Serial longitudinal changes of coronary calcified plaques with clear outer borders under intensive lipid management: insights from optical coherence tomography.

Percutaneous coronary intervention (PCI) for calcified lesions is one of the most challenging procedures related to worse clinical outcomes. To stabilize vulnerable plaques, intensive lipid management is recommended; however, the serial changes of calcified plaques under intensive lipid management are unknown. A total of 31 patients (mean age, 63 ± 10 years; men, 29 patients) who underwent PCI with intensive lipid management were retrospectively studied. We evaluated the serial longitudinal changes of calcified plaques with clear outer borders using optical coherence tomography (OCT) at two time points: at the time of PCI (baseline) and the chronic phase. The median interval from PCI to chronic phase was 287 (233-429) days. Twenty-eight patients (90.3%) had increased calcium volume at the chronic phase compared with those at baseline (2.6 [1.3-5.1] vs. 1.8 [0.7-4.3] mm2, p < 0.05), and the median increase rate of calcium volume was 27.4% at the chronic phase. According to the median increase rate of calcium volume (27.4%), patients were divided into the following two groups: rapid progression (≥ 27.4%, RP group) and non-rapid progression (< 27.4%, non-RP group). The RP group had more patients with diabetes, and diabetes was independently associated with rapid progression by multivariate analysis. Furthermore, patients with diabetes had significantly higher changes in calcium index and volume from the baseline to the chronic phase than those without diabetes. Coronary calcification progression during relatively short intervals was observed using OCT even under intensive lipid management. Diabetes was an independent predictor for rapid coronary calcification progression.

Incidence, Predictors, and Outcome Associated With Ventricular Tachycardia or Fibrillation in Patients Undergoing Primary Percutaneous Coronary Intervention for Acute Myocardial Infarction.

BACKGROUND: The characteristics and clinical outcomes associated with sustained ventricular tachycardia and fibrillation (VT/VF) in Japanese acute myocardial infarction (AMI) patients remain unknown.Methods and Results: Consecutive AMI patients (n=1,941) transferred to the Hirosaki University Hospital and treated with primary percutaneous coronary intervention (PCI) within 12 h of onset were retrospectively studied. The incidence of VT/VF during hospitalization was 8.3%, and 75% of cases occurred by the end of PCI. Independent predictors associated with VT/VF occurrence by the end of PCI and after PCI, respectively, were identified. Additionally, the differences between patients with VT and VF were examined, which revealed that the characteristics of patients and predictors for VT and VF were clearly different. Additionally, the QRS duration during VT was measured, which demonstrated the possible involvement of Purkinje fibers for VT in the acute phase of AMI. Of the patients with VT/VF, 12% required ECMO support due to refractory VT/VF despite intravenous antiarrhythmic agents such as ß-blockers, amiodarone, and nifekalant. Among the patients discharged alive, 1,690 were followed up for a mean of 3.7 years. VT/VF occurrence during hospitalization did not affect the mid-term clinical outcomes even in patients with VT. CONCLUSIONS: The results clearly indicated that VT/VF is still a serious complications of AMI. We need to identify patients at high risk of developing VT/VF for careful observation and appropriate intervention.

Association of single nucleotide polymorphisms in the NRF2 promoter with vascular stiffness with aging.

PURPOSE: Pulse wave velocity (PWV), an indicator of vascular stiffness, increases with age and is increasingly recognized as an independent risk factor for cardiovascular disease (CVD). Although many mechanical and chemical factors underlie the stiffness of the elastic artery, genetic risk factors related to age-dependent increases in PWV in apparently healthy people are largely unknown. The transcription factor nuclear factor E2 (NF-E2)-related factor 2 (Nrf2), which is activated by unidirectional vascular pulsatile shear stress or oxidative stress, regulates vascular redox homeostasis. Previous reports have shown that a SNP in the NRF2 gene regulatory region (-617C>A; hereafter called SNP-617) affects NRF2 gene expression such that the minor A allele confers lower gene expression compared to the C allele, and it is associated with various diseases, including CVD. We aimed to investigate whether SNP-617 affects vascular stiffness with aging in apparently healthy people. METHODS: Analyzing wide-ranging data obtained from a public health survey performed in Japan, we evaluated whether SNP-617 affected brachial-ankle PWV (baPWV) in never-smoking healthy subjects (n = 642). We also evaluated the effects of SNP-617 on other cardiovascular and blood test measurements. RESULTS: We have shown that not only AA carriers (n = 55) but also CA carriers (n = 247) show arterial stiffness compared to CC carriers (n = 340). Furthermore, SNP-617 also affected blood pressure indexes such as systolic blood pressure and mean arterial pressure but not the ankle brachial pressure index, an indicator of atherosclerosis. Multivariate analysis showed that SNP-617 accelerates the incremental ratio of baPWV with age. CONCLUSIONS: This study is the first to show that SNP-617 affects the age-dependent increase in vascular stiffness. Our results indicate that low NRF2 activity induces premature vascular aging and could be targeted for the prevention of cardiovascular diseases associated with aging.

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.

D-dimer and C-reactive Protein as Potential Biomarkers for Diagnosis of Trousseau's Syndrome in Patients with Cerebral Embolism.

BACKGROUND: Differentiating stroke due to Trousseau's syndrome from other types of cerebral embolism is challenging, especially in patients with occult cancer. The current study aimed to determine predicting factors and biomarkers of stroke due to Trousseau's syndrome. METHODS: This retrospective study comprised 496 consecutive patients with acute cerebral embolism, including 19, 85, 310, and, 82 patients with stroke due to Trousseau's syndrome, artery-to-artery embolism, cardioembolic stroke, and embolic stroke with undetermined source, respectively. All patients were evaluated within 72 hours of onset. The clinical characteristics, laboratory findings, and patterns on diffusion-weighted magnetic resonance imaging (DWI) were compared among the groups. RESULTS: Plasma D-dimer and C-reactive protein (CRP) levels were significantly higher in the Trousseau's syndrome than in the other causes of cerebral embolism. Multivariate analyses demonstrated that female sex, multiple lesions on DWI, high D-dimer and CRP levels, and low platelet and low brain natriuretic peptide levels were independent predictors that could distinguish Trousseau's syndrome from the other causes of cerebral embolism. The cutoff values of D-dimer and CRP to identify stroke due to Trousseau's syndrome was 2.68 µg/mL fibrinogen equivalent units and .29 mg/dL, respectively. CONCLUSIONS: The elevated D-dimer and CRP levels on admission in addition to specific clinical features may be useful for diagnosis of Trousseau's syndrome in patients with cerebral embolism.

Emerging evidence for crosstalk between Nrf2 and mitochondria in physiological homeostasis and in heart disease.

Nrf2 regulates redox homeostasis in cells by coordinately regulating a range of antioxidant enzymes and proteins. An increase in oxidative stress is one of the hallmarks of aging, and Nrf2 protein levels and activity decrease with aging. Decreased mitochondrial functions, such as decreased ATP production, also occur with aging, leading to the increased generation of reactive oxygen species (ROS) and oxidative stress. Thus, understanding the relationships between Nrf2 and the mitochondria is important for clarifying the regulatory mechanisms of aging. It is becoming clear that Nrf2 is activated in a tissue-specific manner in response to mitochondrial or NADPH oxidase-generated ROS. As the heart consists of postmitotic cells that utilize ATP produced mainly by mitochondrial oxidative phosphorylation, cardiomyocytes are equipped with highly sophisticated mitochondrial quality control mechanisms. Consistent with these findings, it has been reported that Nrf2 in the heart is regulated via a specific translational mechanism and that Nrf2 activation confers cardioprotective effects in various disease models. Thus, Nrf2 is a promising target for anti-aging strategies to combat age-related heart diseases, such as age-related cardiomyopathy.

Novel Electrocardiographic Criteria for the Diagnosis of Left Ventricular Hypertrophy in the Japanese General Population.

Although there are several diagnostic criteria for left ventricular hypertrophy (LVH), their sensitivity remains low. A recent study reported that the sum of the amplitude of the deepest S wave in any lead (SD) and the S wave in lead V4 (SV4) (SD + SV4) improved sensitivity compared with commonly used criteria. To test whether this new formula improves sensitivity in the Japanese general population, we analyzed 12-lead electrocardiograms for Japanese residents participating in the Iwaki Health Promotion Project (n = 866). Left ventricular mass was calculated by echocardiography, indicating that 156 (18%) of the study population had LVH. In receiver operating characteristic analyses, the sum of the R wave in limb lead Ι (RLΙ) and the S wave in V4 (SV4) (RLΙ + SV4) showed a higher area under the curve (AUC = 0.76) than the Sokolow-Lyon voltage criteria (0.61) and the SD + SV4 criteria (0.63), and almost the same AUC as the Cornell voltage criteria (0.74) and the Cornell product criteria (0.76). The validation study also showed similar results. The cutoff values of RLΙ + SV4 criteria were ≥1.6 mV in men and ≥1.4 mV in women with a sensitivity of 39% and a specificity of 89%, whereas the sensitivity and specificity calculated based on SD + SV4 criteria were 21% and 94%, respectively. Thus, the diagnostic criterion of RLΙ + SV4 seems to be more useful than the previous criteria for diagnosing LVH in the Japanese general population.