Functional genetic variants of the catecholamine-release-inhibitory peptide catestatin in an Indian population: allele-specific effects on metabolic traits.

Catestatin (CST), a chromogranin A (CHGA)-derived peptide, is a potent inhibitor of catecholamine release from adrenal chromaffin cells and postganglionic sympathetic axons. We re-sequenced the CST region of CHGA in an Indian population (n = 1010) and detected two amino acid substitution variants: G364S and G367V. Synthesized CST variant peptides (viz. CST-Ser-364 and CST-Val-367) were significantly less potent than the wild type peptide (CST-WT) to inhibit nicotine-stimulated catecholamine secretion from PC12 cells. Consistently, the rank-order of blockade of nicotinic acetylcholine receptor (nAChR)-stimulated inward current and intracellular Ca(2+) rise by these peptides in PC12 cells was: CST-WT > CST-Ser-364 > CST-Val-367. Structural analysis by CD spectroscopy coupled with molecular dynamics simulations revealed the following order of α-helical content: CST-WT > CST-Ser-364 > CST-Val-367; docking of CST peptides onto a major human nAChR subtype and molecular dynamics simulations also predicted the above rank order for their binding affinity with nAChR and the extent of occlusion of the receptor pore, providing a mechanistic basis for differential potencies. The G364S polymorphism was in strong linkage disequilibrium with several common CHGA genetic variations. Interestingly, the Ser-364 allele (detected in ∼15% subjects) was strongly associated with profound reduction (up to ∼2.1-fold) in plasma norepinephrine/epinephrine levels consistent with the diminished nAChR desensitization-blocking effect of CST-Ser-364 as compared with CST-WT. Additionally, the Ser-364 allele showed strong associations with elevated levels of plasma triglyceride and glucose levels. In conclusion, a common CHGA variant in an Indian population influences several biochemical parameters relevant to cardiovascular/metabolic disorders.

Percutaneous coronary intervention in cardiogenic shock complicating acute ST-elevation myocardial infarction-a single centre experience.

BACKGROUND: Mortality in acute myocardial infarction (AMI) complicated by cardiogenic shock (CS) approaches 70 - 80%, regardless of the type of pharmacological treatment. Early revascularisation improves survival in AMI with CS. Our aim is to assess the predictors of mid-term outcome after percutaneous coronary intervention (PCI) in patients with ST-segment elevation myocardial infarction (STEMI) and CS. METHODS: Forty-one patients who underwent primary or rescue PCI for CS were analysed comparing their baseline, angiographic, PCI data, 30-day and 1-year survival. RESULTS: There were no significant differences between survivors and non-survivors in baseline characters, except for more number of transfer admissions (P= 0.0005), and cardiopulmonary resuscitations (P= 0.015) in the later group. The mean time between myocardial infarction (MI) onset to shock and MI onset to revascularisation were 12.8 ± 12.9 hours and 17.0 ± 16.8 hours, respectively. Patients with better pre-procedure thrombolysis in myocardial infarction (TIMI) flow in the infarct-related artery (IRA) had better survival (P= 0.0005). Successful PCI was achieved in 48.8% of patients. The 30-day mortality was 56.1% and all were prior to hospital discharge. Patients with successful PCI had better short-term survival in comparison with patients with failed PCI (80% vs 9.6%). Eighteen patients who survived at 30 days were followed up for 12-72 months (mean 28.5 ± 5.4 months). Fifteen patients survived at 1 year after PCI and all were in good functional status. CONCLUSION: Mortality remains high even with PCI. Achieving IRA patency with TIMI 3 flow is the main determinant of survival. Survival and functional status are good in patients who are discharged from hospital.