Second-Hand Smoke–Induced Cardiac Fibrosis Is Related to the Fas Death Receptor Apoptotic Pathway without Mitochondria-Dependent Pathway Involvement in Rats

Exposure to environmental tobacco smoke has been epidemiologically linked to heart disease among nonsmokers. However, the molecular mechanism behind the pathogenesis of cardiac disease is unknown. In this study, we found that Wistar rats, exposed to tobacco cigarette smoke at doses of 5, 10, or 15 cigarettes for 30 min twice a day for 1 month, had a dose-dependently reduced heart weight to body weight ratio and enhanced interstitial fibrosis as identified by histopathologic analysis. The mRNA and activity of matrix metalloprotease-2 (MMP-2), representing the progress of cardiac remodeling, were also elevated in the heart. In addition, we used reverse-transcriptase polymerase chain reaction and Western blotting to demonstrate significantly increased levels of the apoptotic effecter caspase-3 in treated animal hearts. Dose-dependently elevated mRNA and protein levels of Fas, and promoted apoptotic initiator caspase-8 (active form), a molecule of a death-receptor–dependent pathway, coupled with unaltered or decreased levels of cytosolic cytochrome c and the apoptotic initiator caspase-9 (active form), molecules of mitochondria-dependent pathways, may be indicative of cardiac apoptosis, which is Fas death-receptor apoptotic-signaling dependent, but not mitochondria pathway dependent in rats exposed to second-hand smoke (SHS). With regard to the regulation of survival pathway, using dot blotting, we found cardiac insulin-like growth factor-1 (IGF-1) and IGF-1 receptor mRNA levels to be significantly increased, indicating that compensative effects of IGF-1 survival signaling could occur. In conclusion, we found that the effects of SHS on cardiomyocyte are mediated by the Fas death-receptor–dependent apoptotic pathway and might be related to the epidemiologic incidence of cardiac disease of SHS-exposed non-smokers

An Eight-Week, Multicenter, Randomized, Double-Blind Study to Evaluate the Efficacy and Tolerability of Fixed-Dose Amlodipine/Benazepril Combination in Comparison with Amlodipine as First-Line Therapy in Chinese Patients with Mild to Moderate Hypertension

AIMS: This study sought to compare the antihypertensive efficacy and tolerability of a fixed-dose combination with amlodipine/benazepril with that of amlodipine monotherapy in Chinese hypertensive subjects. RESULTS: This multicenter, double-blind, 8-week study randomized 111 patients to fixed- dose amlodipine besylate/benazepril HCl (2.5/5 mg/day titrated to 5 /10 mg/day as needed at week 4 to reach goal blood pressure (BP) <140/90 mmHg) or amlodipine besylate monotherapy (5 mg/day titrated to 10 mg/day as needed). At week 8, patients randomized to combination therapy compared with monotherapy had a comparable BP control rate (56.0% vs. 46.2%; p = 0 .32). Fixed-dose combination resulted in similar reductions in sitting systolic (SBP) and diastolic BP (DBP) compared with monotherapy (SBP: -19. 3 +/- 12.5 vs.- 20.9 +/- 13.3 mmHg; DBP: -9.2 +/- 10.4 vs. -11.3 +/-9.3 mmHg; both p=NS). Safety profiles did not differ between groups, but cough was more common in the combination group ( 11.0% vs. 0%; p = 0.013). CONCLUSIONS: In this group of patients, comparable antihypertensive effects were seen with the fixed-dose combination therapy, compared with amlodipine monotherapy. Both treatments appeared well tolerated in the studied population, but cough was more common in the fixed- dose combination group

Long-Term Prognosis of Febrile Individuals with Right Precordial Coved-Type ST-Segment Elevation Brugada Pattern: A 10-Year Prospective Follow-Up Study

A febrile state may provoke a Brugada electrocardiogram (ECG) pattern and trigger ventricular tachyarrhythmias in susceptible individuals. However, the prognostic value of fever-induced Brugada ECG pattern remains unclear. We analyzed the clinical and extended long-term follow-up data of consecutive febrile patients with a type 1 Brugada ECG presented to the emergency department. A total of 21 individuals (18 males; mean age, 43.7 ± 18.6 years at diagnosis) were divided into symptomatic (resuscitated cardiac arrest in one, syncope in two) and asymptomatic (18, 86%) groups. Sustained polymorphic ventricular tachycardias were inducible in two patients with previous syncope. All 18 asymptomatic patients had no spontaneous type 1 Brugada ECG recorded at second intercostal space and no family history of sudden death. Among asymptomatic individuals, 4 had a total 12 of repeated non-arrhythmogenic febrile episodes all with recurrent type 1 Brugada ECGs, and none had a ventricular arrhythmic event during 116 ± 19 months of follow-up. In the symptomatic group, two had defibrillator shocks for a new arrhythmic event at 31- and 49 months follow-up, respectively, and one without defibrillator therapy died suddenly at 8 months follow-up. A previous history of aborted sudden death or syncope was significantly associated with adverse outcomes in symptomatic compared with asymptomatic individuals (log-rank p &lt; 0.0001). In conclusion, clinical presentation or history of syncope is the most important parameter in the risk stratification of febrile patients with type 1 Brugada ECG. Asymptomatic individuals with a negative family history of sudden death and without spontaneous type 1 Brugada ECG, have an exceptionally low future risk of arrhythmic events. Careful follow-up with timely and aggressive control of fever is an appropriate management option

Relationship of Genetic Polymorphisms of the Chemokine, CCL5, and Its Receptor, CCR5, with Coronary Artery Disease in Taiwan

The chemokine receptor CCR5 polymorphism, which confers resistance to HIV infection, has been associated with reduced risk of cardiovascular disease. However, the association of the chemokine, CCL5, and its receptor, CCR5, polymorphism and coronary artery disease (CAD) in the Taiwanese has not been studied. In this study, 483 subjects who received elective coronary angiography were recruited from Chung Shan Medical University Hospital. CCL5-403 and CCR5-59029 were determined by polymerase chain reaction-restriction fragment length polymorphism. We found that CCL5-403 with TT genotype frequencies was significantly associated with the risk of CAD group (odds ratio = 3.063 and p=0.012). Moreover, the frequencies of CCR5-59029 with GG or GA genotype were higher than AA genotype in acute coronary syndrome individuals (odds ratio = 1.853, CI = 1.176–2.921, p=0.008). In conclusion, we found that CCL5-403 polymorphism may increase genetic susceptibility of CAD. CCL5-403 or CCR5-59029 single nucleotide polymorphism may include genotype score and it may predict cardiovascular event

MicroRNA Let-7a, -7e and -133a Attenuate Hypoxia-Induced Atrial Fibrosis via Targeting Collagen Expression and the JNK Pathway in HL1 Cardiomyocytes

Fibrosis is a hallmark of atrial structural remodeling. The main aim of this study was to investigate the role of micro-ribonucleic acids (miRNAs) in the modulation of fibrotic molecular mechanisms in response to hypoxic conditions, which may mediate atrial fibrosis. Under a condition of hypoxia induced by a hypoxia chamber, miRNA arrays were used to identify the specific miRNAs associated with the modulation of fibrotic genes. Luciferase assay, real-time polymerase chain reaction, immunofluorescence and Western blotting were used to investigate the effects of miRNAs on the expressions of the fibrotic markers collagen I and III (COL1A, COL3A) and phosphorylation levels of the stress kinase c-Jun N-terminal kinase (JNK) pathway in a cultured HL-1 atrial cardiomyocytes cell line. COL1A and COL3A were found to be the direct regulatory targets of miR-let-7a, miR-let-7e and miR-133a in hypoxic atrial cardiac cells in vitro. The expressions of COL1A and COL3A were influenced by treatment with miRNA mimic and antagomir while hypoxia-induced collagen expression was inhibited by the delivery of miR-133a, miR-let-7a or miR-let-7e. The JNK pathway was critical in the pathogenesis of atrial fibrosis. The JNK inhibitor SP600125 increased miRNA expressions and repressed the fibrotic markers COL1A and COL3A. In conclusion, MiRNA let-7a, miR-let-7e and miR-133a play important roles in hypoxia-related atrial fibrosis by inhibiting collagen expression and post-transcriptional repression by the JNK pathway. These novel findings may lead to the development of new therapeutic strategies

Prevalence of Metabolic Syndrome and Its Relationship with Cardiovascular Disease among Hypertensive Patients 55-80 Years of Age

Patients with metabolic syndrome (MetS) are at an increased risk for developing cardiovascular disease (CVD). This study sought to assess the prevalence of MetS, and its association with CVD in older hypertensive subjects in Taiwan. We conducted a hospital-based cross-sectional study of 3,472 hypertensive patients age 55-80 years (1,763 men, 1,709 women), from 38 sites across Taiwan from November 2005-December 2006. MetS was defined using the modified criteria of the US National Cholesterol Education Program (NCEP) Adult Treatment Panel III, and the International Diabetes Federation (IDF). CVD included a diagnosis of angina pectoris (AP), myocardial infarction (MI), congestive heart failure (CHF), and stroke. The prevalence of MetS based on the modified NCEP criteria was 73.13% (68.29% in men, 78.12% in women). Use of the revised IDF definition significantly decreased the prevalence to 54.67% (46.63% in men, 62.96% in women). Subjects with MetS defined by IDF, or both criteria, had significantly higher odds ratios (ORs) of AP, CHF and all CVD. ORs of AP, MI, stroke, CHF, and all CVD were all significantly increased in subjects with MetS based on NCEP criteria. Those patients who met the NCEP, but not the IDF criteria, had a significantly elevated OR for MI. In contrast, those who met the IDF, but not the NCEP criteria did not have a significantly elevated OR for any CVD. MetS is highly prevalent in hypertensive patients 55-80 years of age in Taiwan, particularly women. Patients with MetS defined by either criteria have significantly higher ORs for CHF, AP and all CVD than those without MetS. Accordingly, NCEP criteria seems to be more suitable than IDF criteria for estimating cardiovascular risks in this Taiwanese population

A novel procalcitonin-based score for detecting sepsis among critically ill patients.

BackgroundProcalcitonin (PCT) has been widely investigated as an infection biomarker. The study aimed to prove that serum PCT, combining with other relevant variables, has an even better sepsis-detecting ability in critically ill patients.MethodsWe conducted a retrospective cohort study in a regional teaching hospital enrolling eligible patients admitted to intensive care units (ICU) between July 1, 2016, and December 31, 2016, and followed them until March 31, 2017. The primary outcome measurement was the occurrence of sepsis. We used multivariate logistic regression analysis to determine the independent factors for sepsis and constructed a novel PCT-based score containing these factors. The area under the receiver operating characteristics curve (AUROC) was applied to evaluate sepsis-detecting abilities. Finally, we validated the score using a validation cohort.ResultsA total of 258 critically ill patients (70.9±16.3 years; 55.4% man) were enrolled in the derivation cohort and further subgrouped into the sepsis group (n = 115) and the non-sepsis group (n = 143). By using the multivariate logistic regression analysis, we disclosed five independent factors for detecting sepsis, namely, "serum PCT level," "albumin level" and "neutrophil-lymphocyte ratio" at ICU admission, along with "diabetes mellitus," and "with vasopressor." We subsequently constructed a PCT-based score containing the five weighted factors. The PCT-based score performed well in detecting sepsis with the cut-points of 8 points (AUROC 0.80; 95% confidence interval (CI) 0.74-0.85; sensitivity 0.70; specificity 0.76), which was better than PCT alone, C-reactive protein and infection probability score. The findings were confirmed using an independent validation cohort (n = 72, 69.2±16.7 years, 62.5% men) (cut-point: 8 points; AUROC, 0.79; 95% CI 0.69-0.90; sensitivity 0.64; specificity 0.87).ConclusionsWe proposed a novel PCT-based score that performs better in detecting sepsis than serum PCT levels alone, C-reactive protein, and infection probability score