Prognostic Impact of Diabetes Mellitus on Clinical Outcomes in Lean Patients With Acute Myocardial Infarction.

BACKGROUND/AIM: Little is known about the impact of diabetes mellitus (DM) on clinical outcomes in lean patients with acute myocardial infarction (AMI). We conducted this study to evaluate the impact of DM on clinical outcomes in AMI patients based on body mass index (BMI) level. PATIENTS AND METHODS: A total of 1,282 consecutive AMI patients who underwent emergent percutaneous coronary intervention within 24 hours from onset were retrospectively studied. The patients were divided into 2 groups based on BMI: Underweight group (BMI <18.5 kg/m2, n=61) and non-Underweight group (BMI ≥18.5 kg/m2, n=1,221). The primary endpoint was all-cause death, and the secondary endpoint was major adverse cardiovascular and cerebrovascular events. The median follow-up period was 3.8 (1.7-5.0) years. RESULTS: The Underweight patients were older and included more females than the non-Underweight patients, and had a lower prevalence of coronary risk factors including DM. The primary and secondary endpoints were significantly higher in the Underweight patients (both p<0.05 by the Log-rank test). When divided by the presence of DM, the secondary endpoint was significantly higher in the non-Underweight patients with DM than in those without DM (p<0.05). However, there was no significant difference between Underweight patients with DM and those without DM. Multivariate analyses showed that DM was an independent predictor for the primary and secondary endpoints in non-Underweight patients, but not in Underweight patients. CONCLUSION: DM was associated with worse clinical outcomes in normal-weight or obese AMI patients, but not in underweight AMI patients.

Diltiazem Inhibits Coronary Spasm via Inhibition of Cav1.2Phosphorylation and Protein Kinase C Activation in a Mouse Model of Coronary Spastic Angina.

Calcium antagonists are used for coronary spastic angina (CSA) treatment. We previously identified a phospholipase C (PLC) -δ1 gene variant that results in enhanced PLC activity in patients with CSA and developed a CSA animal model by generating vascular smooth muscle cell-specific human variant PLC-δ1 overexpression (PLC-TG) mice. In this study, we investigated the molecular mechanism of CSA using the PLC-TG mice and the inhibitory effect of a calcium antagonist, diltiazem hydrochloride (DL).We treated the PLC-TG and wild-type (WT) mice with oral DL or trichlormethiazide (TM) (control) for 2 weeks. Ergometrine injection-induced coronary spasm was observed on the electrocardiogram in all 5 PLC-TG mice treated with TM, but only in 1 of 5 PLC-TG mice treated with DL. Voltage-dependent calcium channel (Cav1.2) phosphorylation and protein kinase C (PKC) activity were enhanced in the aortas of PLC-TG mice treated with TM. DL treatment significantly inhibited Cav1.2 phosphorylation and PKC activity. Although total Cav1.2 expression was similar between WT and PLC-TG mice treated with TM, DL treatment significantly increased its expression in PLC-TG mice. Furthermore, its expression remained high after DL discontinuation. DL and PKC inhibitor suppressed intracellular calcium response to acetylcholine in cultured rat aortic smooth muscle cells transfected with variant PLC-δ1.These results indicate that enhanced PLC activity causes coronary spasm, presumably via enhanced Cav1.2 phosphorylation and PKC activity, both of which were inhibited by DL. Enhanced total Cav1.2 expression after DL discontinuation and high PKC activity may be an important mechanism underlying the calcium antagonist withdrawal syndrome.

PolyIC Induces Retinoic Acid-inducible Gene-I and Melanoma Differentiation-associated Gene 5 and Modulates Inflammation in Podocytes.

BACKGROUND/AIM: Viral infection often exacerbates proteinuria, which has been suggested to be due to antiviral responses of podocytes. We examined the effect of polyinosinic-polycytidylic acid (polyIC) on the expression of retinoic acid-inducible gene-I (RIG-I) and melanoma differentiation-associated gene 5 (MDA5) in differentiated human podocytes in culture. MATERIALS AND METHODS: The podocytes were treated with 2 ng/ml to 500 µg/ml of polyIC for 3 to 36 h, and also transfected with siRNA against RIG-I and MDA5. F-actin staining was performed to assess actin reorganization. RESULTS: PolyIC induced the expression of RIG-I and MDA5 in dose- and time-dependent manner, accompanied with interferon-ß (IFN-ß) and interleukin-6 (IL-6) up-regulation and actin reorganization. Temporal knockdown of RIG-I by siRNA decreased IFN-ß expression, while MDA5 siRNA inhibited IFN-ß and IL-6 expression. Actin reorganization was attenuated by RIG-I and MDA5 knockdown. CONCLUSION: RIG-I and MDA5 may play a role in the antiviral responses of podocytes.

Clinical impact of complete atrioventricular block in patients with ST-segment elevation myocardial infarction.

Complete atrioventricular block (CAVB) is a common complication of ST-segment elevation myocardial infarction (STEMI). Although STEMI patients complicated with CAVB had a higher mortality in the thrombolytic era, little is known about the impact of CAVB on STEMI patients who underwent primary percutaneous coronary intervention (PCI). The study aimed at evaluating the clinical impact of CAVB on STEMI patients in the primary PCI era. We consecutively enrolled 1295 STEMI patients undergoing primary PCI within 24 hours from onset. Patients were divided into two groups according to the infarct location: anterior STEMI (n = 640) and nonanterior STEMI (n = 655). The outcomes were all-cause death and major adverse cardiocerebrovascular events (MACCE) with a median follow-up period of 3.8 (1.7-6.6) years. Eighty-one patients (6.3%) developed CAVB. The incidence of CAVB was lower in anterior STEMI patients than in nonanterior STEMI (1.7% vs 10.7%, p < .05). Anterior STEMI patients with CAVB had a higher incidence of all-cause deaths (82% vs 20%, p < .05) and MACCE (82% vs 25%, p < .05) than those without CAVB. Although higher incidence of all-cause deaths was found more in nonanterior STEMI patients with CAVB compared with those without CAVB (30% vs 18%, p < .05), there was no significant difference in the incidence of MACCE (24% vs 19%). Multivariate analysis showed that CAVB was an independent predictor for all-cause mortality and MACCE in anterior STEMI patients, but not in nonanterior STEMI. CAVB is rare in anterior STEMI patients, but remains a poor prognostic complication even in the primary PCI era.

Clinical Outcomes of Acute Myocardial Infarction Patients With a History of Malignant Tumor.

BACKGROUND: Little is known about the clinical outcomes of acute myocardial infarction (AMI) in patients with a history of malignant tumor (MT). PATIENTS AND METHODS: We retrospectively studied 1,295 consecutive patients with AMI who underwent primary percutaneous coronary intervention within 24 hours of onset. The patients were divided into two groups: those with a history of MT (MT group, n=50) and those without (non-MT group, n=1,245). RESULTS: The MT group was older, and had lower hemoglobin, total protein, and albumin levels. All-cause mortality and re-admission rates due to acute decompensated heart failure (ADHF) were significantly higher in the MT group. Multivariate analysis showed that a history of MT was an independent predictor for all-cause mortality and re-admission due to ADHF. CONCLUSION: The clinical outcomes of patients with AMI with a history of MT are poor, and a history of MT is an independent predictor for all-cause mortality and re-admission due to ADHF. These patients may need careful risk management for heart failure to avoid re-admissions due to ADHF.

Blockade of PAR-1 Signaling Attenuates Cardiac Hypertrophy and Fibrosis in Renin-Overexpressing Hypertensive Mice.

Background Although PAR-1 (protease-activated receptor-1) exerts important functions in the pathophysiology of the cardiovascular system, the role of PAR-1 signaling in heart failure development remains largely unknown. We tested the hypothesis that PAR-1 signaling inhibition has protective effects on the progression of cardiac remodeling induced by chronic renin-angiotensin system activation using renin-overexpressing hypertensive (Ren-Tg) mice. Methods and Results We treated 12- to 16-week-old male wild-type (WT) mice and Ren-Tg mice with continuous subcutaneous infusion of the PAR-1 antagonist SCH79797 or vehicle for 4 weeks. The thicknesses of interventricular septum and the left ventricular posterior wall were greater in Ren-Tg mice than in WT mice, and SCH79797 treatment significantly decreased these thicknesses in Ren-Tg mice. The cardiac fibrosis area and monocyte/macrophage deposition were greater in Ren-Tg mice than in WT mice, and both conditions were attenuated by SCH79797 treatment. Cardiac mRNA expression levels of PAR-1, TNF-α (tumor necrosis factor-α), TGF-ß1 (transforming growth factor-ß1), and COL3A1 (collagen type 3 α1 chain) and the ratio of ß-myosin heavy chain (ß-MHC) to α-MHC were all greater in Ren-Tg mice than in WT mice; SCH79797 treatment attenuated these increases in Ren-Tg mice. Prothrombin fragment 1+2 concentration and factor Xa in plasma were greater in Ren-Tg mice than in WT mice, and both conditions were unaffected by SCH79797 treatment. In isolated cardiac fibroblasts, both thrombin and factor Xa enhanced ERK1/2 (extracellular signal-regulated kinase 1/2) phosphorylation, and SCH79797 pretreatment abolished this enhancement. Furthermore, gene expression of PAR-1, TGF-ß1, and COL3A1 were enhanced by factor Xa, and all were inhibited by SCH79797. Conclusions The results indicate that PAR-1 signaling is involved in cardiac remodeling induced by renin-angiotensin system activation, which may provide a novel therapeutic target for heart failure.