Peak VO(2) is more potent than B-type natriuretic peptide as a prognostic parameter in cardiac patients.

BACKGROUND: It is well-known that both B-type natriuretic peptide (BNP) and peak oxygen uptake (VO(2)) are independent predictors of mortality in patients with heart failure. This study investigates the predictive power of BNP and peak VO(2) for survival in cardiac patients. METHODS AND RESULTS: A total of 609 patients with cardiac disease participated in the study. They underwent cardiopulmonary exercise testing to determine peak VO(2), with BNP being measured before exercise testing During 502.5 median follow-up days, 29 patients died of cardiovascular disease. In the univariate Cox proportional hazards analysis, peak VO(2) and BNP were both found to be significant prognostic indices for survival. The time-dependent ROC curve analysis (Heagerty 2006) was applied to 3 predictors: peak VO(2), BNP, and then both, with gender and age as adjusted variables. The area under the curve (AUC) compared with the follow-up period curves of peak VO(2) and the 2 combined variables (ie, BNP and peak VO(2)) were consistently over that of BNP. The integrated AUC indices were 0.80 (peak VO(2)), 0.81 (peak VO(2) and BNP) and 0.70 (BNP), respectively. CONCLUSIONS: These results indicate that peak VO(2) is more potent than BNP for predicting the mortality in patients with mixed cardiac disease.

Angiotensin type 1 receptor blockade prevents endocardial dysfunction of rapidly paced atria in rats.

INTRODUCTION: Atrial fibrillation (AF) per se causes atrial endocardial dysfunction leading to local coagulation imbalance on the internal surface of the atrium, which contributes to thrombus formation in the fibrillating left atrium. MATERIALS AND METHODS: To test a hypothesis that blockade of angiotensin II type 1 receptor (AT1-receptor) prevents the endocardial dysfunction by AF, we examined the effects of olmesartan on the expression of tissue factor pathway inhibitor (TFPI), thrombomodulin (TM), endothelial nitric oxide synthase (eNOS) and plasminogen activator inhibitor-1 (PAI-1) in the endocardium of the rapidly paced rat atria. RESULTS: Rapid pacing induced a significant decrease in TFPI, TM and eNOS and an increase in PAI-1 protein in the left atrium. Pre-administration of low-dose olmesartan significantly prevented the down-regulation of TFPI, TM and eNOS and also attenuated the up-regulation of PAI-1. Immunohistochemistry identified these changes predominantly in the atrial endocardium. While the drug was without any effect on mRNA levels of TFPI, TM and eNOS, there was a significant decrease in its PAI-1 mRNA expression. CONCLUSIONS: AT1-receptor blocker could partially prevent the atrial endocardial dysfunction by rapid atrial pacing, which would provide one theoretical basis for beneficial effects for stroke prevention in AF.

A method for the simultaneous analysis of mRNA levels of multiple cardiac ion channels with a multi-probe RNase protection assay.

AIMS: Various pathological conditions can alter cardiac electrophysiological properties not only by physiological responses but also by modifying the gene expression of ion channels (electrical remodelling). To investigate the underlying mechanisms of the latter, electrophysiological alterations would require a simultaneous and comprehensive analysis of the mRNA level of the ion channel genes. METHODS AND RESULTS: We designed 19 cardiac ion channel cDNA templates to analyse the corresponding mRNAs and classified them into three template sets. Those sets were a voltage-dependent K(+) channel series (rat erg, KvLQT1, Kv4.3, Kv4.2, Kv2.1, Kv1.5, Kv1.4, Kv1.2), an inwardly rectifying K(+) channel series (rat Kir6.2, SUR2A/B, Kir3.4, Kir3.1, Kir2.2, Kir2.1), and an inward cationic ion channel series (rat SCN5A, alpha1C, beta2, alpha2delta2 of cardiac L-type Ca(2+) channel and alpha1G). These cDNA templates were used to synthesize antisense digoxigenin-labelled RNA probes. An amount of the total RNA of 25 microg was adequate to analyse simultaneously the mRNA levels of the ion channel genes with the use of multi-probe RPA, and these three multi-probe template sets enabled us to evaluate the profile of the spatial and temporal transcripts of the cardiac ion channels. CONCLUSION: The newly developed ion channel multi-probe RPA templates provide an aid in the comprehensive analysis of the electrical remodelling of the heart.

Molecular and electrophysiological differences in the L-type Ca2+ channel of the atrium and ventricle of rat hearts.

BACKGROUND: Many pathological conditions induce electrical remodeling, possibly through intracellular Ca2+ overload, but the currently available L-type Ca2+ channel blockers may be detrimental because of their global negative inotropic effects. METHODS AND RESULTS: To determine whether the L-type Ca2+ channel is identical throughout the heart, the distribution of the mRNAs and proteins comprising the L-type Ca2+ channel and its electrophysiological properties were analyzed in rat atria and ventricles. The mRNA of alpha2delta-2 (Cacna2d2) was more abundantly expressed in the atrium (approximately 5-fold) than in the ventricle. In contrast, alpha1C (Cacna1c) (Cav1.2) mRNA was significantly less abundant in the atrium. The level of the alpha1C (Cacna1c) (Cav1.2) protein was decreased (approximately 0.5-fold) and that of alpha2 delta-1 (Cacna2d1) was increased (approximately 2-fold) in the atrium compared with the ventricle. Although the peak ICa,L density showed no significant differences, voltage dependence of inactivation and activation of the current showed a more depolarized shift in the atrium than in the ventricle. CONCLUSION: These results indicate that in the rat heart the L-type Ca2+ channel differs between the atrium and ventricle with regard to gene expression and electrophysiological properties.

Premature atrial complex with P'R prolongation indicates multiple atrioventricular nodal pathways.

BACKGROUND: The goal of the present study was to test if ambulatory Holter recordings can predict the electrophysiologic study (EPS) findings in patients with supraventricular tachycardia (SVT). METHODS AND RESULTS: The study involved 110 patients with SVT who underwent Holter recording, and then EPS. The hypotheses were that (1) a P'R interval of premature atrial complexes (PACs) between 280 and 400 ms in the Holter recordings predicted dual atrioventricular nodal (AVN) pathways, (2) P'R interval >400 ms predicted triple or more AVN pathways, and (3) SVT initiated by a single PAC suggested easy SVT induction during the EPS. The EPS revealed dual AVN pathways in 14 (93%) of 15 patients with P'R intervals between 280 and 400 ms on the Holter recordings, and triple or more AVN pathways in 18 (90%) of 20 patients with P'R intervals >400 ms. In addition, a single extrastimulus easily induced SVT during the EPS in 11 (85%) of 13 patients in whom SVT was initiated by a single PAC during Holter recording. CONCLUSION: The ambulatory Holter recording criteria specifically predicted the EPS findings, thereby providing useful advance information.

Cibenzoline attenuates upregulation of Kv1.5 channel gene expression by experimental paroxysmal atrial fibrillation.

Antiarrhythmic drugs exert their effects by inhibiting the ion channels of cardiomyocytes. However, these effects could also modify the ionic environment around them, and thereby affect the expression of ion channels, leading to biochemical enhancement or attenuation of the antiarrhythmic effects. To test this hypothesis, the physiological and biochemical effects of cibenzoline were evaluated in a rapid atrial pacing model in rats. In rats with rapid atrial pacing, pretreatment with cibenzoline significantly inhibited the increases in Kv1.5 mRNA at 2 hours and immunoreactive protein at 4 hours by 35 +/- 15% and 30 +/- 10%, respectively. These effects were observed only in the rapid atrial pacing group, not in the sham-operated group. With cibenzoline pretreatment, 4-hour rapid atrial pacing resulted in significant prolongation of the atrial refractory period compared to the untreated group even after removal of cibenzoline. In contrast, the sham and rapid atrial pacing model with and without cibenzoline pretreatment showed similar acute physiological responses to cibenzoline. In conclusion, in addition to the acute physiological effects, pretreatment with cibenzoline exerted pleiotropic effects of inhibition of Kv1.5 channel upregulation by rapid pacing, implying differences in the cibenzoline effects when administered before and after onset of paroxysmal atrial fibrillation.

Progressive nature of paroxysmal atrial fibrillation. Observations from a 14-year follow-up study.

BACKGROUND: Atrial fibrillation (AF) is believed to occur first as paroxysmal, then be gradually perpetuated, and finally become chronic as the end result. However, this presumed clinical course has not been well confirmed. METHODS AND RESULTS: The clinical course of recurrent paroxysmal AF (PAF) from its onset was examined in 171 patients (mean follow-up period: 14.1+/-8.1 years). This study population consisted of patients with no structural heart disease (n=88), ischemic heart disease (n=28), dilated or hypertrophic cardiomyopathy (n=17), valvular heart disease (n=35) or other cardiac diseases. The mean age at the onset of AF was 58.3 +/-11.8 years old. During the mean follow-up period of 14.1 years, PAF eventually developed into its chronic form in 132 patients under conventional antiarrhythmic therapy (77.2%, 5.5% of patients per year). The independent factors for early development into chronic AF were aging (hazard ratio (HR) 1.27 per 10 years, 95% confidence interval (CI) 1.06-1.47)), dilated left atrium (HR 1.39 per 10 mm, 95% CI 1.11-1.69), myocardial infarction (HR 2.33, 95% CI 1.13-4.81), and valvular diseases (HR 2.29, 95% CI 1.22-4.30). CONCLUSIONS: The present long-term observations definitely and quantitatively revealed the progressive nature of PAF.

Relation between variability of ventricular response intervals and exercise capacity in patients with non-valvular atrial fibrillation.

BACKGROUND: Reduced variability of the ventricular response interval (VRI) has been reported to predict adverse prognosis in patients with atrial fibrillation (AF). To examine whether it could be related also to the quality of the daily life of patients with AF, the relationships between VRI variability and exercise tolerance, one of the markers for quality of life, were determined in patients with persistent AF. METHODS AND RESULTS: Thirty-one patients with idiopathic AF were included in the present study. Holter monitoring results and symptom-limited treadmill exercise testing were correlated in these patients without medications for the rate control of AF. The VRI variability, both the SD of the mean R-R interval (SDNN) and the SD of the 5-min mean R-R interval (SDANN), showed significant positive correlation with the exercise capacity (r=0.583, p=0.0004, and r=0.543, p=0.0013, respectively), whereas age, left ventricular ejection fraction and body mass index did not have any significant relationships. Multiple regression analysis revealed that increased SDNN was the only independent predictor of good exercise capacity during the treadmill exercise testing. CONCLUSIONS: Increased VRI variability, independently of other clinical variables, can predict good exercise capacity in patients with idiopathic AF, thus being a new sensitive maker for quality of life in AF.

Thrombomodulin and tissue factor pathway inhibitor in endocardium of rapidly paced rat atria.

BACKGROUND: Atrial fibrillation (AF) is well known as one of the cardiogenic causes for thromboembolism. Although decreased flow and hypercoagulable state of the blood in the fibrillating atrium have been emphasized as the underlying mechanisms, endocardial dysfunction in maintaining the local coagulation balance could also contribute to the thrombogenesis in AF. METHODS AND RESULTS: The paroxysmal AF model was created by rapid atrial pacing in anesthetized rats. To test the hypothesis that AF induces local coagulation imbalance by disturbing the atrial endocardial function, the gene expression of intrinsic anticoagulant factors, thrombomodulin (TM) and tissue factor pathway inhibitor (TFPI), were determined by means of ribonuclease protection assay, Western blotting, and immunohistochemistry. Rapid atrial pacing for 8 hours significantly decreased TM and TFPI mRNA levels in the left atrium but not in the ventricle, leading to the downregulation of their immunoreactive proteins. Immunohistochemical analysis revealed that TM and TFPI were expressed predominantly in the endocardial cells of the normal atrium, presumably preventing local blood coagulation, and that rapid atrial pacing induced the loss of TM and TFPI expression in the endocardium, leading to deficiency in anticoagulant barriers between the atria and the blood. CONCLUSIONS: Rapid atrial pacing acutely downregulated the gene expression of TM and TFPI in the atrial endocardium, thereby inducing local coagulation imbalance on the internal surface of the atrial cavity. These results would support the validity of supplement of anticoagulant molecules deficient in AF.

[Relationship between exercise capacity and brain natriuretic peptide in patients after cardiac surgery].

OBJECTIVES: Physical training in cardiac patients can increase exercise capacity and reduce plasma brain natriuretic peptide(BNP) concentration, but these effects may depend on the etiology of cardiac disease. The change in exercise capacity and BNP during the training period were investigated in patients with different cardiac diseases. METHODS: Ninety-one patients after coronary artery bypass grafting(CABG) and 78 patients after valve replacement (VR) underwent a symptom-limited incremental cardiopulmonary exercise test before (1 month) and 6 months after physical training. Anaerobic threshold and peak oxygen uptake(peak-Vo2) were measured during the cardiopulmonary exercise test. Before each cardiopulmonary exercise test, a blood sample was obtained in the resting condition for measuring BNP. RESULTS: Anaerobic threshold and peak-Vo2 were increased significantly from 1 month to 6 months in both groups. BNP in the CABG group indicated a tendency to decrease (194.6 +/- 155.3-->144.2 +/- 232.2 pg/ml, p < 0.1) from 1 month to 6 months. BNP in VR group was significantly decreased (159. 9 +/- 115.5-->112.8 +/- 131.7 pg/ml, p < 0.05) during the training period. The CABG group showed a significant negative correlation between peak-Vo2 and BNP at 1 month(r = -0.28, p < 0.01) and at 6 months(r = -0.39, p = 0.001). The VR group showed a significant negative correlation between peak-Vo2 and BNP at 6 months(r = -0.32, p < 0.01), but not at 1 month. CONCLUSIONS: Six months of physical training in patients after cardiac surgery may improve exercise capacity and reduce BNP. BNP concentration in the VR group before physical training did not reflect functional capacity.

Nifekalant hydrochloride, a novel class III antiarrhythmic agent, suppressed postoperative recurrent ventricular tachycardia in a patient undergoing coronary artery bypass grafting and the Dor approach.

A patient with 3-vessel coronary artery disease and left ventricular aneurysm underwent coronary artery bypass grafting combined with the Dor approach. Five days later, ventricular tachycardia following short-coupled ventricular premature contractions suddenly occurred and was not responsive to class IB drugs (lidocaine and mexiletine), requiring frequent electrical cardioversion. After the administration of a novel class III drug, nifekalant hydrochloride, this electrical storm of ventricular tachycardia was completely suppressed together with the disappearance of ventricular premature contractions. Nifekalant hydrochloride (MS-551), a pure K(+) channel blocker, might be effective for postoperative recurrent ventricular tachyarrhythmias that are refractory to other antiarrhythmic agents.

Circadian variation of cardiac K+ channel gene expression.

BACKGROUND: Many cardiac arrhythmias have their own characteristic circadian variations. Because the expression of many genes, including clock genes, is regulated variably during a day, circadian variations of ion channel gene expression, if any, could contribute to the fluctuating alterations of cardiac electrophysiological characteristics and subsequent arrhythmogenesis. METHODS AND RESULTS: To examine whether cardiac K+ channel gene expression shows a circadian rhythm, we analyzed the mRNA levels of 8 Kv and 6 Kir channels in rat hearts every 3 hours throughout 1 day. Among these channels, Kv1.5 and Kv4.2 genes showed significant circadian variations in their transcripts: approximately 2-fold increase of Kv1.5 mRNA from trough at Zeitgeber time (ZT) 6 to peak at ZT18 and a completely reverse pattern in Kv4.2 mRNA ( approximately 2-fold increase from trough at ZT18 to peak at ZT6). Actually, along with the variations in the immunoreactive proteins, the density of the transient outward and steady-state currents in isolated myocytes and the responses of atrial and ventricular refractoriness to 4-aminopyridine in isolated-perfused hearts showed differences between ZT6 and ZT18, a circadian pattern comparable to that of Kv1.5 and Kv4.2 gene expression. Reversal of light stimulation almost inverted these circadian rhythms, although pharmacological autonomic blockade only partially attenuated the rhythm of Kv1.5 but not of Kv4.2 transcripts. CONCLUSIONS: Among all the cardiac K+ channels, Kv1.5 and 4.2 channels are unique in showing characteristic circadian patterns in their gene expression, with Kv1.5 increase during the dark period partially dependent on beta-adrenergic activities and Kv4.2 increase during the light period independent of the autonomic nervous function.

Anti-anginal effect of fasudil, a Rho-kinase inhibitor, in patients with stable effort angina: a multicenter study.

Rho-kinase plays an important role in calcium sensitization for vascular smooth muscle (VSMC) contraction and may be involved in the inappropriate coronary vasoconstriction during exercise-induced myocardial ischemia. In this multicenter phase II study, the anti-anginal effect of fasudil, which is metabolized to a specific Rho-kinase inhibitor hydroxyfasudil after oral administration, was examined in patients with stable effort angina. In the phase IIa trial, after a 2-week washout period of anti-anginal drugs, 45 patients received increasing doses of fasudil (5, 10, and 20 mg TID for every 2 weeks). The fasudil treatment significantly prolonged the maximum exercise time and the time to the onset of 1-mm ST segment depression on treadmill exercise test (both p < 0.01), whereas blood pressure and heart rate during exercise were unchanged before and after the treatment. Higher doses of fasudil (20 and 40 mg TID) were subsequently tested in 22 patients in the same manner with similar positive results. In the phase IIb trial, after a 2-week washout period of anti-anginal drugs, 125 patients were assigned, in a double-blind manner, to a 4-week oral treatment with a different dose of fasudil (5, 10, 20, or 40 mg TID) and treadmill exercise test was performed before and after the treatment. Again, both maximum exercise time and time to the onset of 1-mm ST segment depression were prolonged in all groups. A significant dose-response relation was noted across the treatment groups for the exercise tolerance index that was determined by the combined effect of exercise time and ST segment depression (p = 0.006). Fasudil was well tolerated in both trials without any serious adverse reactions. These results suggest the efficacy and adequate safety profile of fasudil, the first drug in a novel class of vasodilators, for the treatment of stable effort angina.

J wave and ST segment elevation in the inferior leads: a latent type of variant Brugada syndrome?

In a patient referred for the evaluation of non-sustained monomorphic ventricular tachycardia on Holter recordings, ventricular fibrillation was electrically induced during electrophysiologic study. Despite the absence of structural heart diseases, his ECG revealed J wave and ST segment elevation in the inferior leads, which showed circadian variation and were augmented by the sodium channel blocker, pilsicainide. This case might lead us to notice a new concept, a 'latent' type of variant Brugada syndrome, and these ECG findings and changes might serve as its diagnostic sign.

[Prevalence and clinical background of exercise-induced ventricular tachycardia during exercise testing].

OBJECTIVES: This study assessed the prevalence and clinical background of exercise-induced ventricular tachycardia during exercise testing. METHODS: Complications during exercise testing were reviewed in 25,075 consecutive patients, 14,037 men and 11,038 women, who underwent a total of 47,656 maximal treadmill or bicycle exercise tests between April 1985 and March 1999. The mean age of the patients was 53.3 +/- 8.8 (mean +/- SD) years. Non-sustained ventricular tachycardia was defined as 8 or more consecutive ventricular ectopic beats at > 100 beats/min. A total of 126 patients undergoing exercise testing to evaluate the efficacy of pharmacotherapy for ventricular tachycardia were excluded. RESULTS: The major reasons for the exercise test were chest pain (27.0%) and screening (20.3%). Twenty patients (0.08%) had exercise-induced ventricular tachycardia. Six patients had ischemic heart disease, two had cardiomyopathy, five had other cardiac diseases, and seven patients showed no clinical evidence of heart disease. The incidence of ventricular tachycardia in patients with cardiomyopathy (2/109) was higher than in other patients, but the number of patients with ventricular tachycardia was small. Ventricular tachycardia was documented at heart rates of more than 80% of predicted maximal heart rate in 12 of the 20 patients. CONCLUSIONS: These results suggest that the exercise testing can be done safely when the end-point criteria are properly applied.

Mechanisms of acute gain and late lumen loss after atherectomy in different preintervention arterial remodeling patterns.

The main mechanism of restenosis after directional coronary atherectomy (DCA) remains obscure. We investigated mechanisms of restenosis after DCA in different coronary artery remodeling patterns. DCA was performed in 51 de novo lesions. The lesions were evaluated by intravascular ultrasound (IVUS) before, immediately after, and 6 months after the procedure. According to the IVUS findings before DCA, we classified the lesions into the following 3 groups: (1) positive (n = 10), (2) intermediate (n = 25), and (3) negative (n = 16) remodeling. We measured lumen area, vessel area, and plaque area using IVUS before DCA, immediately after DCA, and at follow-up. Lumen area increase after DCA was mainly due to plaque area reduction in the positive and intermediate remodeling groups (90 plus minus 15% and 80 plus minus 25% increase in lumen area, respectively), whereas that in the negative remodeling group was due to both plaque area reduction (57 plus minus 22% increase in lumen area) and vessel area enlargement (43 plus minus 33% increase in lumen area). The plaque area increase correlated strongly with late lumen area loss in the positive and intermediate remodeling groups (r = 0.884, p <0.001; r = 0.626, p <0.001, respectively), but the decrease in vessel area was not correlated with lumen area loss. In contrast, both an increase in plaque area and a decrease in vessel area were correlated with late lumen area loss (r = 0.632, p = 0.009; r = 0.515, p = 0.041) in the negative remodeling group. Coronary artery restenosis after atherectomy was primarily due to an increase in plaque in the positive and/or intermediate remodeling groups. However, in the negative remodeling group, late lumen loss might have been caused by both an increase in plaque and vessel shrinkage.

Effects of nitric oxide inhalation on periodic breathing in awake patients with chronic heart disease.

BACKGROUND: Periodic breathing, an abnormal pattern of respiration consisting of alternating hyperpnea and hypopnea, has been recognized in patients with heart failure. Although fluctuations in pulmonary blood flow have been considered as a possible cause of this type of breathing, its patho-physiological mechanisms are not fully understood. In this study, we sought to determine whether inhaled nitric oxide (NO), a selective pulmonary vasodilator, attenuates periodic breathing. METHODS: Eight cardiac patients who exhibited clear oscillatory ventilation while awake (age: 62 +/- 16 years, left ventricular ejection fraction: 48 +/- 20%) were enrolled in the study. After breathing room air (RA) for 15 min, the subjects inhaled air containing 30 ppm of NO for 15 min. Respiratory gas variables including minute ventilation (VE) were measured on a breath-by-breath basis throughout the test. RESULTS: There were no differences in VE (10.7 +/- 1.5 vs. 11.0 +/- 1.7 l/min) or among any of the other hemodynamic or respiratory gas variables studied in the control and NO tests, with the exception of the end-tidal CO(2) partial pressure (5.0 +/- 0.4 vs. 4.8 +/- 0.5%; p = 0.018). The % magnitude of oscillation (i.e., the difference between the peak and nadir of oscillating VE, divided by the mean VE) was 40.0 +/- 22.4% in RA and not influenced by inhaled NO (43.9 +/- 20.8%, p = 0.57). CONCLUSION: Inhaled NO at a concentration of 30 ppm did not attenuate periodic breathing in awake patients with mild heart failure.