Vasoactive intestinal polypeptide (VIP) contributes to the regulation of coronary vasomotor tone and circulating levels of VIP have been reported to increase during acute myocardial infarction. However, the changes in VIP concentration during exercise-induced ischemia have not been studied yet. Therefore, we sought to determine whether circulating levels of VIP change during treadmill exercise testing and whether they could be used as a marker of exercise-induced myocardial ischemia. Twenty-nine subjects with definitive positive (group-I) and 20 subjects (group-II) with negative results on treadmill exercise testing were included in this study. In order to assess circulating levels of VIP, blood samples were collected in both groups before exercise, at 5 minutes of exercise, at peak exercise, and at 10 minutes in the recovery period. There were no differences between the two groups with respect to the baseline demographics of age, sex, heart rate, or blood pressure. The metabolic equivalents (METs) values, peak heart rate achieved, peak systolic-diastolic blood pressure, and exercise duration did not differ between the two groups. No significant differences were found in the circulating levels of VIP at any stage of the exercise between the two groups (10.5 ± 2.5 versus 11.0 ± 3.5 pmol/L, P = 0.5, 10.6 ± 2.3 versus 10.6 ± 3.3 pmol/L, P = 0.9, 10.9 ± 3.1 versus 11.5 ± 3.4 pmol/L, P = 0.5, and 10.7 ± 1.8 versus 11.7 ± 4.1 pmol/L, P = 0.3, respectively).
There was no relationship between the circulating level of VIP and exercise-induced myocardial ischemia, and therefore it could not be used as a marker of exercise-induced myocardial ischemia.

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Previous studies have suggested that microvascular abnormalities and endothelial dysfunction cause slow coronary flow (SCF). The objective of this study was to assess the plasma nitric oxide (NO) level and determine its role in the pathogenesis of SCF phenomenon. Thirty-six patients with SCF (group 1) and otherwise patent coronary arteries and 34 subjects with normal coronary flow (group 2) were included in the study. Coronary flow was quantified according to the TIMI Frame Count (TFC) method. Brachial artery endothelium-dependent flow-mediated dilatation (FMD) and nitroglycerin (NTG)-induced endothelium-independent dilatation were studied in both groups. In addition, plasma NO levels were measured and their contribution to FMD was determined. The sex, age, body mass index, arterial blood pressure, and heart rate distributions were similar in both groups. TFC was significantly higher in group 1 compared to group 2 for each artery. The plasma NO level was lower in patients with SCF than in control subjects (18.4 ± 4.4 versus 25.2 ± 6.3 μmol/L P = 0.001). FMD was significantly smaller in group 1 than in group 2 (4.0 ± 3.2% versus 10.6 ± 5.8%, P = 0.0001). The percent NTG-induced dilatation was similar in the two groups (16.8 ± 1.1% versus 17.1 ± 1.1%, P = 0.42). In group 1, the plasma NO level was correlated with percent of FMD. Also, the plasma NO level was inversely correlated with TFC for each artery. Reduced NO bioactivity as well as impaired FMD support the presence of endothelial damage in the pathogenesis of SCF phenomenon.

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To obtain greater insight into atrial remodeling at the molecular level we analyzed the changes in gene expression in human atrial tissue between patients with chronic atrial fibrillation (AF) and those with normal sinus rhythm (NSR). cDNA microarray analysis was used to identify genes differentially expressed during sustained AF of more than 6 months (n = 9, mean age, 45 ± 12, 6 males and 3 females) as compared to those with NSR (n = 9, mean age, 47 ± 13, 6 males and 3 females). Western blot analysis was performed to confirm the altered gene expression and to establish the changes in protein expression. DNA gel electrophoresis to establish DNA ladder formation, which was associated with apoptosis in response to chronic AF, was performed. Microscopic findings were observed via electron microscopy. In the microarray analysis, out of 8,167 candidate genes, 66 genes showed a significant change in the expression level in the patients with chronic AF, which was in contrast to those with NSR. Among those, 31 genes were consistently down-regulated and 35 up-regulated more than 2-fold. The relative amounts of the Bcl-2 and p27 in the atrial tissue were decreased and angiotensin II type 2 (AT2) receptor and p21 were increased in the patients with chronic AF as compared to those with NSR. The atrial cardiomyocytes in chronic AF showed a prominent DNA ladder, which is a biochemical hallmark of apoptosis. The expression of Bcl-2, AT2 receptor, p21, and p27 were consistent with a significant role in the apoptosis of cardiac myocytes in the patients with chronic AF.

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Inflammation and genetics may play a role in the pathogenesis of rheumatic heart disease (RHD). The aim of this study was to test whether interleukin (IL)-1β, IL-1 receptor antagonist (IL-1Ra), IL-4, or IL-10 gene polymorphisms could be used as markers of susceptibility to or severity of RHD among the Chinese population in Taiwan.
A group of 115 patients with RHD diagnosed by echocardiography, and 163 age- and sex-matched normal control subjects were studied. IL-1β promoter, IL-1β exon 5, IL-1Ra, IL-4 promoter, IL-4 intron 3, and IL-10 gene polymorphisms were identified by polymerase chain reaction-based restriction analysis.
There was no significant difference in the distribution of genotypes and allelic frequencies between RHD cases and controls for IL-1β promoter, IL-1β exon 5, IL-1Ra, IL-4 promoter, IL-4 intron 3, and IL-10 gene polymorphisms. Further categorization of the RHD patients into mitral valve disease and combined valve disease subgroups also revealed no statistical difference in these gene polymorphisms when compared with controls.
These findings suggest that the IL-1β, IL-1Ra, IL-4, or IL-10 gene polymorphisms are not suitable genetic markers for RHD in Taiwan Chinese.

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A high prevalence of hepatitis C virus (HCV) infection has been reported among idiopathic dilated cardiomyopathy (DCM) patients. We examined the prevalence of DCM patients with HCV antibody, and the pathophysiological characteristics and responsiveness to neurohormonal antagonism in DCM with HCV. HCV antibodies were determined in 540 patients with cardiac diseases. In 117 DCM patients, clinicopathologic data were evaluated before and 1 year after angiotensin converting enzyme inhibitor and/or beta-blocker (ACE-inhibitor/BB) administration and their prognosis was followed-up for a mean of 72 ± 41 months. HCV antibodies were found in 12 of 135 DCM patients (8.9%) and in 37 of 405 patients without DCM (9.1%) (P = NS). At baseline, contrary to DCM without HCV, DCM with HCV was associated (P < 0.05) with greater left ventricular (LV) end-diastolic and end-systolic dimension, LV mass, and myocardial diameter in endomyocardial biopsy, and lower % fractional shortening. By multivariate analysis, HCV infection was independently associated with larger LV end-systolic dimension among DCM patients (P = 0.005). The advanced LV dilatation and hypertrophy in DCM with HCV decreased more in response to the ACE-inhibitor/BB therapy compared to DCM without HCV. There were no differences between DCM patients with and without HCV in survival and cardiac event-free rates. In summary, although HCV infection appears not to be the specific cause of DCM, HCV may enhance ventricular remodeling leading to heart failure among DCM patients. Nevertheless, the advanced ventricular remodeling with HCV was adequately reversed by neurohormonal antagonism, and did not lead to an unfavorable outcome.

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Congestive heart failure (CHF) is highly prevalent in the elderly. The aim of this study was to identify the predictors of CHF mortality in patients over 65 years of age who were free of CHF at initial screening. A total of 3,282 elderly subjects were recruited in a population-based frame and 12-year events were recorded. Continuous items were divided into tertiles and for each tertile adjusted the relative risk (RR) with 95% confidence intervals (CI) was derived in both genders from multivariate Cox analysis of CHF mortality.
Age ≥ 72 years ([RR]: 2.24; 95% CI 1.56 − 3.24), male gender ([RR]: 1.4; 95%CI 1.02 − 1.76), clinical history of coronary artery disease ([RR]: 1.25; 95% CI 1.02 − 1.76), pulse pressure ≥ 79 mmHg ([RR]: 1.33; 95% CI 1.03 − 1.87), heart rate ≥ 81 bpm ([RR]: 1.32; 95% CI 1.10 − 1.96), atrial fibrillation ([RR]: 1.82; 95% CI 1.18 − 2.81), left ventricular hypertrophy ([RR]: 1.42; 95% CI 1.01 − 2.02), diabetes ([RR]: 1.35; 95% CI 1.02 − 1.78), vital capacity ≤ 81% of the theoretical value ([RR]: 2.50; 95% CI 1.88 − 3.32), forced expiratory volume in 1 second ≤ 72% of the theoretical value ([RR]: 2.02; 95% CI 1.55 − 2.72) and serum sodium level ≤ 139 mmol/L ([RR]: 1.95; 95% CI 1.44 − 2.63) predicted CHF mortality.
This model is able to identify elderly people at increased risk of death from CHF.

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Patients with moderate to severe hypertension may need more than two antihypertensive drugs in combination to achieve ideal blood pressure (BP) control. The purpose of this study was to compare the efficacy and safety of administering the antihypertensive agents either all together in the morning or separately with two agents in the morning and one calcium channel blocker (CCB) in the evening. Twenty-four-hour ambulatory BP monitoring (ABPM) was performed among 15 patients (mean, 59 years) with moderate to severe essential hypertension. All patients received at least 3 antihypertensive drugs for ideal BP control. Two treatment regimens were given to each patient: Regimen 1: All antihypertensive agents were given once a day in the morning; Regimen 2: All antihypertensive agents were given in the morning, except the CCB which was given at 4:00 pm. After receiving regimen 1 for 4 weeks, each patient underwent 24-hour ABPM to analyze the BP control. After the first ABPM, each patient was switched to regimen 2. After 4 weeks of treatment with regimen 2, each patient underwent the second ABPM measurement. The pretreatment mean systolic and diastolic BP were 179.6 ± 21.7 and 107.4 ± 19.9 mmHg, respectively. Between the two regimens, there was no significant difference in the mean 24-hour BP (126.1 ± 5.8/73.3 ± 3.8 versus 130.2 ± 6.2/75.1 ± 4.7 mmHg), daytime BP (128.2 ± 6.5/75.3 ± 3.8 versus 132.4 ± 5.8/77.2 ± 4.4 mmHg), nighttime BP (125.2 ± 4.9/72.4 ± 3.3 versus 130.9 ± 6.2/73.8 ± 4.1 mmHg), and 24-hour heart rate (65.1 ± 3.8 versus 64.2 ± 3.4 bpm). The circadian BP and heart rate profiles were almost identical between regimen 1 and regimen 2. We conclude that in patients with moderate to severe hypertension treated with at least 3 antihypertensive agents, administering a CCB simultaneously with other antihypertensive agents in the morning or separately in the evening did not affect the 24-hour BP control.

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Friedreich's ataxia (FRDA), the most common subtype of early onset hereditary ataxia, is an autosomal recessive neurodegenerative disorder caused by unstable GAA expansions. Two-dimensional, pulse, and pulse tissue Doppler echocardiographic examinations were performed on 21 patients with GAA expansion.
There was no association between left ventricle ejection fraction, tissue Doppler systolic s wave, and left ventricle diastolic functions examined by pulse and tissue Doppler. The septum thickness of patients with Friedreich's ataxia was significantly increased when compared with that of the control group and wall thickness was found to be associated with GAA repeats.
In patients with FRDA, despite a correlation between genetic abnormality with left ventricular early and late diastolic parameters, global diastolic functions were preserved when examined by tissue Doppler.

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A B-type natriuretic peptide (BNP)-guided strategy is being widely used as a superior management technique for heart failure (HF). However, the optimal target level of BNP to improve the prognosis of HF in clinical practice remains unclear. Several studies have recently demonstrated that the existence of atrial fibrillation (AF) affects plasma BNP levels. We evaluated the prognostic value of BNP assay for HF management and found the optimal target level under the BNP-guided HF management according to the basal cardiac rhythms: AF or sinus rhythm (SR).
Patients hospitalized for HF exacerbation between 1996 and 2002 were stratified into SR (n = 129) and chronic AF (CAF, n = 58) groups as basal cardiac rhythms during hospitalization. Cardiac events including death and re-admission for HF exacerbation after discharge were analyzed in relation to the plasma BNP levels at predischarge. Receiver-operating characteristic (ROC) analysis demonstrated that the cut-off values for predischarge BNP, which predict cardiac events at 36 months after discharge, were 125 pg/mL in the SR group and 165 pg/mL in the CAF group. The area under the ROC curve was 0.72 and 0.82, respectively. Stratified subgroup analysis using the Kaplan-Meier method demonstrated that the risk of a cardiac event decreased in a stepwise fashion across a decreasing predischarge BNP range above these cut-off levels, while the minimum decreased risk was recognized at a BNP range below these cut-off levels in each group.
In conclusion, the optimal target levels of plasma BNP at predischarge to improve the prognosis of HF should be different and distinguishable depending on with or without AF.

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This cross-sectional study was performed to establish the rationale for BNP testing for identifying subjects at high risk of congestive heart failure (CHF) in a screening setting.
Plasma BNP concentrations were measured in 8,178 community-dwelling residents (mean age, 62 ± 12 years; 3,194 males). First, in order to determine age- and sex-related reference values for plasma BNP levels, subjects having factors known to influence plasma BNP levels were excluded. The remaining 3,410 subjects were eligible for the reference study. Second, to verify BNP testing for screening for subjects at high risk of CHF, the clinical characteristics of subjects showing abnormally high plasma BNP levels (≥ 97.5 percentile for each age- and sex-specific value of the reference cohort) were examined.
In the reference subjects, plasma BNP levels increased with age in both genders, and were higher in women than in men. In the original cohort, age- and sex-specific reference values for high plasma BNP levels were related to the presence of major ECG abnormalities, hypertension, mildly elevated serum creatinine levels, and a history of coronary heart disease.
The results of the present study indicate that individuals with high plasma BNP levels in the community have accumulating risk factors for CHF. This suggests that plasma BNP measurement may be a useful screening test for identification of individuals at high risk of CHF within a Japanese general population.

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Plasma B-type natriuretic peptide (BNP) levels have been reported to be elevated in various types of cardiac disorders and in precursors of CHF. To elucidate the potential ability of BNP testing to identify individuals with structural cardiac disease (ie, hypertensive heart disease, coronary heart disease, valvular heart disease) among community-dwelling elderly persons, cases which were positive on BNP testing were compared to those positive on ECG testing.
In the initial phase, we performed plasma BNP measurements and ECG in 856 participants (age ≥ 65 years) selected from a general population. From within this group, subjects with an abnormal ECG (n = 125) were selected according to the Minnesota code. Subjects with elevated BNP were selected independently on the basis of plasma levels (n = 112). In the next phase, subjects in both groups were invited to complete Rose's angina questionnaire and to undergo physical examination and transthoracic echocardiography. In this subject group (positive in ECG testing and/or BNP testing), the two tests had comparable sensitivity (65% versus 59%: NS) and specificity (40% versus 41%: NS) for identifying hypertensive heart disease (n = 17). For coronary heart disease (n = 12), the two tests had also comparable sensitivity (58% versus 42%: NS) and specificity (39% versus 41%: NS). However, for selection of valvular heart disease (n = 7), BNP testing had higher sensitivity than ECG testing (100% versus 14%; P < 0.01) with comparable specificity (43% versus 40%: NS).
Several types of structural heart disease, in particular valvular heart disease, could be identified exclusively by BNP testing, suggesting that BNP measurement can make a significant contribution to screening for CHF precursors when used in combination with ECG in elderly populations.

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Mortality and morbidity appear to be higher in a Cimbrian population representing an enclave of people who migrated from medieval Germany to the secluded Leogra valley in Italy.
A population-based study was organized, recruiting 881 elderly subjects of Cimbrian origin and comparing them with a standard control population (SCP, n = 3282) having comparable general characteristics and lifestyle. Serum lipids and glucose, blood pressure, heart rate, respiratory function, ECG abnormalities, and historical events were used as risk indicators.
Age-adjusted systolic and pulse pressure were higher in the Cimbrians than in the SCP, while diastolic blood pressure was comparable. The prevalences of arterial hypertension, isolated systolic hypertension, and pulse hypertension were significantly more represented among Cimbrians than SCP. The prevalences of diabetes, hypercholesterolemia, and hypertriglyceridemia were higher among the former than the latter. The ratio between apolipoproteins B and A1 was also higher, while the HDL fraction was significantly lower in Cimbrians than in the SCP. In Cimbrians, the relative risk (RR) for ischemic heart disease was 1.92 (1.57-2.34) in women, 2.30 (1.54-3.43) in men and 1.03 (1.00-1.06) in women for stroke, 2.43 (1.54-3.83) in men and 1.45 (1.01-1.12) in women for atrial fibrillation, 3.85 (2.83-5.24) in men and 1.39 (1.20-1.60) in women for respiratory disease, 1.97 (1.32-2.94) in men and 6.81 (4.38-10.60) in women for intermittent claudication, and 3.31 (2.44-4.50) in men and 2.30 (1.76-3.01) in women for left ventricular hypertrophy.
The subjects living in the secluded Leogra valley are at higher cardiovascular risk than the standard controls. Whether this depends on genetic factors, lifestyle, or both will need to be clarified by further analysis.

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We compared the effect of an ATP-sensitive potassium channel opener, YM934, with that of nitroglycerin (NTG) on impaired coronary circulation in dogs. Coronary stenosis was produced in 7 dogs by placing a hydraulic occluder around the proximal left circumflex coronary (LCx) artery and abolishing reactive hyperemia to compromise the LCx flow. The following parameters were measured: the aortic pressure, LCx flow velocity, LCx vessel diameter, LCx peripheral pressure, and segment length in the LCx area. Subsequently, we occluded the LCx artery for 15 seconds and measured the recovery-interval (time required for the segment shortening to return to the preocclusion value). The measurements were recorded under three study conditions: (1) at baseline without LCx stenosis; (2) with LCx stenosis under NTG infusion (3 μg/Kg/min); and (3) with LCx stenosis after intravenous administration of YM934 (0.3 μg/kg). The heart rate and aortic pressure were similar under the three study conditions. Mean LCx flow velocity and segment shortening did not significantly change either. However, LCx peripheral pressure decreased after the induction of stenosis (P < 0.05) and showed no response to either NTG or YM934. YM934 administration significantly increased LCx flow in the presence of LCx stenosis, (P < 0.05), whereas NTG infusion did not. YM934 significantly shortened the recovery-interval of the segment shortening after 15-sec LCx occlusion (P < 0.05), whereas NTG did not. These findings suggest that YM934 improves coronary blood flow and prevents myocardial ischemic damage in severely impaired coronary circulation.

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Myosin-induced autoimmune myocarditis in rats is a model of human dilated cardiomyopathy. Rapamycin is a potent immunosuppressant and specifically inactivates the mammalian target of rapamycin (mTOR).
To examine the role of mTOR in autoimmune myocarditis, we administered rapamycin to rats immunized with cardiac myosin. Phosphorylation of p70 ribosomal S6 kinase 1 (S6K1), a target of mTOR, was increased by 6.9 fold in the heart tissue of myosin immunized rats. Rapamycin (2 mg/kg/day) completely suppressed S6K1 and S6 phosphorylation. The amount of interleukin-1β, interferon-γ, interleukin-2, or tumor necrosis factor-α mRNA in the heart tissue was markedly increased in myosin-immunized rats, and rapamycin significantly attenuated the cytokine gene expressions. Rapamycin improved the survival of the rats and preserved cardiac function. The plasma level of brain natriuretic peptide increased by 4.7 fold in myosin-immunized rats, and rapamycin attenuated the increase in plasma brain natriuretic peptide. The heart weight/tibial length ratio of vehicle-treated myosin-immunized rats was increased by 1.81 ± 0.06 fold compared with vehicle-treated unimmunized rats, and rapamycin suppressed the increase in heart weight. Rapamycin decreased the cellular infiltration and fibrosis of the myocardium. The amount of phosphorylated S6 was increased in the infiltrating mononuclear cells in vehicle-treated myosin-immunized rats.
Rapamycin significantly ameliorated myocardial injury and preserved cardiac function in a rat model of autoimmune myocarditis.

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Few previous reports have described a sinus of Valsalva fistula without an aneurysm in Japanese patients. A single origin of the coronary arteries is a rare coronary anomaly. We describe a 75-year-old woman with a single origin of the coronary arteries and a sinus of Valsalva fistula without a typical aneurysm. Echocardiography showed turbulent flow from the right coronary sinus of Valsalva to the right ventricle throughout the cardiac cycle. Aortography confirmed the presence of a right coronary sinus of Valsalva-right ventricle shunt jet. Echocardiography and aortography demonstrated that there was no deformity of the sinus of Valsalva. Cardiac catheterization revealed that the left-to-right shunt rate was 29% and the Qp/Qs was 1.41. Aortography and coronary angiography did not identify a right coronary artery originating from the right sinus of Valsalva. Coronary angiography revealed that the right coronary artery arose from the proximal part of the left anterior descending artery and did not detect significant organic stenosis of the coronary artery. She was diagnosed as having a sinus of Valsalva to right ventricle fistula without an aneurysm, and a single origin of the coronary arteries.

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Azygos continuation is seen in 0.6% of patients with congenital heart disease. The major significance of this anomaly lies in its association with complex cardiac defects and the technical difficulty that can accompany cardiac catheterization. We report our experience with successful catheter ablation of a right posteroseptal concealed accessory pathway in a 6-year-old boy with infrahepatic interruption of the inferior vena cava and azygos continuation.

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We document serial changes in the electrocardiogram (ECG) and myocardial markers in a case of severe heat stroke treated with cooling procedures. A 23-year-old comatose male with heat stroke was presented in the emergency room. The condition of the patient was complicated by hepatic failure, rhabdomyolysis, acute renal failure, and cardiac abnormalities. ECG revealed diffuse ST-T elevation; serum levels of myocardial markers were remarkably high and diffuse hypokinesis was observed on the echocardiogram. Cooling procedures, including applying cold vapor to the patient's skin, a gastric lavage with cold water, and an intravenous cold fluid infusion were not successful. Since multiple organ damage (heart, liver, central nervous system, and kidney) was evident, we utilized continuous hemodialysis and hemofiltration, using cold dialysate for efficient cooling. The patient recovered from the multiple organ damage and was removed from the intensive care unit 14 days after the onset. The cardiac abnormalities had normalized within several days without any damage to the myocardium. Q waves were not detected in any lead in the ECG. When interpreting ST-T elevation in the ECG of a heat stroke patient, caution should be used so as to not misdiagnose it as an acute myocardial infarction.

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A 19 year-old woman who underwent corrective surgery for an atrial septal defect (ASD) and ventricular septal defect (VSD) 12 years previously presented with pulmonary hypertension. Cardiac catheterization showed a fistula between the right subclavian artery and vena jugularis interna. In this case, a rare example of secondary pulmonary hypertension due to acquired arteriovenous fistula after cardiac surgery is presented.

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Percutaneous interventional procedures in the renal arteries are usually performed employing a femoral or brachial vascular access. In contrast, the transradial approach has been established for coronary angiography and angioplasty. We encountered a patient with Leriche syndrome who had renovascular hypertension ascribed to a severe left renal artery stenosis. To stabilize his blood pressure, we made an attempt to relieve the renal artery stenosis with Leriche syndrome by transradial renal artery angioplasty and stenting, using devices for coronary intervention. The procedure was successful without complications or residual stenosis. His hypertension improved with less antihypertensive medications. This case suggests that the radial approach might become an alternative entry site for renal artery interventions.

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We present two female nonsmoker Buerger's disease cases with anticardiolipin autoantibodies and a poor prognosis. One was a 64-year-old female who has had multiple lower and upper extremity amputations, while the other was a 32-year-old female with extremity and visceral artery involvement. Since both were positive for anticardiolipin antibodies, we speculate that Buerger's disease is an autoimmune disorder.

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