Carvedilol accelerate elevation of serum potassium in chronic heart failure patients administered spironolactone plus furosemide and either enalapril maleate or candesartan cilexetil.

OBJECTIVE: To retrospectively investigate the effect of carvedilol and spironolactone plus furosemide, administered concomitantly with an angiotensin II converting enzyme inhibitor (ACE-I) or an angiotensin II receptor blocker (ARB) to patients with chronic heart failure (CHF). METHODS: Patients with CHF, who visited Departments of Cardiovascular Internal Medicine at the National Hospital Organization Osaka Medical Center, were enrolled for this study. Serum potassium, blood urea nitrogen (BUN), serum creatinine (Scr) and serum sodium were measured in every patient at the time of start of treatment and after 3 and 12 months of treatment. Data from patients in groups A (20 mg/day carvedilol + 25 mg/day spironolactone + 40 mg/day furosemide + an ACE-I) and B (20 mg/day carvedilol + 25 mg/day spironolactone + 40 mg/day furosemide + ARB) were compared. RESULTS: When 20 mg/day carvedilol plus 25 mg/day spironolactone plus 5 mg/day enalapril maleate (enalapril, group A) or 8 mg/day candesartan cilexetil (candesartan, group B) plus 40 mg/day furosemide were used concomitantly, the mean serum potassium increased significantly in both groups of patients. Seven of 59 (11.9%) patients had hyperkalemia (>5.5 mEq/L) during 12 months of treatment whereas 8.5% of patients (five of 59) had hypokalemia (< or =3.5 mEq/L). CONCLUSION: When carvedilol is used concomitantly with spironolactone, furosemide and enalapril or candesartan, it is necessary to monitor serum potassium concentration, even if spironolactone is administered at a low dose of 25 mg/day.

Serum concentration of potassium in chronic heart failure patients administered spironolactone plus furosemide and either enalapril maleate, losartan potassium or candesartan cilexetil.

OBJECTIVE: To retrospectively investigate elevation of serum potassium when spironolactone (25 or 50 mg/day) and furosemide were administered concomitantly with an angiotensin II converting enzyme inhibitor (ACE-I) or angiotensin II receptor blocker (ARB) to patients with chronic heart failure for 12 months and occurrence of hyperkalemia and hypokalemia because of concomitant administration of spironolactone plus an ACE-I or ARB and furosemide. METHODS: Patients with chronic heart failure, who visited departments of cardiovascular internal medicine and cardiovascular surgery at the National Hospital Organization Osaka Medical Center, were enrolled for this study. Serum potassium, blood urea nitrogen (BUN), serum creatinine, uric acid, and serum sodium were determined in every patient at the time of start of treatment and at 3 and 12 months of treatment. Data from patients in Groups A (25 mg/day spironolactone + 40 mg/day furosemide + an ACE-I or ARB) and B (50 mg/day spironolactone + 40 mg/day furosemide + an ACE-I or ARB) were analysed for differences with respect to the ACE-I and ARB used. RESULTS: When 50 mg/day spironolactone plus 5 mg/day enalapril maleate (enalapril) or 50 mg/day losartan potassium (losartan) or 8 mg/day candesartan cilexetil (candesartan) plus 40 mg/day furosemide were concomitantly used, the mean value of serum potassium was significantly elevated only in the group treated with 50 mg/day spironolactone regardless of the concomitant drug. The number of patients with hyperkalemia (>5.5 mEq/L) at 12 months of treatment was 12 (8.8%), while the number of patients with hypokalemia (

Attenuation of hypercapnic carbon dioxide chemosensitivity after postinfarction exercise training: possible contribution to the improvement in exercise hyperventilation.

OBJECTIVE: To elucidate the responsible mechanisms of increased slope of minute ventilation relative to carbon dioxide production (VE/VCO(2)) during exercise after acute myocardial infarction without overt signs of heart failure, patients who had an acute myocardial infarction were examined after participating in a three month supervised exercise training programme. DESIGN: Exercise testing, hypercapnic CO(2) chemosensitivity measurement (rebreathing method), and pulmonary function test were repeated at entry and after three months in 50 acute myocardial infarction patients with neither symptoms nor signs of heart failure who completed the training programme. Ten patients who performed initial inhospital training served as controls. RESULTS: Age, peak oxygen uptake, left ventricular ejection fraction, CO(2) chemosensitivity, respiratory parameters (percentage of predicted normal vital capacity (%VC), forced expiratory volume in one second, and carbon monoxide transfer factor (%TLCO)) were all significantly correlated with VE/VCO(2) slope. Multivariate regression analysis showed that age (beta = 0.29, p = 0.01), %TLCO (beta = -0.27, p = 0.01), and CO(2) chemosensitivity (beta = 0.49, p < 0.001) were independent determinants of VE/VCO(2) slope. After three months, there was no significant change in these parameters in the control group. Peak oxygen uptake, %TLCO, and %VC and attenuation in CO(2) chemosensitivity increased significantly in the training group. The VE/VCO(2) slope decreased marginally (p = 0.11). The changes in VE/VCO(2) slope were correlated only with those in CO(2) chemosensitivity (r = 0.50, p < 0.001). CONCLUSION: After acute myocardial infarction, exercise hyperventilation is seen in association with aging, enhanced hypercapnic CO(2) chemosensitivity, and reduced TLCO, even in the absence of overt heart failure. The correlation of VE/VCO(2) attenuation after training with the reduction in CO(2) chemosensitivity suggests that exercise training may reduce increased VE/VCO(2) slope, at least partially by reducing CO(2) chemosensitivity.

Comparative left ventricular functional and neurohumoral effects of chronic treatment with carvedilol versus metoprolol in patients with dilated cardiomyopathy.

The efficacy of treating dilated cardiomyopathy with metoprolol was compared with that of carvedilol. Metoprolol was administered to 29 patients, and carvedilol to 62. Patients who could not be dosed with up to 40 mg daily of metoprolol or 20 mg daily of carvedilol were defined as intolerant. As well as the tolerability of these beta-blockers, the effects on left ventricular end-diastolic dimension (LVDd), fractional shortening (FS), plasma atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) concentrations, the delayed heart and mediastinum (H/M) ratio determined from metaiodobenzylguanidine imaging were compared. Drug intolerance occurred in 24% of patients in the metoprolol group and 19% in the carvedilol group. Among the drug-tolerant patients, LVDd, FS and plasma BNP concentration improved in both groups and to the same degree. Only 25% of drug-tolerant patients in the metoprolol group had a delayed H/M ratio below 1.9 compared with 57% in the carvedilol group. Both metoprolol and carvedilol, when tolerated, improve cardiac function and neurohumoral factors to the same degree. However, carvedilol is preferable to metoprolol for patients with a low delayed H/M ratio.

An enhanced method for left ventricular volume and ejection fraction by triggered harmonic contrast echocardiography.

To elucidate the validity and reproducibility of the use of intravenous echo-contrast agent in the evaluation of left ventricular (LV) performance, we measured LV volume and ejection fraction (EF) in 42 patients with triggered harmonic contrast imaging (THCI), compared with continuous harmonic imaging without contrast agent (CHI) and with cineventriculography (CVG). In 10 of 42 patients, THCI improved LV border delineation which could not be obtained even with CHI. LV end-diastolic, end-systolic volumes and EF by both CHI and THCI correlated well with those by CVG. Although LV volumes are underestimated, THCI lessened the mean differences to about in half, compared with CHI. The observer variabilities obtained using THCI were smaller than those by CHI. These results indicate the validity of LV enhancement and the measurement of EF using THCI. We suggest that this method noninvasively provides more accurate LV systolic function with the acceptable reproducibility.

Clinical analysis of myocardial perfusion and metabolism in patients with hypertrophic cardiomyopathy by single photon emission tomography and positron emission tomography.

BACKGROUND AND OBJECTIVES: Changes in myocardial energy metabolism and their relation to coronary flow reserve in hypertrophic cardiomyopathy were assessed by myocardial fatty acid imaging with iodine-123 beta-methyliodophenyl pentadecanoic acid single photon emission tomography (123I-BMIPP SPECT) (fasting), glucose imaging with fluorine-18 fluorodeoxyglucose positron emission tomography (18F-FDG PET) (fasting), and perfusion imaging with nitrogen-13 (13N)-ammonia PET (dipyridamole-stress and at rest) in adult patients with hypertrophic cardiomyopathy and with asymmetric septal hypertrophy. RESULTS: 123I-BMIPP defects mismatched with thallium-201 (201Tl) uptake were often observed in the hypertrophic septal regions indicating reduced fatty acid utilization incidence of 59% (22/37). 18F-FDG images showed diffusely increased uptake in most of the patients (73%, 27/37), but showed regionally increased 18F-FDG uptake at the septal regions in only two patients. Study of 18 hypertrophic cardiomyopathy patients with the mismatched 123I-BMIPP defects found that the severity of the defects correlated with reduced coronary flow reserve determined by the 13N-ammonia PET study. On the other hand, changes in 18F-FDG images were not related to those in coronary flow reserve. CONCLUSIONS: These results suggest that the mismatched 123I-BMIPP defects, which indicate abnormality in myocardial fatty acid metabolism, occur under reduced coronary flow reserve, and may contribute to the prediction of progressive myocardial failure in patients with hypertrophic cardiomyopathy. The significance of 18F-FDG in patients with hypertrophic cardiomyopathy is still uncertain.

Synthesis of branched cyclomaltooligosaccharide carboxylic acids (cyclodextrin carboxylic acids) by microbial oxidation.

Novel branched cyclomaltooligosaccharide carboxylic acid (cyclodextrin carboxylic acid) derivatives were synthesized by microbial oxidation using Pseudogluconobacter saccharoketogenes to oxidize five types of branched cyclodextrins, including maltosyl beta-cyclodextrin (maltosyl-beta-CyD). For each novel cyclodextrin carboxylic acid derivative synthesized, the hydroxymethyl group of the terminal glucose residue in the branched part of the molecule was regiospecifically oxidized to a carboxyl group to give the corresponding uronic acid. In addition, the physicochemical properties of cyclomaltoheptaosyl-(6-->1)-alpha-D-glucopyranosyl-(4-->1)-alpha-D-glucopyranosiduronic acid (GUG-beta-CyD) (1) and its sodium salt were studied more extensively, as these compounds are most likely to have a practical application.

Excessive ventilation after acute myocardial infarction and its improvement in 4 months.

The relationship between ventilation (VE) and CO2 output (VCO2) is fitted linearly. The steeper gradient implies excessive ventilation. Through an evaluation of the VE-VCO2 slopes, this study investigated whether patients with acute myocardial infarction (AMI) have excessive ventilation and whether it improved in 4 months. The VE-VCO2 slopes were determined in exercise tests at 1 and 4 months in 131 patients with AMI. Patients were divided into 3 groups according to the 1 month VE-VCO2 slope value: (i) normal (<30); (ii) intermediate (30-32); and (iii) excessive (>32). In the normal group (n=76), at 4 months, the slope decreased in 10, increased in 5 and remained unchanged in 61 patients; in the intermediate (n=31) group, 9, 2 and 20; and in the excessive (n=24) group, 15, 3 and 6, respectively, showing that the slope reduction was greater in the excessive group (p<0.01). The slope correlated with age and acute phase heart failure. The percent reduction of the slope did not correlate with these parameters. In conclusion, a substantial fraction of patients with AMI have excessive ventilation that improves in 4 months. The improvement is greater in patients with greater excessive ventilation but is not associated with an improvement in exercise capacity nor hemodynamics.

Improvement in cardiac function and free fatty acid metabolism in a case of dilated cardiomyopathy with CD36 deficiency.

A 27-year-old man diagnosed as having dilated cardiomyopathy (DCM) without myocardial accumulation of 123I-beta-methyl-iodophenylpentadecanoic acid, and he was found to have type I CD36 deficiency. This abnormality of cardiac free fatty acid metabolism was also confirmed by other methods: 18F-fluoro-2-deoxyglucose positron emission tomography, measurements of myocardial respiratory quotient and cardiac fatty acid uptake. Although the type I CD36 deficiency was reconfirmed after 3 months, the abnormal free fatty acid metabolism improved after carvedilol therapy and was accompanied by improved cardiac function. Apart from a cause-and-effect relationship, carvedilol can improve cardiac function and increase free fatty acid metabolism in patients with both DCM and CD36 deficiency.

Early changes in left ventricular function in chronic asymptomatic alcoholics: relation to the duration of heavy drinking.

OBJECTIVES: This study sought to assess preclinical cardiac abnormalities in chronic alcoholic patients and possible differences among alcoholics related to the duration of heavy drinking. BACKGROUND: Chronic excessive alcohol intake has been reported as a possible cause of dilated cardiomyopathy. However, before the appearance of severe cardiac dysfunction, subtle signs of cardiac abnormalities may be identified. METHODS: We studied 30 healthy subjects (age 44 +/- 8 years) and 89 asymptomatic alcoholics (age 45 +/- 8 years, p = NS) divided into three groups, with short (S, 5-9 years, n = 31), intermediate (I, 10-15 years, n = 31) and long (L, 16-28 years, n = 27) duration of alcoholism. Transmitral early (E) and late (A) Doppler flow velocities, E/A ratio, deceleration time of E (DT) and isovolumic relaxation time (IVRT) were obtained. Left ventricular (LV) wall thickness and volumes were also determined by echocardiography, and LV mass and ejection fraction (EF) were calculated. RESULTS: The alcoholics had prolonged IVRT (92 +/- 11 vs. 83 +/- 7 ms, p < 0.001), longer DT (180 +/- 20 vs. 170 +/- 10 ms, p < 0.01), smaller E/A (1.25 +/- 0.34 vs. 1.40 +/- 0.32, p < 0.05), larger LV volumes (73 +/- 8 vs. 65 +/- 7 ml/m2, p < 0.001 for end-diastolic volume index; 25 +/- 4 vs. 21 +/- 2 ml/m2, p < 0.001 for end-systolic volume index), higher LV mass index (92 +/- 14 vs. 78 +/- 8 g/m2, p < 0.001) and thicker posterior wall (9 +/- 1 vs. 8 +/- 1 mm, p < 0.001). Ejection fraction did not differ between the two groups (66 +/- 4 vs. 67 +/- 2%). Deceleration time of the early transmitral flow velocity was longer in groups L (187 +/- 18 ms) and I (185 +/- 16 ms) compared with group S (168 +/- 17 ms, p < 0.001 for L and I vs. S), whereas A was higher in group L compared with S (43 +/- 10 vs. 51 +/- 10 cm/s, p < 0.005). Multiple regression analysis identified duration of heavy drinking as the most important variable affecting DT and A. CONCLUSIONS: Left ventricular dilation with preserved EF and impaired LV relaxation characterized LV function in chronic asymptomatic alcoholic patients. It appeared that the progression of abnormalities in LV diastolic filling related to the duration of alcoholism.

Validity and reproducibility of echocardiographic measurement of left ventricular ejection fraction by acoustic quantification with tissue harmonic imaging technique.

The tissue harmonic imaging technique can enhance detection of the cardiac endocardial border. When combined with an acoustic quantification (AQ) method, an improvement of accuracy and reproducibility of real-time measurement of left ventricular (LV) function might be expected. However, few data exist regarding the measurement of LV function by AQ with the harmonic imaging technique. Therefore, we evaluated the validity and reproducibility of AQ measurement of LV ejection fraction with or without harmonic imaging technique. A total of 50 patients (mean age 58 +/- 10 years) who underwent left ventriculography were included in our study. The LV end-diastolic and end-systolic volumes by ventriculography were 131 +/- 52 mL and 72 +/- 43 mL, respectively, and were underestimated by both conventional (70 +/- 32 mL and 36 +/- 25 mL) and harmonic (67 +/- 30 mL and 34 +/- 22 mL) AQ obtained in the apical 4-chamber view. The calculated ejection fraction by ventriculography was 0.49 +/- 0. 11 and correlated with that by conventional AQ (0.51 +/- 0.11; y = 0. 72x + 0.152; r = 0.73). This was a marked improvement when compared with the ejection fraction by harmonic AQ (0.50 +/- 0.11; y = 0.89x + 0.065; r = 0.91). Interestingly, interobserver and intraobserver variabilities of conventional AQ, which were 15.6% and 8.6%, respectively, were much improved by harmonic AQ (8.9% and 4.5%, respectively). These results indicate the feasibility of real-time measurement of LV ejection fraction by harmonic imaging, although absolute LV volume can be underestimated even by this technique.

Improvement in left ventricular function in response to carvedilol is accompanied by attenuation of neurohumoral activation in patients with dilated cardiomyopathy.

BACKGROUND: We sought to evaluate whether improvement in ejection fraction (EF) with carvedilol therapy is accompanied by improvement in neurohumoral factors. METHODS AND RESULTS: Forty-two patients with dilated cardiomyopathy were given carvedilol for 3 to 5 months. Changes in EF, plasma atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), and norepinephrine levels were determined. Iodine-123 metaiodobenzylguanidine (MIBG) images were also obtained before and after carvedilol therapy. Myocardial uptake of MIBG was calculated as the heart to mediastinal activity ratio (H/M). Storage and release of MIBG was calculated as percent myocardial MIBG washout rate (WR). We divided patients into 2 groups: 27 responders whose EF increased by more than 5% and 15 nonresponders whose EF increased by 5% or less. EF of responders increased by 15 +/- 5% and that of nonresponders by 1 +/- 4%. Although MIBG image-derived indexes of nonresponders remained unchanged, the delayed H/M (1.91 +/- 0.34 v 2.24 +/- 0.53, P < .01) and WR (49 +/- 11 v 39 +/- 9%, P < .01) of responders improved, respectively. The plasma ANP (51 +/- 50 v 27 +/- 24 pg/mL, P < .01) and BNP (194 +/- 197 v 49 +/- 62 pg/mL, P < .01) levels of responders decreased. The degree of changes in the plasma BNP level correlated with changes in EF (r = -.698, P < .01). CONCLUSION: The improvement in EF with carvedilol therapy was proved to be accompanied by an improvement in neurohumoral factors.

Morphology of vulnerable coronary plaque: insights from follow-up of patients examined by intravascular ultrasound before an acute coronary syndrome.

OBJECTIVES: To determine the morphologic features of coronary plaques associated with acute coronary syndrome, we prospectively followed patients with atherosclerotic disease identified by intravascular ultrasound (IVUS). BACKGROUND: Although clinical evaluation of the vulnerable atherosclerotic plaque is important, few data exist regarding the morphology of the vulnerable plaque in clinical settings. METHODS: We examined 114 coronary sites without significant stenosis by angiography (<50% diameter stenosis) in 106 patients. All the sites exhibited atherosclerotic lesions by IVUS. These lesions consisted of 22 concentric and 92 eccentric plaques with a percent plaque area averaging 59 +/- 12%. RESULTS: During the follow-up period of 21.8 +/- 6.4 months (range 1 to 24), 12 patients had an acute coronary event at a previously examined coronary site at an average of 4.0 +/- 3.4 months after the initial IVUS study. All the preexisting plaques related to the acute events exhibited an eccentric pattern and the mean percent plaque area was 67 +/- 9%, which was greater than plaque area in the other 90 patients without acute events (57 +/- 12%, p < 0.05). There was no statistically significant difference in lumen area between two patient groups (6.7 +/- 3.0 vs. 7.5 +/- 3.7 mm2). Among 12 coronary sites with an acute occlusion, 10 sites contained the echolucent zones, eight of these shallow and two deep, likely representing a lipid-rich core. In 90 sites without acute events, an echolucent zone in the shallow portion was seen at only four sites (p < 0.05). CONCLUSIONS: Large eccentric plaque containing an echolucent zone by IVUS can be at increased risk for instability even though the lumen area is preserved at the time of initial study. Compensatory enlargement of vessel wall due to remodeling may contribute to the relatively small degree of stenosis by angiography.

Enhanced methods for visualizing myocardial perfusion with peripheral venous injection of levovist: application of triggered harmonic imaging and triggered harmonic power Doppler imaging techniques.

OBJECTIVES: The purpose of this study was to determine whether triggered harmonic imaging (THI) or triggered harmonic power Doppler imaging (THPDI) could obtain the myocardial contrast enhancement using peripheral venous injection of a first generation echocardiographic contrast agent, Levovist. METHODS: In a phantom model, we examined the influence of an acoustic power, harmonic filters, transmitted frequencies and focus positions of transducer on Levovist. Then fundamental, harmonic or harmonic power Doppler imaging were performed with ECG-triggered imaging in eight closed-chest dogs using bolus injection of Levovist. RESULTS: In a phantom model, the highest transmission power (Mechanical index 1.6), a medium harmonic filter and a focus position (6 cm) resulted in the best enhanced contrast in both THI and THPDI. Furthermore, higher pulse repetition frequency (5500 Hz) of harmonic power Doppler made clearer enhancement. In animal models, we could not observe the apparent myocardial contrast using triggered fundamental imaging, and the intensity of each region of interest (ROI) of myocardium had not changed significantly. However, homogeneous myocardial contrast could be obtained using THI, which was conditioned on the highest transmission power, a medium harmonic filter same as the phantom model, at a lower transmitted frequency (1.8 MHz) and a focus position, which were located in the middle portion of the left ventricle. The peak intensity of each ROI increased significantly in a gray level. Furthermore, THPDI caused emphasized myocardial contrast visually. CONCLUSIONS: These results indicate that THI and THPDI produce obvious MCE using peripheral venous injection of Levovist.

Impact of coronary artery remodeling on misinterpretation of angiographic disease eccentricity: evidence from intravascular ultrasound.

This study was designed to examine the impact of coronary artery remodeling, enlargement or shrinkage, on the angiographic disease eccentricity. A total of 82 coronary sites from 73 patients with significant stenosis (>50%) were prospectively analyzed by both quantitative coronary angiography and intravascular ultrasound. By quantitative coronary angiography, the maximal and minimal distances from the center of the stenosis to the outline of the vessel wall were measured, and the eccentricity index was calculated by the formula [(maximal-minimal)/maximal]. By intravascular ultrasound, the maximal and minimal distances from the center of the lumen to the leading edge of the second echogenic zone were measured, and the eccentricity index was calculated by the same formula. For identifying the vessel remodeling, the total vessel area that was determined by tracing the leading edge of the second echogenic zone was measured at the stenotic sites and the adjacent proximal and distal segments. By quantitative coronary angiography, the maximal and minimal distances were 1.76+/-0.6 and 0.97+/-0.3 mm, respectively, yielding an eccentricity index of 0.42+/-0.2. The maximal and minimal distances by intravascular ultrasound were 2.77+/-0.6 mm and 1.46+/-0.4 mm, respectively, yielding an eccentricity index of 0.45+/-0.2 (NS). Although the average eccentricity index was not different between the two methods, there was substantially no correlation between the eccentricity index determined by the two methods (r = 0.38, y = 0.43x+0.22). However, this correlation was significantly improved (r = 0.55, y = 0.73x+0.12, P<0.001) when 44 stenotic segments with remodeling were excluded for comparison. These results indicate that coronary artery remodeling could be a major contributing factor to angiographic misinterpretation of disease eccentricity. We suggest that intravascular ultrasound is a powerful method that can accurately determine diseases eccentricity as well as disease severity.