Risk stratification assessed by combined lung and heart iodine-123 metaiodobenzylguanidine uptake in patients with idiopathic dilated cardiomyopathy

Iodine-123 metaiodobenzylguanidine (123I-MIBG) has been used to assess myocardial sympathetic nervous activity and severity of heart failure. (123)I-MIBG is also used as a potential marker of pulmonary endothelial cell function and may be related to pulmonary hypertension. Thus, we hypothesized that combined assessment of lung and heart 123I-MIBG kinetics predicts future clinical outcome more accurately than myocardial evaluation alone in patients with chronic heart failure. To test this hypothesis, we examined 123I-MIBG scintigrams in 62 consecutive patients with idiopathic dilated cardiomyopathy. Anterior planar images were obtained 15 minutes and 3 hours after 123I-MIBG injection. Cardiac and pulmonary 123I-MIBG activities were quantified as heart-to-mediastinum activity ratio and lung-to-mediastinum activity ratio. We introduced lung-to-heart activity ratio as the new 123I-MIBG parameter including myocardial sympathetic nerve activity and pulmonary endothelial cell function. Delayed lung-to-heart ratio was correlated with pulmonary vascular resistance (r = 0.48, p <0.0001), disease duration (r = 0.49, p <0.0001), and number of heart failure episodes (r = 0.55, p <0.0001). During a mean follow-up of 25 months, 15 patients had a cardiac event. Area under receiver operating characteristic curves for prediction of the event was greatest in delayed lung-to-heart ratio (lung to heart 0.92, heart to mediastinum 0.83, lung to mediastinum 0.80). In multivariate analysis, the lung-to-heart ratio (hazard ratio 2.76/0.1 increase, p = 0.002) was selected as an independent predictor for a future cardiac event. In conclusion, the combined assessment of lung and heart 123I-MIBG uptake may help to predict future clinical outcome for patients with idiopathic dilated cardiomyopathy more accurately than myocardial evaluation alone.     

Relation between microvolt-level T-wave alternans and cardiac sympathetic nervous system abnormality using iodine-123 metaiodobenzylguanidine imaging in patients with idiopathic dilated cardiomyopathy

We examined the relation between microvolt-level T-wave alternans and cardiac sympathetic nervous system abnormality using iodine-123 metaiodobenzylguanidine imaging in patients with idiopathic dilated cardiomyopathy. Our results strongly indicate that cardiac sympathetic denervation and accelerated sympathetic nervous activity play important roles in the presence of microvolt-level T-wave alternans in patients with idiopathic-dilated cardiomyopathy.     

Cardiac sympathetic activity as measured by myocardial 123-I-metaiodobenzylguanidine uptake and heart rate variability in idiopathic dilated cardiomyopathy.

In patients with idiopathic dilated cardiomyopathy (IDC) the increased sympathetic activity owing to chronic congestive heart failure leads to an imbalance of cardiac autonomic tone, as reflected by decreased heart rate variability (HRV). Iodine-123-metaiodobenzylguanidine (123-I-MIBG), which has the same affinity for sympathetic nerve endings as norepinephrine, can be used to assess the integrity and function of the cardiac sympathetic nervous system. The aim of the present study was to measure cardiac sympathetic activity by assessing 123-I-MIBG uptake compared with HRV in patients with IDC. In 12 patients with IDC and mild to moderate heart failure, myocardial MIBG uptake was calculated from the myocardial (M) to left ventricular cavity (C) voxel values density ratio and the 123-I activity in a blood sample as a reference (= M/C ratio) using a double radionuclide study with 123-I-MIBG and technetium-99m-MIBI. To investigate the relation between myocardial MIBG uptake and HRV in time domain, the linear regression between the M/C ratio, a new scintigraphic parameter, and the mean RR interval or the HRV triangular index, respectively, was determined. A significant correlation between the M/C ratio and mean RR interval (r = 0.52; p = 0.016) or M/C ratio and HRV triangular index (r = 0.76; p = 0.003), respectively, was found. Thus, the significant correlation between the M/C ratio and HRV indicate that they are both suitable noninvasive methods for evaluating cardiac sympathetic activity in patients with IDC and, furthermore, favor the view that there is evidence of a relation between HRV and the disorder of the cardiac presynaptic sympathetic nerve endings as demonstrated by a reduced M/C ratio.     

Dehydroepiandrosterone levels vary according as heart failure condition in patients with idiopathic dilated cardiomyopathy

The secretion of dehydroepiandrosterone sulfate (DHEAS) decreases with age, and the incidence of heart failure rises in the elderly population. We measured plasma DHEAS levels in 50 male patients (mean 66.7+/-9.1 years old) with congestive heart failure due to idiopathic dilated cardiomyopathy before and after treatment. The study included 50 age-matched control subjects with coronary spastic angina (mean 65.5+/-8.8 years old). DHEAS levels were significantly lower in patients with congestive heart failure than in controls (82.2+/-9.9 vs. 122.7+/-18.6 microg/dL, respectively, p<0.01), whereas there was no difference in cortisol levels between the 2 groups. After 3 months of treatment, NYHA functional class improved in all patients, and DHEAS levels increased (from 82.2+/-9.9 to 106.2+/-21.1 microg/dL, p<0.01). DHEAS levels vary according as heart failure condition in patients with idiopathic dilated cardiomyopathy.     

Mitochondrial function in heart muscle from patients with idiopathic dilated cardiomyopathy

OBJECTIVE: To study the mitochondrial respiratory chain enzyme activities in patients with idiopathic dilated cardiomyopathy (IDC). METHODS: Mitochondrial respiratory chain enzyme activities were assessed spectrophotometrically in left ventricular tissue of 17 patients with IDC undergoing cardiac transplantation, as well as in two groups of controls: a group of six patients suffering from ischemic dilated cardiomyopathy (IC) also undergoing cardiac transplantation, and a group of 17 organ donors considered normal from a cardiac point of view. Cytochrome b gene from three IDC patients whose complex III activity was particularly low and from three controls was also sequenced. RESULTS: We found that complex III enzymatic activity was lower not only in IDC but also in IC patients when compared with normal controls. When analysing cytochrome b gene we only found neutral polymorphisms previously described. CONCLUSIONS: In view of such results, we believe that the decrease of respiratory chain complex III activity found in some cases of IDC is a secondary phenomenon, and not due to a primary mitochondrial disease.     

Efficacy of ivabradine in idiopathic dilated cardiomyopathy patients with chronic heart failure

BackgroundThe aim of this study was to investigate the effect of ivabradine on symptoms, quality of life, effort tolerance, and echocardiographic parameters in patients with idiopathic dilated cardiomyopathy presenting with New York Heart Association (NYHA) class III or IV heart failure (HF) symptoms.MethodsWe screened 167 patients hospitalized for NYHA class III or IV chronic HF symptoms and left ventricular (LV) ejection fraction <40%. Of these, 53 were randomly assigned to either guidelines-based medical therapy alone (23 patients, control group) or ivabradine as add-on therapy (30 patients) for 3 months with about 1 year follow up.ResultsAfter 3 months’ treatment, adding ivabradine significantly reduced the heart rate from 96 to 72 bpm (p < 0.0001 versus control group), with more improvement in echocardiographic LV dimensions, LV volumes, LV ejection fraction (p = 0.045), NYHA class symptoms (p = 0.004), exercise tolerance (p = 0.03), and quality of life (p = 0.02). The average number of hospitalizations for HF over a mean longer-term follow-up of 13.5 months was 1.0 ± 1.4 in the ivabradine group versus 2.1 ± 1.1 in the control group (p = 0.003). Heart rate reduction was significantly correlated with better exercise tolerance, quality of life, LV ejection fraction, and NYHA class, together with fewer HF hospitalizations. Multivariate analysis showed heart rate reduction to be a stronger predictor for better LV ejection fraction (p = 0.024) and decreased hospitalizations than ivabradine use.ConclusionAdding ivabradine to optimal medical treatment in HF patients improved symptoms, quality of life, effort tolerance, and echocardiographic parameters, and reduced hospitalization. This beneficial ivabradine effect is probably due to its heart rate–reducing properties.     

Sympathetic activity in patients with heart failure due to idiopathic dilated cardiomyopathy: modification by beta receptor blockers--a therapeutic approach?

Increased sympatho-adrenergic activity is a compensatory mechanism in cardiac failure. Accordingly, beta-receptor blockers are generally regarded as contraindicated for use in heart failure. In 1975, Waagstein reported the first successful use of beta-receptor blockers in patients with idiopathic dilated cardiomyopathy. It was shown that the prognosis of patients with dilated cardiomyopathy could be improved by beta-receptor blockade. In this regard, most experience is associated with metoprolol. It should be stressed that the initial, and long-term dosage, as well, was maintained at a very low level (beginning, for example, with 6.25 mg metoprolol daily). An on-going, international, multicenter study is intended to clarify which patients with dilated cardiomyopathy may benefit from treatment with beta-receptor blockers. Additionally, further information is anticipated with respect to the complex mechanism of action. Beside the direct cardiac action with blockade of the cardiotoxic effect of the extremely high levels of plasma catecholamines, induction of an upregulation of the down-regulated beta-1-receptors there is attenuation of the activity of the renin-angiotensin-aldosterone system. Overall, this leads to interruption of the vicious cycle of maladaption associated with chronic heart failure and its attendant unfavorable vasoconstriction and sodium and water retention. This positive aspect of beta-1-receptor blockade in dilated cardiomyopathy carries with its initially and unavoidable negative inotropic effect and thus, in the individual patient, the net effect is difficult to predict. Consequently, the indication must be established on an individual basis.(ABSTRACT TRUNCATED AT 250 WORDS)     

Anaemia and renal function in heart failure due to idiopathic dilated cardiomyopathy

BACKGROUND: Anaemia and renal dysfunction are common in patients with heart failure (HF). Most studies involve western cohorts with ischaemic aetiology receiving treatment likely to impair renal function. AIMS: To investigate the frequency of anaemia and renal dysfunction and the relationship between the two within a cohort of 163 newly diagnosed Black African idiopathic cardiomyopathy patients prior to commencing HF treatments and compare those findings to those of western HF cohorts. METHODS: Single-centre retrospective analysis. Anaemia defined as haemoglobin concentration<13.0 g/dL for males (n=85) and <12 g/dL for females (n=78). Probable renal dysfunction defined as an estimated glomerular filtration rate of <60 mL/min/1.73 m2, using serum creatinine concentrations. RESULTS: The mean age was 48+/-11 years, 52% were male. Overall, 13.5% of patients were anaemic and 11.8% had evidence of renal dysfunction, while 1.2% had both. Renal dysfunction was significantly more common in older patients (mean age 58+/-13 vs. 47+/-10 years: p<0.001). CONCLUSION: The frequency of anaemia and renal dysfunction in this cohort was lower than that reported in western HF cohorts. These data infer a more limited relationship between HF, anaemia and renal dysfunction in patients without atherothrombotic disease; hence extrapolation of HF data from the western world to other populations should be interpreted cautiously.     

Sympathetic activity in patients with heart failure due to idiopathic dilated cardiomyopathy: effect of ACE inhibitors and other vasodilators

A decrease in cardiac output in patients with congestive heart failure due to dilated cardiomyopathy is compensated by stimulation of the sympathetic nervous system and the renin-angiotensin-aldosterone system. The increase in plasma norepinephrine and depletion of norepinephrine in the myocardium as well as the disturbance of beta-adrenal and baroreceptor function reflect the limits of the sympathetic nervous stimulation. Together with augmented levels of angiotensin II and vasopressin, this stimulation leads to a significant increase in systemic vascular resistance. Sustained stimulation of at least one of these mechanisms can cause further impairment of the left ventricular function. The severity and prognosis of congestive heart failure due to dilated cardiomyopathy is expressed by the plasma norepinephrine concentration and by its myocardial depletion. Ultimately, activation of the compensatory mechanisms provides the basis for therapeutic approaches: 1. reduction of afterload and systemic vascular resistance and/or 2. diminution of the sympathetic nervous activity. For about the last ten years, ACE inhibitors have been used as pharmacological treatment in addition to positive inotropic and vasodilating substances. Captopril, one of the first orally applicable drugs, reduces left ventricular filling pressure, pulmonary capillary pressure, systemic vascular resistance and increases the cardiac output. Beside the hemodynamic improvement, a decrease in plasma norepinephrine and aldosterone can be observed. Vasodilators and alpha-blocking agents can also reduce afterload and systemic vascular resistance in patients with congestive heart failure due to dilated cardiomyopathy, and may lead to hemodynamic improvement. The main limitations of their long-term application are relatively short duration of action, reflex activation of the renin-angiotensin system due to vasodilation and induction of tolerance.     

A polymorphism in the endothelin-A receptor gene predicts survival in patients with idiopathic dilated cardiomyopathy.

AIMS: The endothelin system plays a role in the complex pathophysiology of idiopathic dilated cardiomyopathy. We investigated whether genetic polymorphisms of the endothelin system might be associated with dilated cardiomyopathy-related cardiac phenotypes and differences in disease outcome. METHODS: One hundred and twenty-five unrelated dilated cardiomyopathy patients of a well characterized dilated cardiomyopathy cohort were genotyped for six common polymorphisms of the endothelin-1, endothelin-A (ETA) and endothelin-B (ETB) receptor genes using hybridization with allele-specific oligonucleotides. RESULTS: The H323H (C/T) polymorphism in exon 6 of the ETA receptor gene was significantly associated with a shorter survival time after diagnosis. The odds ratio for carriers of the less frequent ET(A)T allele to die within 2 years after diagnosis was 5.5 (95% confidence interval, 1.4 to 21.0, P=0.013) compared to non-carriers. Kaplan-Meier analysis revealed a significantly different survival time for T allele carriers as compared to non-carriers as tested by logrank (P=0.0196), Breslow (P=0.0195), and Tarone tests (P=0.020). The influence of the ETA H323H polymorphism on survival remained significant when known predictors of prognosis such as left ventricular ejection fraction, left ventricular end-diastolic diameter, age and NYHA functional classification were entered in a Cox proportional hazards analysis. In this model, end-diastolic diameter showed a trend to influence survival (P=0.07) but only the ETA H323H polymorphism (P=0.0029) was a significant independent predictor of survival. CONCLUSIONS: Our results suggest that genetic variation in the ETA receptor predicts survival in dilated cardiomyopathy patients, which might have important consequences for the identification of high-risk individuals.     

Iodine-123 meta-iodobenzylguanidine scintigraphy: a noninvasive method to demonstrate myocardial adrenergic nervous system disintegrity in patients with idiopathic dilated cardiomyopathy

Iodine-123 (I-123) meta-iodobenzylguanidine (MIBG) imaging was performed in 31 patients. Three patients were without cardiac disease and 28 had idiopathic dilated cardiomyopathy with various degrees of left ventricular dysfunction. The qualitatively assessed myocardial I-123 MIBG scintigrams and the myocardial versus mediastinal I-123 MIBG uptake ratio were related to I-123 MIBG activity and norepinephrine concentration determined from endomyocardial biopsy samples taken from the right side of the interventricular septum. Scintigrams and the MIBG uptake ratio were also related to plasma catecholamine concentrations, left ventricular ejection fraction and New York Heart Association functional class. Patients with distinct myocardial I-123 MIBG uptake (score 1) had a normal ejection fraction (58 +/- 16%). Patients with diffusely reduced uptake or scintigraphic defects (score 2) had a significantly lower ejection fraction (38 +/- 9%, p less than 0.05), whereas patients with shadowy or no visible myocardial uptake (score 3) had the lowest ejection fraction (23 +/- 6%, p less than 0.002 versus patients with score 2). The scintigraphically determined I-123 MIBG activity in the septal region correlated significantly with I-123 MIBG activity from the endomyocardial biopsy samples (r = 0.78, p less than 0.001, n = 9). The myocardial versus mediastinal I-123 MIBG activity ratio was significantly related to myocardial norepinephrine concentration (r = 0.63, n = 28) and to left ventricular ejection fraction (r = 0.74, n = 31). These data suggest that myocardial I-123 MIBG scintigraphy is a useful noninvasive method for the assessment of myocardial adrenergic nervous system disintegrity in patients with idiopathic dilated cardiomyopathy.     

Prognostic value of iodine-123 metaiodobenzylguanidine imaging in patients with heart failure

Abnormalities of myocardial sympathetic nerve function were reported in congestive heart failure (CHF). To assess myocardial sympathetic nerve function, we obtained metaiodobenzylguanidine (MIBG) images 15 min and 180 min after the injection of iodine-123 MIBG at a dose of 111 MBq and calculated the ratio of heart to mediastinum count (H/M) and the washout rates (WRs) in 59 consecutive patients with CHF and age-matched subjects without CHF (n=23). The plasma levels of B-type natriuretic peptide were measured. H/M ratio was significantly lower in the CHF group (1.8±0.9) than in the control group (2.6±0.4; P<0.01). WR was higher in the CHF group (38±4%) than in the control group (28±3%; P<0.01). H/M was inversely correlated with the plasma B-type natriuretic peptide (r=−0.46, P<0.05). Eighteen patients suffered cardiac events (two deaths, 16 hospitalizations) during a mean follow-up period of three years. Kaplan-Meier analysis showed that a low H/M was associated with a poor prognosis in patients with CHF. These findings indicate that the H/M ratio on MIBG imaging is a useful predictor of mortality and morbidity in patients with CHF.     

Sympathetic nervous system response to exercise in patients with congestive heart failure

The response of the sympathetic nervous system to exercise in patients with congestive heart failure was studied in 65 patients (NYHA functional class I 28, II 23, and III 14) and 22 normal subjects (N) by submaximal treadmill testing with the modified Bruce's or Sheffield's protocols. Plasma norepinephrine (NE) and epinephrine (E) levels were also measured at rest, at the end of each stage, and immediately after and 5 min after exercise. In accordance with the severity by NYHA functional class, the exercise duration became shorter and the discontinuation of exercise with symptoms occurred more frequently. Systolic blood pressure and double products (DP) at the peak exercise were significantly lower in patients with NYHA class III. NE and increments of NE increased during exercise [peak NE (pg/ml); N: 589, I: 646, II: 1253, and III: 997] and were higher at rest, during exercise and in recovery in patients with NYHA classes II and III than in the normal subjects and NYHA class I patients. E increased gradually during exercise [peak E (pg/ml); N: 60, I: 66, II: 63, and III: 66] and there were no significant differences among the four groups. A negative correlation (r = -0.53) between the peak NE and exercise duration was observed in normal subjects, while a positive correlation (r = 0.55) was observed in patients with NYHA class II. A positive correlation (r = 0.54) between DP at the peak exercise and the peak NE was observed in patients with NYHA class I, whereas a negative correlation (r = -0.46) was observed in patients with NYHA class III. The NE response in patients with NYHA classes II and III increased significantly, suggesting compensatory activation of the sympathetic nervous system for impaired cardiac function. In conclusion, the NE response to submaximal exercise testing differs in each NYHA functional class and it might be a useful indicator to evaluate cardiac function of patients with congestive heart failure.     

Relation of iodine-123 metaiodobenzylguanidine myocardial scintigraphy to endomyocardial biopsy findings in patients with dilated cardiomyopathy

Background: Iodine-123 metaiodobenzylguanidine (¹²³I-MIBG) concentrates in adrenergic neurons and has been developed for evaluation of the sympathetic nervous system. Recent studies have demonstrated that the normal heart is clearly visualized by ¹²³I-MIBG cardiac scintigraphy, whereas abnormal ¹²³I-MIBG myocardial uptake and washout have been demonstrated in patients after myocardial infarction and in patients with congestive cardiomyopathy, long QT syndrome, and ventricular tachycardia. Hypothesis: Based on evidence from recent studies, it can be hypothesized that ¹²³I-MIBG uptake is related to histopathologic changes in the myocardium. Methods: The relation of ¹²³I-MIBG uptake to the histologic findings for the heart was studied in 24 patients with dilated cardiomyopathy (DCM). The study group did not include patients with complicating disorders that primarily affect the adrenergic nervous system. The ¹²³I-MIBG uptake was visually assigned one of four grades using the two criteria of the mean score for six regional uptake grades (mean score) and the global score obtained by visual evaluation of the entire image (global score). The ¹²³I-MIBG uptake score was also determined for the region at which the biopsy specimen was obtained (biopsy region score). The histologic findings were evaluated by assigning one of four grades for each of the following five factors: myocyte hypertrophy, myocardial fibrotic change, myocyte degeneration and necrosis, mononuclear cell infiltration, and myocyte disarray. The sum for all grades was defined as the total score, and the global score was also assigned to the overall histologic findings. Results: All of the global, mean, and biopsy region scores for ¹²³I-MIBG uptake correlated significantly with the global and total scores for the histologic findings. Among the histologic factors, myocyte degeneration showed score correlated with all global, mean, and biopsy region scores for the uptake. Myocyte hypertrophy was associated weakly with the ¹²³I-MIBG uptake scores. Conclusion: These results indicate that ¹²³I-MIBG uptake imaging is associated with histopathologic abnormalities in patients with DCM.     

Comparison of left ventricular systolic and diastolic function in patients with idiopathic dilated cardiomyopathy and mild heart failure versus those with severe heart failure

Achieving recommended cholesterol and triglyceride targets for the prevention of cardiovascular events is difficult and frequently requires the use of >1 lipid-lowering medication. This study evaluated the tolerability and effectiveness of combination regimens in high-risk dyslipidemic patients resistant to monotherapy. A retrospective chart review of all patients referred to a cardiovascular risk reduction clinic over a 7.5-year period identified 136 patients who received combination therapy with a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor (statin) plus fibrate (n = 106) or a statin plus niacin (n = 30) regimen. During follow-up (mean 18.5 months), 28 patients (20.6%) discontinued combination therapy: 11 (8.1%) experienced myalgia with or without elevated creatine kinase, 3 had gastrointestinal upset, and 1 had asymptomatic creatine kinase elevation. No patient had combination therapy discontinued due to elevated liver enzymes. Medications were stopped in 8 patients for reasons other than reported adverse effects or biochemical abnormalities, and 5 patients were switched to alternate monotherapy. Mean percent change from baseline to treatment with combination therapy for total cholesterol (-35%), low-density lipoprotein cholesterol (-37%), high-density lipoprotein cholesterol (+23%), triglycerides (-62%), and total cholesterol/high-density lipoprotein cholesterol ratio (-41%) were all statistically significant (p <0.01). These results demonstrate that combination statin-fibrate and statin-niacin regimens are safe and effective in managing dyslipidemias in most patients at risk for cardiovascular events who are inadequately treated with one of these agents alone.