Efficacy of CHA2DS2-VASc scores in predicting chronic kidney disease risk in patients treated in cardiac intensive care units.

The CHA2DS2 -VASc score is a vital clinical tool for evaluating thromboembolic risk in patients with atrial fibrillation (AF). This study investigated the efficacy of the CHA2DS2 -VASc score in a cohort of 737 heterogeneous patients (mean age: 63 years) receiving care in cardiac intensive care units (CICUs), with a creatinine-based estimated glomerular filtration rate (eGFR) of ≥60 mL/min/1.73 m2 upon admission and discharge. Incident chronic kidney disease (CKD) was defined as the emergence of a new-onset eGFR<60 mL/min/1.73 m2, accompanied by a decline of >5 mL/min/1.73 m2 compared to that at discharge. The primary endpoint was the incidence of CKD, and the secondary endpoints included all-cause mortality, cardiovascular events, and progression to end-stage kidney disease. In this cohort, 210 (28 %) patients developed CKD. Multivariate analyses revealed that CHA2DS2 -VASc score was a significant independent predictor of incident CKD, regardless of the presence of AF. Integration of CHA2DS2 -VASc scores with eGFR enhanced the predictive accuracy of incident CKD, as evidenced by the improved C-index, net reclassification improvement, and integrated discrimination improvement values (all p < 0.05). Over the 12-month follow-up period, a composite endpoint was observed in 61 patients (8.3 %), with elevated CHA2DS2 -VASc scores being independently associated with this endpoint. In conclusion, CHA2DS2-VASc scores have emerged as robust predictors of both CKD incidence and adverse outcomes. Their inclusion substantially refined the 12-month risk stratification of patients with preserved renal function hospitalized in the CICUs.

Renal dysfunction is a time-varying risk predictor of sudden cardiac death in heart failure.

AIMS: Sudden cardiac death (SCD) is a common mode of death in patients with congestive heart failure (CHF). Implantable cardioverter defibrillator (ICD) implantation is established treatment for SCD prevention, but current eligibility criteria based on left ventricular ejection fraction (LVEF) and New York Heart Association (NYHA) functional class may be due for reconsideration given the increasing effectiveness of pharmacological therapy. We sought to reconsider the risk stratification of SCD in patients with symptomatic CHF. METHODS: In total, 1,676 consecutive patients (74 ± 13 years old; 56% male) with NYHA class II or III CHF between 2008 and 2015 were enrolled for this prospective study. The endpoint was SCD. RESULTS: During a median (interquartile range) follow-up period of 25 (4-70) months, 198 (11.8%) patients suffered SCD. Of those events, 23% occurred within 3 months of discharge. In the adjusted analyses, estimated glomerular filtration rate (eGFR) < 30 ml/min/1.73 m2 [hazard ratio (HR) 1.73, 95% confidence interval (CI) 1.11-2.70, P = 0.01] and LVEF ≤ 35% (HR 2.31, 95% CI 1.47-3.66, P < 0.01) were independent risk predictors of SCD. Addition of eGFR to LVEF significantly improved prediction of SCD in the C-index (P = 0.04), and in two metrics, net reclassification improvement (P = 0.01) and integrated discrimination improvement (P = 0.03). The predictive power of eGFR declined time-dependently over 2 years. CONCLUSIONS: The addition of eGFR to current eligibility criteria may be useful for risk assessment of SCD, although its predictive power wanes over time. Roughly a quarter of the SCD occurred within 3 months after discharge in patients with CHF.

Resting echocardiographic parameters to detect patients with less symptomatic primary mitral regurgitation who require exercise stress echocardiography.

Objectives: We aimed to identify which resting echocardiographic parameters can detect asymptomatic or mildly symptomatic patients with primary mitral regurgitation (MR) who require exercise stress echocardiography (ESE) to determine their suitability for surgery. Methods: We examined 56 consecutive patients with primary moderate/severe MR who underwent ergometer-based ESE. Patients who met the surgical indications at rest were excluded. Eligible patients were divided into Group I (pulmonary artery systolic pressure [PASP] during exercise >60 mmHg; n=11) and Group II (PASP during exercise ≤60 mmHg; n=30). Results: Forty-one patients were included. Group I was significantly older (65±12 vs. 54±14 years, P=0.042) and had significantly higher serum N-terminal pro-B-type natriuretic peptide concentrations than Group II (351±278 vs. 125±163 pg/mL, P=0.002). The univariate analysis demonstrated that peak E wave velocity (Group I vs. Group II: 125±45 vs. 101±24 cm/sec, P=0.050), left ventricular (LV) end-diastolic diameter index (32±4 vs. 30±3 mm/m2, P=0.035), and left atrial volume index (LAVI; 45±14 vs. 30±11 mL/m2, P=0.008) were predictors of increased PASP during exercise. In the multivariate analysis, resting LAVI best predicted exercise-induced pulmonary hypertension (hazard ratio 1.081 [95% confidence interval 1.009-1.158], P=0.028), with a cutoff value of 37 mL/m2. Conclusions: In asymptomatic or mildly symptomatic patients with primary moderate/severe MR, increased resting LAVI indicates the requirement for ESE, even without LV dilatation.

Resting echocardiographic parameters can exclude significant coronary artery disease: A comparison with coronary computed tomography angiography.

INTRODUCTION: Coronary computed tomography angiography (CCTA) is known to have a high negative predictive value (NPV) in identifying coronary artery disease (CAD). This study aimed to examine whether resting echocardiographic parameters could exclude significant CAD on CCTA. METHODS: We recruited 142 patients who had undergone both CCTA and echocardiography within a 3-month window. Based on the CCTA findings, patients were divided into two groups: Group A (non-significant CAD, defined as all coronary segments having <50% stenosis) and Group B (significant CAD). Resting echocardiographic parameters were compared between the two groups to identify predictors of non-significant CAD on CCTA. RESULTS: A total 92 patients (mean age, 68 ± 13 years; males, 62%) were eligible for this study; 50 in Group A and 42 in Group B. Among the various echo parameters, left atrial volume index (LAVI) and left ventricular (LV) global longitudinal strain (GLS) were significantly lower in Group A (23.5 ± 7.6 vs. 33.6 ± 7.4 mL/m2 , p < .001; -20.2 ± 1.8% vs. -16.8 ± 2.0%, p < .001, respectively). Analysis of the receiver operating characteristic curve revealed that the cutoff value to exclude significant CAD on CCTA was 29.0 mL/m2 for LAVI (NPV 80.8%) and -18.1% for GLS (NPV 80.7%). The NPV increased to 95.0% when these parameters were combined (LAVI < 29.0 mL/m2 and GLS < -18.1%). CONCLUSION: The combination of resting LAVI and GLS was clinically useful in excluding significant CAD via CCTA.

Differences in Prognosis and Cardiac Function According to Required Percutaneous Mechanical Circulatory Support and Histological Findings in Patients With Fulminant Myocarditis: Insights From the CHANGE PUMP 2 Study.

Background Prognoses and long-term cardiac function of patients with fulminant myocarditis have not been fully elucidated. Therefore, we clarified the prognoses and long-term cardiac function according to required percutaneous mechanical circulatory support and histological findings among patients with fulminant myocarditis. Methods and Results We conducted a multicenter retrospective medical record review of 216 patients with fulminant myocarditis requiring percutaneous mechanical circulatory support. Sixty-one patients were treated with intra-aortic balloon pump or Impella alone, and 155 patients received veno-arterial extracorporeal membrane oxygenation and were treated with or without intra-aortic balloon pump or Impella. Histologically, 107 patients had lymphocytic myocarditis; 34, eosinophilic myocarditis; and 4, giant cell myocarditis. Freedom from composite end point (death, durable left ventricular assist device implantation, and heart transplantation) was 66% at 90 days, 62% at 1 year, and 57% at 6 years. Veno-arterial extracorporeal membrane oxygenation use was associated with poor prognosis in the multivariable analysis (hazard ratio [HR], 5.27; 95% CI, 1.60-17.36). The eosinophilic myocarditis subgroup showed better prognosis (HR, 0.28; 95% CI, 0.10-0.80) compared with the lymphocytic myocarditis subgroup but not in the multivariable analysis. Ventricular tachycardia/ventricular fibrillation rhythm at admission, high C-reactive protein level, and no endomyocardial biopsy were also associated with poor prognosis. The left ventricular ejection fraction at 1 year was ≤50% in 16% of patients and was lower in patients with eosinophilic myocarditis (median: 57.9% [48.8-65.0%]) than in those with lymphocytic myocarditis (65.0% [58.6-68.7%]) (P=0.036). Conclusions Patients with fulminant myocarditis who received veno-arterial extracorporeal membrane oxygenation had a poor prognosis. Long-term cardiac function was impaired in some patients, especially those with eosinophilic myocarditis.

Prognostic score based on physical frailty in patients with heart failure: a multicenter prospective cohort study (FLAGSHIP).

BACKGROUND: In patients with heart failure (HF), physical frailty should be assessed to enable risk stratification. No conventional frailty criteria have so far been developed considering HF-specific outcomes. This study aimed to propose a frailty-based prognostic score using a nationwide cohort study of Japanese patients with HF. METHODS: We analysed 2721 patients hospitalized for HF and capable of walking at discharge (median age: 76 years [interquartile range 67-83], men: 60.5%). Physical frailty was evaluated at discharge using four quantitative measures: usual walking speed, grip strength, Performance Measure for Activities of Daily Living-8 (PMADL-8), and Self-Efficacy for Walking-7 (SEW-7). The primary outcome was a composite of HF rehospitalization and all-cause mortality within 2 years. A cut-off point was identified for each measure using receiver operating characteristic analysis in a derivation cohort (n = 1778). Cox proportional hazards model was used to assign a score to each frailty domain according to the correlation with the endpoint. Patients were divided into four categories according to the sum score, and survival was compared by analysing the Kaplan-Meier curve and Cox proportional hazards model. Cumulative incidences of the events according to frailty categories were compared between the derivation cohort and a validation cohort (n = 943). RESULTS: The cut-off value and assigned score of each indicator was determined as follows: usual walking speed < 0.98 m/s = 4 points; grip strength < 30.0 kg (men) or 17.5 kg (women) = 5 points; PMADL-8 ≥ 21 points = 2 points; SEW-7 ≤ 20 points = 3 points. We stratified patients into four categories according to the sum score: Category I, ≤3 points; Categories II, 4-8 points; Category III, 9-13 points; and Category IV, 14 points. The prevalence and cumulative incidence of the composite outcome for Categories I to IV in the derivation cohort were 27.4%, 25.2%, 26.4%, and 21.0%, and 9.5, 16.3, 26.3, and 36.8/100 person-years, respectively. Similar results were confirmed in the validation cohort. In Cox proportional hazards model, frailty categories were associated with the composite outcome independent of potential confounders (hazard ratio [95% confidence interval] in reference to Category I: Categories II, 1.51 [0.84-2.72], P = 0.169; Category III, 2.37 [1.32-4.23], P = 0.004; Category IV, 2.66 [1.45-4.89], P = 0.002). CONCLUSIONS: The frailty-based prognostic score proposed in this study was well associated with prognosis and will serve for risk stratification in patients with HF.

Activation of cardiac sarcoidosis associated with development of gastric cancer: a case report.

BACKGROUND: The high 18F-fluorodeoxyglucose (FDG) uptake in sarcoidosis lesions reflects infiltration of inflammatory cells such as macrophages. An increased incidence of cancer in patients with sarcoidosis has been suggested, and some combination of the following mechanisms has been proposed: chronic inflammation, immune dysfunction, shared aetiologic agents, and genetic susceptibility to both cancer and autoimmune diseases. CASE SUMMARY: A 73-year-old man was admitted to our hospital due to effort dyspnoea. Initial investigations showed complete atrioventricular block on electrocardiography, basal thinning of the interventricular septum, and preserved left ventricular (LV) systolic function on echocardiography, and late gadolinium enhancement (LGE) in all layers of the basal interventricular septum on cardiac magnetic resonance imaging. FDG positron emission tomography/computerized tomography (FDG-PET/CT) showed no abnormal uptake in the whole-body including myocardium. After discussion, corticosteroid was not initiated then. One year later, he developed stomach adenocarcinoma. Repeated investigations demonstrated enlargement of the LV (LV diastolic diameter 63 mm) and diffuse systolic impairment of LV function (LV ejection fraction 31%) on echocardiography, and abnormal focal uptake at the lateral walls of LV and hilar lymph nodes on FDG-PET/CT imaging. One more year after the surgery for gastric cancer and corticosteroid initiation, echocardiography showed recovery of systolic function and FDG-PET/CT showed no uptake in either the myocardium or hilar lymph nodes. DISCUSSION: In the present case, it is speculated that the first inflammation which left scarred areas showing LGE was already completed before the first FDG-PET/CT. The development of gastric cancer may be associated with the reactivation of cardiac sarcoidosis.

Significant association of RNF213 p.R4810K, a moyamoya susceptibility variant, with coronary artery disease.

BACKGROUND: The genetic architecture of coronary artery disease has not been fully elucidated, especially in Asian countries. Moyamoya disease is a progressive cerebrovascular disease that is reported to be complicated by coronary artery disease. Because most Japanese patients with moyamoya disease carry the p.R4810K variant of the ring finger 213 gene (RNF213), this may also be a risk factor for coronary artery disease; however, this possibility has never been tested. METHODS AND RESULTS: We genotyped the RNF213 p.R4810K variant in 956 coronary artery disease patients and 716 controls and tested the association between p.R4810K and coronary artery disease. We also validated the association in an independent population of 311 coronary artery disease patients and 494 controls. In the replication study, the p.R4810K genotypes were imputed from genome-wide genotyping data based on the 1000 Genomes Project. We used multivariate logistic regression analyses to adjust for well-known risk factors such as dyslipidemia and smoking habits. In the primary study population, the frequency of the minor variant allele was significantly higher in patients with coronary artery disease than in controls (2.04% vs. 0.98%), with an odds ratio of 2.11 (p = 0.017). Under a dominant model, after adjustment for risk factors, the association remained significant, with an odds ratio of 2.90 (95% confidence interval: 1.37-6.61; p = 0.005). In the replication study, the association was significant after adjustment for age and sex (odds ratio = 4.99; 95% confidence interval: 1.16-21.53; p = 0.031), although it did not reach statistical significance when further adjusted for risk factors (odds ratio = 3.82; 95% confidence interval: 0.87-16.77; p = 0.076). CONCLUSIONS: The RNF213 p.R4810K variant appears to be significantly associated with coronary artery disease in the Japanese population.

Impact of circulating cathepsin K on the coronary calcification and the clinical outcome in chronic kidney disease patients.

Chronic kidney disease (CKD) is a cause of coronary artery calcification (CAC) and an independent predictor of major adverse cardiac and cerebrovascular events (MACCE). Cathepsin K (CatK) is a lysosomal cysteine protease which affects vascular calcification and glucose metabolism disorder. We investigated the relationships among CatK, CAC, diabetes mellitus (DM) and MACCE in CKD patients. 113 consecutive CKD patients were enrolled. Their CAC was evaluated by computed tomography. Their plasma CatK level was measured by ELISA. They were divided into two groups by CatK levels and followed up for up to 3 years. The impact of CatK was analyzed in all participants, diabetic patients and non-diabetic patients. Kaplan-Meier analysis demonstrated a significant higher incidence of MACCE in the high CatK group (P = 0.028). The CatK level was significantly higher in patients with MACCE compared to that in patients without MACCE (P = 0.034). Cox's model revealed the higher plasma CatK and BNP level as independent predictors of MACCE (P = 0.043 and P < 0.01, respectively). Only in non-diabetic patients, there was a significant correlation between CatK and CAC score, and high CatK group had a significant higher level of LDL-C and LDL-C/HDL-C ratio (P < 0.05 and P < 0.001, respectively) than low CatK group. And these lipid disorders were independent predictors of CatK elevation. In CKD patients, our results indicated an impact of higher CatK level on their MACCE. The significant association among the CatK level, CAC and MACCE was found in non-diabetic CKD patients.

Epigenome-wide association study suggests that SNPs in the promoter region of RETN influence plasma resistin level via effects on DNA methylation at neighbouring sites.

AIMS/HYPOTHESIS: To investigate epigenetic regulation of the plasma concentration of resistin, we performed an epigenome-wide association study for this variable and DNA methylation (DNAm) in an elderly Japanese cohort and then assessed the relation of single nucleotide polymorphisms (SNPs) associated with the plasma resistin concentration to DNAm level at identified sites. METHODS: The association of plasma resistin level with DNAm status was examined in 191 nondiabetic elderly men with the Illumina Infinium HumanMethylation450 BeadChip array. The association between DNAm status at specific sites in the flanking region of the resistin gene (RETN) and RETN mRNA abundance was then evaluated with a public data set for 1202 monocyte samples from a multi-ethnic cohort. Finally, the association of DNAm status and SNPs in the promoter region of RETN was assessed in two cohorts comprising a total of 478 Japanese individuals. RESULTS: DNAm status at cg02346997 located in the RETN promoter region showed a negative genome-wide significant association with the plasma resistin level (p = 6.02 × 10(-10)). Four DNAm sites in the RETN promoter region including cg02346997 (p = 4.23 × 10(-70)) showed a negative genome-wide significant association with RETN mRNA abundance in monocytes. Furthermore, the number of minor alleles of the RETN promoter SNPs rs34861192 and rs3219175 was negatively associated with DNAm level at cg02346997 (p = 4.43 × 10(-17)). CONCLUSIONS/INTERPRETATION: Our results suggest that RETN promoter SNPs might influence the circulating resistin level through an effect on DNAm at cg02346997 and on RETN mRNA abundance in monocytes.

Combinational risk factors of metabolic syndrome identified by fuzzy neural network analysis of health-check data.

BACKGROUND: Lifestyle-related diseases represented by metabolic syndrome develop as results of complex interaction. By using health check-up data from two large studies collected during a long-term follow-up, we searched for risk factors associated with the development of metabolic syndrome. METHODS: In our original study, we selected 77 case subjects who developed metabolic syndrome during the follow-up and 152 healthy control subjects who were free of lifestyle-related risk components from among 1803 Japanese male employees. In a replication study, we selected 2196 case subjects and 2196 healthy control subjects from among 31343 other Japanese male employees. By means of a bioinformatics approach using a fuzzy neural network (FNN), we searched any significant combinations that are associated with MetS. To ensure that the risk combination selected by FNN analysis was statistically reliable, we performed logistic regression analysis including adjustment. RESULTS: We selected a combination of an elevated level of γ-glutamyltranspeptidase (γ-GTP) and an elevated white blood cell (WBC) count as the most significant combination of risk factors for the development of metabolic syndrome. The FNN also identified the same tendency in a replication study. The clinical characteristics of γ-GTP level and WBC count were statistically significant even after adjustment, confirming that the results obtained from the fuzzy neural network are reasonable. Correlation ratio showed that an elevated level of γ-GTP is associated with habitual drinking of alcohol and a high WBC count is associated with habitual smoking. CONCLUSIONS: This result obtained by fuzzy neural network analysis of health check-up data from large long-term studies can be useful in providing a personalized novel diagnostic and therapeutic method involving the γ-GTP level and the WBC count.

Altered microRNA expression associated with reduced catecholamine sensitivity in patients with chronic heart failure.

AIMS: MicroRNAs (miRNAs) are small non-coding RNAs discovered as potential new gene regulators. Their roles in the development of chronic heart failure (CHF), however, are largely unknown. Reduced catecholamine sensitivity is an early step of CHF. We examined whether altered expression of miRNAs was related to reduced catecholamine sensitivity in patients with CHF. METHODS AND RESULTS: Maximum first derivative of left ventricular pressure (LV dP/dt(max)) at baseline and during infusion of dobutamine (10 µg kg(-1)min(-1)) were determined in 14 asymptomatic or mildly symptomatic (New York Heart Association class I or II) patients with idiopathic dilated cardiomyopathy (DCM). We performed microarray analysis for a total of 485 miRNAs using endomyocardial biopsy specimens from these 14 patients. Patients were classified into 2 groups based on a percent increase in LV dP/dt(max) by dobutamine infusion (ΔLV dP/dt(max)). These are Group I (n=7) with ΔLV dP/dt(max)>90%, and Group II (n=7) with ΔLV dP/dt(max)<90%. Out of 485 miRNAs, 32 were differentially expressed in the myocardium with reduced catecholamine sensitivity. Among those, four miRNAs were decreased and one miRNA was increased in the Group II compared to the Group I (p<0.01). LVEF measured by left ventriculography at baseline did not differ between the 2 groups. Also there were no differences in plasma norepinephrine levels between the 2 groups. CONCLUSIONS: Altered expression of several miRNAs was related to the reduced catecholamine sensitivity in mildly symptomatic patients with DCM. These findings shed light on the potential of miRNAs to provide possible etiologic insights as well as therapeutic targets for CHF.

Comparison of tissue characteristics between acute coronary syndrome and stable angina pectoris. An integrated backscatter intravascular ultrasound analysis of culprit and non-culprit lesions.

BACKGROUND: Patients with acute coronary syndrome (ACS) have multiple complex coronary plaques associated with plaque vulnerability. The present study assessed the tissue characteristics of coronary plaques between ACS and stable angina pectoris (SAP) of culprit and non-culprit lesions using integrated backscatter intravascular ultrasound (IB-IVUS). METHODS AND RESULTS: IVUS was performed in 165 patients (40 patients with ACS) with 225 culprit (65 lesions in ACS) and 171 non-culprit lesions (42 lesions in ACS). The percentage of fibrous area (fibrous area/plaque area, %FIB) and the percentage of lipid area (lipid area/plaque area, %LIP) at the segment with minimal luminal area were calculated using IB-IVUS system. Culprit and non-culprit lesions with ACS showed a significant increase in %LIP (38±18 vs. 30±15%, P=0.002, and 38±21 vs. 32±17%, P=0.03, respectively) and a significant decrease in %FIB (59±15 vs. 63±12 %, P=0.04, and 57±18 vs. 62±14%, P=0.04, respectively) compared to those with SAP. On logistic regression analysis, not only culprit lesions but also non-culprit lesions with ACS patients were significantly associated with the lipid-rich plaque. CONCLUSIONS: Non-culprit coronary lesions with ACS patients are associated with the lipid-rich plaque, suggesting the extensive development of plaques instability in these patients.

Cumulative episodes of rejection altered myocardial sarcoplasmic reticulum Ca(2+)-ATPase and ryanodine receptor-2 mRNA expression in heart transplant recipients.

The aim of the present study was to investigate the relationship between rejections and gene expression of Ca(2+)-handling proteins in heart transplant recipients. Thirty-seven heart transplant recipients underwent routine endomyocardial biopsy. Levels of sarcoplasmic reticulum Ca(2+)-ATPase (SERCA2) and ryanodine receptor-2 mRNAs in endomyocardial tissue were quantified by a real-time quantitative reverse transcription polymerase chain reaction (RT-PCR) method. Rejections were diagnosed according to the conventional International Society for Heart and Lung Transplantation criteria. Patients were classified as follows; group AR(+) (n = 9) with rejection grade of 2 or higher versus group AR(-) (n = 28) with rejection grade of 0, 1a or 1b at the time of biopsy, and group Rec-AR(+) (n = 6) with a history of more than 4 episodes of treatment required rejection versus group Rec-AR(-) (n = 31) without history of recurrent rejection. The mRNA levels of the SERCA2/GAPDH ratio and ryanodine receptor-2/GAPDH ratio were not different between group AR(+) and group AR(-); however, they were reduced in group Rec-AR(+) more than in group Rec-AR(-) (0.83 +/- 0.07 versus 0.90 +/- 0.07, P = 0.034, 0.74 +/- 0.06 versus 0.84 +/- 0.10, P = 0.027, respectively). A single episode of on-going rejection would not affect myocardial Ca(2+)-handling proteins; however, cumulative rejection episodes might alter the gene expression of myocardial Ca(2+)-handling proteins in heart transplant recipients.

Dobutamine-induced mechanical alternans is a marker of poor prognosis in idiopathic dilated cardiomyopathy.

1. To date, few prognostic indicators for ambulatory patients with idiopathic dilated cardiomyopathy (IDCM) have been identified. The purpose of the present study was to investigate the relationship between the occurrence of dobutamine-induced mechanical alternans (MA) and prognosis in ambulatory patients with IDCM. 2. Left ventricular pressure was measured during right atrial pacing and after intravenous infusion of dobutamine at incremental doses in 90 ambulatory patients with IDCM in sinus rhythm. Endomyocardial biopsy specimens were also obtained for quantitative analysis of gene expression. The patients were followed up for a mean of 2.5 years. 3. Patients were classified into three groups: (i) 60 patients who exhibited neither pacing- nor dobutamine-induced MA (Group N); (ii) 20 patients who manifested only pacing-induced MA (Group P); and (iii) 10 patients who developed both pacing- and dobutamine-induced MA (Group D). The sarcoplasmic/endoplasmic reticulum calcium ATPase 2a:phospholamban mRNA ratio was significantly higher in Group D patients than in patients in Groups N or P. Multivariate analysis revealed that dobutamine-induced MA (odds ratio 4.05; 95% confidence interval 1.35-12.2) was a significant independent predictor of cardiac events. Cardiac event-free survival in Group D was significantly lower than in Groups N or P, as determined by Kaplan-Meier analysis (P=0.002). 4. The occurrence of dobutamine-induced MA is a potentially useful clinical predictor of poor prognosis in ambulatory patients with IDCM in sinus rhythm.

Mutation of ARHGAP9 in patients with coronary spastic angina.

Coronary artery spasm has an important function in the etiology of variant angina and other acute coronary syndromes. Abnormal activation of Rho-family GTPases has been observed in cardiovascular disorders, but the function of genetic variability in Rho-family GTPases remains to be evaluated in cardiovascular disorders. We examined the genetic variability of Rho-family GTPases and their regulators in coronary artery spasm. We performed a comprehensive candidate gene analysis of 67 single nucleotide polymorphisms with amino-acid substitution in Rho-family GTPases and their regulators in 103 unrelated Japanese patients with acetylcholine-induced coronary artery spasm and 102 control Japanese subjects without acetylcholine-induced coronary artery spasm. We noted an association of the single nucleotide polymorphism of ARHGAP9 (rs11544238, Ala370Ser) with coronary artery spasm (odds ratio =2.67). We found that ARHGAP9 inactivated Rac as RacGAP and that the mRNA level of ARHGAP9 was strongly detected in hematopoietic cells. ARHGAP9 negatively regulated cell migration. The Ala370Ser polymorphism counteracted ARHGAP9-reduced cell migration, spreading and adhesion. The Ala370Ser polymorphism in the ARHGAP9 gene is associated with coronary artery spasm. These data suggest that the polymorphism of ARHGAP9 has a critical function in the infiltration of hematopoietic cells into the endothelium and inflammation leading to endothelial dysfunction.

Long-term administration of nifedipine attenuates cardiac remodeling and diastolic heart failure in hypertensive rats.

The Ca2+ channel blocker nifedipine has been reported to reduce the rate of new overt heart failure. We investigated the effects of nifedipine on left ventricular remodeling, oxidative stress, and gene expression in the failing heart of Dahl salt-sensitive (DS) rats. DS rats fed a high-salt diet from 7 weeks of age were treated with a non-antihypertensive (1 mg/kg per day, Nif-L) or mild-antihypertensive dose of nifedipine (3 mg/kg per day, Nif-H) or with vehicle (Vehicle) from 12 to 19 weeks. Marked left ventricular hypertrophy and fibrosis were apparent and the ratio of collagen type I to type III mRNA levels and the activity of matrix metalloproteinase (MMP)-2 and its mRNA expression in the myocardium were increased in Vehicle at 19 weeks in comparison with Control. Load-induced left ventricular hypertrophy was reduced in Nif-H, but not in Nif-L, relative to that in Vehicle. Treatment with either dose of nifedipine reduced the extent of fibrosis, the collagen type I to type III mRNA ratio, and MMP-2 activity and its mRNA expression compared with those in Vehicle. The decrease in the ratio of reduced to oxidized glutathione and the increase in NADPH oxidase activity apparent in the left ventricle of Vehicle were also inhibited by nifedipine at both doses. Nifedipine thus inhibited the development of left ventricular fibrosis and diastolic heart failure in DS rats, independently of its antihypertensive effect. The overall protective action of nifedipine is likely attributable to its antioxidant effect as well as to its antihypertensive action.

Relation of functional and morphological changes in mitochondria to myocardial contractile and relaxation reserves in asymptomatic to mildly symptomatic patients with hypertrophic cardiomyopathy.

AIMS: To examine the relation between mitochondrial dysfunction and myocardial contractile and relaxation reserves in hypertrophic cardiomyopathy (HCM). METHODS AND RESULTS: Thirty HCM patients (LVEF >or=60%) underwent biventricular cardiac catheterization analysis both at rest and during atrial pacing as well as myocardial (99m)Tc-sestamibi scintigraphy at rest to calculate washout rate. Endomyocardial biopsy specimens were obtained for quantitative mRNA analysis and electron microscopy. The HCM patients were divided into two groups-group A: normal force-frequency relation and a pressure half-time (T(1/2)) of <30 ms (n = 15); group B: abnormal force-frequency relation or T(1/2) of >or=30 ms (n = 15). The (99m)Tc-sestamibi washout rate was significantly correlated with T(1/2) for all patients (r = 0.74, P < 0.01) and was also significantly greater in group B (29.2 +/- 6.3%) than in group A (19.3 +/- 3.1%). The abundance of mRNAs for mitochondrial electron transport-related enzymes was significantly higher in group A than in group B. Mitochondria showed a greater variation in size and were more disorganized in group B than in group A. CONCLUSION: Mitochondria showed functional impairment and morphological disorganization in the left ventricle of HCM patients without baseline systolic dysfunction. These mitochondrial changes were associated with impaired myocardial contractile and relaxation reserves.

Dobutamine stress testing as a diagnostic tool for evaluation of myocardial contractile reserve in asymptomatic or mildly symptomatic patients with dilated cardiomyopathy.

OBJECTIVES: We performed dobutamine stress testing for evaluation of myocardial contractile reserve in asymptomatic or mildly symptomatic patients with dilated cardiomyopathy (DCM). BACKGROUND: Catecholamine sensitivity is reduced in failing hearts as a result of myocardial abnormalities in the beta-adrenergic receptor signaling pathway. However, little is known about adrenergic myocardial contractile reserve in asymptomatic or mildly symptomatic patients with DCM. METHODS: The maximal first derivative of left ventricular pressure (LV dP/dt(max)) was determined during infusion of dobutamine (10 microg kg(-1) min(-1)) in 46 asymptomatic or mildly symptomatic (New York Heart Association functional class I or II) patients with DCM. The expression of messenger ribonucleic acid (mRNA) for contractile regulatory proteins in endomyocardial biopsy specimens was quantified by reverse transcription and real-time polymerase chain reaction analysis. Plasma norepinephrine levels were measured in all patients and [(123)I]metaiodobenzylguanidine (MIBG) scintigraphy performed. RESULTS: Patients were classified into 3 groups based on the percentage increase in LV dP/dt(max) induced by dobutamine (DeltaLV dP/dt(max)) and on LV ejection fraction (LVEF) at baseline: group I (n = 18): DeltaLV dP/dt(max) >100% and LVEF >25%; group IIa (n = 17): DeltaLV dP/dt(max) 25%; and group IIb (n = 11): DeltaLV dP/dt(max)