insulin resistance. Interventions including exercise training are frequently used to modify cardiovascular disease risk factors. Consequently, this project examined associations between the IL-6 -174 genotype and oral glucose tolerance test outcomes in 50- to 75-yr-old sedentary men and postmenopausal women before and after aerobic exercise training. Among the 87 individuals who started the study, 56 were retested after 6 mo of aerobic exercise training. Subject characteristics at baseline did not differ between the IL-6 genotype groups with the exception of fasting glucose, which was higher (P = 0.02, covariates age, gender, and ethnicity) in the CC genotype group. The training-induced change in glucose area under the curve during the oral glucose tolerance test varied between the IL-6 -174 genotype groups (P = 0.05, covariates age, gender, ethnicity, baseline glucose area under the curve, and percent body fat change) with a significant decrease occurring only in the GG genotype group. Insulin outcomes did not differ among the groups at baseline or after training. Training-induced changes in weight, percent body fat, maximal oxygen consumption, fasting glucose, and an insulin sensitivity index also changed similarly among the genotype groups. In conclusion, fasting glucose and the extent to which glucose tolerance changes with exercise training may be influenced by the IL-6 -174 gene polymorphism.

Human gender differences in fibrinolytic responses to exercise training and their determinants.

Endurance exercise training improves fibrinolysis, but this training-induced adaptation may differ somewhat between men and women. We sought to determine whether the potential gender differences in training-induced changes in selected fibrinolysis measures were related to changes in adiposity and/or plasma lipoprotein lipid levels. Seventeen men and 28 women, 50-75 years old, who were generally overweight to obese, were assessed for plasminogen activator inhibitor-1 (PAI-1) and tissue plasminogen activator (t-PA) activity, t-PA antigen and plasma lipoprotein-lipid levels, and body composition before and after 6 months of endurance exercise training while on a low-fat diet. At baseline, there were no differences in fibrinolytic measures between the men and women. Baseline levels of these fibrinolytic markers in both men and women were primarily related to other fibrinolytic measures and body composition, with a smaller contribution from plasma high-density lipoprotein cholesterol (HDL-C) levels. Exercise training reduced t-PA antigen levels in both men and women, but the reduction was significantly greater in men (-1.6 +/- 0.3 versus -0.5 +/- 0.2 ng ml(-1), P = 0.007). Exercise training decreased PAI-1 activity more in men than in women (-2.6 +/- 1.4 versus +0.9 +/- 0.9 IU ml(-1), P = 0.03). Men and women both showed increased t-PA activity with exercise training to the same extent (+0.38 +/- 0.12 versus +0.36 +/- 0.24 U ml(-1)). The changes in fibrinolytic measures with exercise training in men and women were correlated with changes in other fibrinolytic measures, although in men abdominal fat changes were a strong predictor of fibrinolytic changes with training. These findings suggest that training-induced improvements in endogenous fibrinolysis markers are somewhat greater in men compared to women and may be more strongly associated with abdominal obesity in men.

K ATP channels of primary human coronary artery endothelial cells consist of a heteromultimeric complex of Kir6.1, Kir6.2, and SUR2B subunits.

Functional ATP-sensitive potassium (K(ATP)) channels can be reconstituted by expression of various combinations of different pore-forming subunits (Kir6.1 and Kir6.2) and sulfonylurea receptor (SUR) subunits. Using dominant negative and gene knockout approaches, Kir6.2 subunits have been identified as required pore-forming components of plasmalemmal K(ATP) channels in ventricular myocytes. Previous data obtained in heterologous expression systems suggest that Kir6.1 and Kir6.2 subunits are capable of forming a functional heteromultimeric channel complex. However, until now the existence of such heteromultimeric Kir6.1/Kir6.2 complexes has not been demonstrated for native K(ATP) channels. The primary aim of this study was to identify the molecular composition of native K(ATP) channels in primary human coronary artery endothelial cells (HCAEC) and smooth muscle cells (HCASMC) from human origin. We specifically investigated the potential that heteromultimeric Kir6.1/Kir6.2 channels exist in these cells. Using reverse transcriptase-polymerase chain reaction, we detected the expression of Kir6.1, Kir6.2, and SUR2B in both cell types. Western blotting and immunoprecipitation assays demonstrated the presence of Kir6.1 protein in both HCAEC and HCASMC; however, Kir6.2 protein was only expressed in HCAEC. Interaction between Kir6.1 and Kir6.2 subunits was demonstrated by reciprocal co-immunoprecipitation of these two subunits in HCAEC. Furthermore, Kir6.1 and Kir6.2 were detected in the immunoprecipitate when using an anti-SUR2 antibody. Confocal microscopy imaging demonstrated Kir6.1 and Kir6.2 subunits to co-localize at the cell surface membrane in HCAEC. In conclusion, our data characterize the molecular composition of primary human coronary smooth muscle and endothelial cells. We demonstrate that human coronary endothelial K(ATP) channels consist of a heteromultimeric complex of Kir6.1, Kir6.2, and SUR2B subunits.