Neuronal dysfunction in heart failure assessed by cardiac 123-iodine metaiodobenzylguanidine scintigraphy

In patients with chronic heart failure, increased sympathetic activity and cardiac sympathetic neuronal dysfunction are present and have been related to unfavourable clinical outcome. Modification of these alterations with the objective to improve prognosis has become an important aim of pharmacological therapy for these patients. A noninvasive technique to assess sympathetic neuronal function at the cardiac level may be valuable in evaluating newly developed therapeutic strategies. 123-iodine metaiodobenzylguanidine can be used visualize cardiac sympathetic nerve function and activity. Single photon emission computerized tomographic is preferred to planar scintigraphy since it does not depend on superposition of other anatomical structures and may allow assessment of regional cardiac 123-iodine metaiodobenzylguanidine uptake. Although the quantitation of cardiac uptake in these tomographic images has several limitations, the use of the left ventricular cavity as a reference, calibrated by the 123-iodine activity in a blood sample drawn at the time of acquisition, may have clinical applications, with respect to the evaluation of therapeutical intervention in patients with heart failure.Abbreviations BS blood sample - CD count density - dP/dt change in pressure over time - [¹²³I] 123-iodine - K_m affinity constant - MIBG metaiodobenzylguanidine - MB_q mega Bequerel - SPECT single photon emission computerized tomography - V_m capacity constant     

Cardiac autonomic nervous system in heart failure: imaging technique and clinical implications

The autonomic nervous system interacts in the pathophysiology of heart failure. Dysfunction of the sympathetic nervous system has been identified as an important prognostic marker in patients with chronic heart failure. At present, cardiac sympathetic nerve imaging with 123-iodine metaiodobenzylguanidine [123-I MIBG] has been employed most frequently for the assessment of cardiac sympathetic innervation and activation pattern. The majority of studies have shown that cardiac sympathetic dysfunction as assessed with 123-I MIBG imaging is a powerful predictor for heart failure mortality and morbidity. Additionally, 123-I MIBG imaging can be used for prediction of potentially lethal ventricular tachyarrhythmias in heart failure patients. At present however, the lack of standardization of 123-I MIBG imaging procedures represents an evident issue. Standardized criteria on the use of 123-I MIBG imaging will further strengthen the clinical use of 123-I MIBG imaging in heart failure patients.     

A case of reversible dilated cardiomyopathy after alpha-interferon therapy in a patient with renal cell carcinoma

A 47-year-old man with renal cell carcinoma underwent nephrectomy, and postoperative chemotherapy was performed with recombinant alpha-interferon. Five years later, he experienced dyspnea during physical exertion. An echocardiogram revealed dilatation and systolic dysfunction of the left ventricle, and thallium-201 myocardial scintigraphy showed diffuse heterogeneous perfusion. We diagnosed congestive heart failure because of cardiomyopathy induced by alpha-interferon therapy. Withdrawal of interferon therapy and the combination of an angiotensin-converting enzyme inhibitor, diuretics, and digitalis improved left ventricular systolic function. Furthermore, myocardial scintigraphy using [123I] beta-methyl-p-iodophenylpentadecanoic acid (123I-BMIPP) or [123 I]metaiodobenzylguanidine (123I-MIBG) revealed normal perfusion after the improvement of congestive heart failure. This is a rare case of interferon-induced cardiomyopathy that resulted in normal myocardial images in 123I-BMIPP and 123I-MIBG scintigrams after withdrawal of interferon therapy.     

Positron emission tomographic imaging of cardiac sympathetic innervation and function

Sites of uptake, storage, and metabolism of [18F]fluorodopamine and excretion of [18F]fluorodopamine and its metabolites were visualized using positron emission tomographic (PET) scanning after intravenous injection of the tracer into anesthetized dogs. Radioactivity was concentrated in the renal pelvis, heart, liver, spleen, salivary glands, and gall bladder. Uptake of 18F by the heart resulted in striking delineation of the left ventricular myocardium. Pretreatment with desipramine markedly decreased cardiac positron emission, consistent with dependence of the heart on neuronal uptake (uptake-1) for removal of circulating catecholamines. In reserpinized animals, cardiac positron emission was absent within 30 minutes after injection of [18F]-6-fluorodopamine, demonstrating that the emission in untreated animals was from radioactive labeling of the sympathetic storage vesicles. Decreased positron emission from denervated salivary glands confirmed that the tracer was concentrated in sympathetic neurons. Radioactivity in the gall bladder and urinary system depicted the hepatic and renal excretion of the tracer and its metabolites. Administration of tyramine or nitroprusside increased and ganglionic blockade with trimethaphan decreased the rate of loss of myocardial radioactivity. The results show that PET scanning after administration of [18F]fluorodopamine can be used to visualize sites of sympathetic innervation, follow the metabolism and renal and hepatic excretion of catecholamines, and examine cardiac sympathetic function.     

Hemodynamic correlates of baroreflex impairment of heart rate in experimental canine heart failure

The arterial baroreflex has been shown to be depressed in both clinical and experimental heart failure. The mechanism and significance of this depression remains controversial. Part of the change may reside in the baroreceptor as well as in the target organ. Previous studies in this laboratory have shown that there is no central depression of the baroreflex in anesthetized dogs. The present study was undertaken to determine the relationship between the change in baroreflex sensitivity (BRS) and the impairment of various hemodynamic parameters during the development of chronic heart failure in conscious dogs (n=15). The animals were instrumented to record pressures and derivatives in the left atrium, aorta and the left ventricle. Heart failure was achieved by rapid left ventricular pacing (250 bpm) until the development of clinical signs. BRS was determined by correlating systolic arterial blood pressure and pulse interval during bolus injections of nitroglycerin and phenylephrine. Data were analyzed by correlating the changes in BRS (n=90) with respect to changes in each parameter. No or a weak correlation was found between the changes in the baroreflex and parameters of systolic function or time of pacing. A stronger correlation was found between BRS and parameters of preload such as left ventricular enddiastolic pressure and left atrial pressure (p<0.001). In general, the bradycardia responses were depressed less than the tachycardia responses. The correlation between BRS and left atrial or left ventricular end diastolic pressure is consistent with the view that augmented input from cardiac receptors may contribute to the depressed baroreflex function in heart failure. These data also suggest that the sympathetic limb of baroreflex control of heart rate in chronic heart failure is depressed earlier and to a greater extent then the vagal limb.     

Childhood familial pheochromocytoma. Conflicting results of localization techniques

Childhood familial pheochromocytoma was investigated in four patients by abdominal computed tomographic scan, [131I]metaiodobenzylguanidine scan, and vena caval catecholamine sampling. Results conflicted with surgical findings. Computed tomographic scan identified all four adrenal tumors but missed two midline tumors in one patient. [131I]metaiodobenzylguanidine scan identified two of three adrenal tumors but also suggested extra-adrenal tumors not confirmed at operation in two of three patients. Vena caval sampling for catecholamines confirmed all adrenal tumors but suggested additional tumors not verified at operation in two of three patients. All patients are asymptomatic and have normal urinary catecholamines 15 to 51 months after operation. Because of the frequency of multiple tumors in familial pheochromocytoma, different diagnostic techniques were employed. False-positive results were more frequent with [131I]metaiodobenzylguanidine and vena caval sampling. Reinterpretation of the [131I]metaiodobenzylguanidine scans at a later date led to less false-positive interpretation, although the false-negative rate remained unchanged. More pediatric experience with [131I]metaiodobenzylguanidine scans and vena caval sampling in familial pheochromocytoma is needed. Confirmation of tumor and its localization rest with meticulous surgical exploration.     

A pressure overload model of congestive heart failure in rats

Approximately 32% of the rats used as animal models showed an elevated heart weight/body weight ratio (0.432[SEM 0.022] g.100 g-1 compared to 0.293[0.009] g.100 g-1 for sham-operated rats), a hydrothorax, pulmonary and liver congestion, and specific histological changes 82-93 weeks after surgically induced aortic constriction. The histological changes were comparable to those observed in hearts of people suffering from long term hypertension. Cardiac failure was also confirmed by depressed contractility as measured by maximum and minimum dP/dt (first derivative of left ventricular pressure), which were 4604(346) and 3627(526) mm Hg.sec-1, respectively, compared with 9165(745) and 5835(268) mm Hg.sec-1 respectively in rats that did not develop left ventricular hypertrophy and failure (CLIP rats). Systolic and left ventricular blood pressures measured under anaesthesia were also decreased: 71.6(5.0) and 88.1(6.3) mm Hg respectively in rats with congestive heart failure, compared with 83.6(2.4) and 109.5(3.6) mm Hg in CLIP rats. Except for a prolonged mean PQ interval associated with a lower heart rate and for a slightly shorter QRS interval in the conscious state, the electrocardiograms of rats with congestive heart failure did not show any major abnormalities specific to ventricular hypertrophy and/or failure. This model could be useful for studying the pathology and adaptative mechanisms in compensated pressure overload induced congestive heart failure as well as in studies comparing pathological changes and means of treatment of congestive heart failure with different aetiologies encountered in the human population.     

Utilização da cintigrafia com iodo-123-metaiodobenzilguanidina na estratificação do risco de morte súbita na insuficiência cardíaca

Metaiodobenzylguanidine (MIBG) is a false neurotransmitter noradrenaline analogue that is taken up by the ‘uptake 1’ transporter mechanism in the cell membrane of presynaptic adrenergic neurons and accumulates in catecholamine storage vesicles. Since it is practically unmetabolized, it can be labeled with a radioisotope (iodine-123) in scintigraphic exams to noninvasively assess the functional status of the sympathetic innervation of organs with a significant adrenergic component, including the heart. Studies of its application in nuclear cardiology appear to confirm its value in the assessment of conditions such as coronary artery disease, heart failure, arrhythmias and sudden death.Heart failure is a global problem, with an estimated prevalence of 2% in developed countries. Sudden cardiac death is the main cause of its high mortality. The autonomic nervous system dysfunction, including sympathetic hyperactivity, that accompanies chronic heart failure is associated with progressive myocardial remodeling, declining left ventricular function and worsening symptoms, and contributes to the development of ventricular arrhythmias and sudden death.Since 123I-MIBG cardiac scintigraphy can detect changes in the cardiac adrenergic system, there is considerable interest in its role in obtaining diagnostic and prognostic information in patients with heart failure.In this article we present a literature review on the use of 123I-MIBG scintigraphy for risk stratification of sudden death in patients with heart failure.     

Prediction of cardiac sympathetic nerve activity and cardiac functional outcome after treatment in patients with dilated cardiomyopathy: examination using dobutamine gated blood pool scintigraphy

OBJECTIVES: This study evaluated whether dobutamine gated blood pool scintigraphy can predict improvement of cardiac sympathetic nerve activity and cardiac function. METHODS: Sixteen patients(10 men and 6 women, mean age 59 +/- 13 years) with dilated cardiomyopathy underwent dobutamine gated blood pool scintigraphy to measure left ventricular ejection fraction (LVEF) using tracer at 0, 5, 10 and 15 micrograms/kg/min before treatment. Patients were divided into good responders (LVEF increase > or = 15%) 8 patients(GR Group) and poor responders(LVEF increase < 15%) 8 patients (PR Group) after treatment with beta-blocker or amiodarone with a background treatment of digitalis, diuretics and angiotensin converting enzyme inhibitor. I-123 metaiodobenzylguanidine(MIBG) imaging to evaluate cardiac sympathetic nerve activity and echocardiography were performed before and at one year after treatment. MIBG imaging was obtained 4 hours after tracer injection, and the heart/mediastinum count ratio(H/M ratio) calculated from the anterior planar image and the total defect score(TDS) from the single photon emission computed tomography image. LVEF and left ventricular endo-diastolic dimension (LVDd) were measured by echocardiography and New York Heart Association(NYHA) functional class was evaluated. RESULTS: The GR Group showed TDS decreased from 28 +/- 6 to 17 +/- 12(p < 0.05), H/M ratio increased from 1.79 +/- 0.26 to 2.07 +/- 0.32(p < 0.05), LVEF increased from 29 +/- 8% to 48 +/- 10%(p < 0.01), and LVDd decreased from 65 +/- 4 mm to 58 +/- 5 mm(p < 0.05). In contrast, the PR Group showed no significant changes in TDS, H/M ratio, LVEF and LVDd. NYHA functional class improved in both groups. The improvement was better in the GR Group than in the PR Group. CONCLUSIONS: Dobutamine gated blood pool scintigraphy is useful to predict the improvement of the cardiac sympathetic nerve activity and cardiac function, and symptoms after treatment in patients with dilated cardiomyopathy.     

QT Interval Variability in Type 2 Diabetic Patients with Cardiac Sympathetic Dysinnervation Assessed by 123I‐Metaiodobenzylguanidine Scintigraphy

QT Variability and Sympathetic Dysinnervation . Introduction: The mechanism of adverse prognosis attributable to proarrhythmic cardiac sympathetic dysinnervation in patients with type 2 diabetes is incompletely understood. This study sought the association of cardiac sympathetic dysinnervation with temporal instability of ventricular repolarization assessed by beat‐to‐beat QT interval variability. Methods and Results: ¹²³I‐metaiodobenzylguanidine (¹²³I‐MIBG) scintigraphy was analyzed in 31 type 2 diabetic patients for cardiac sympathetic dysinnervation (4‐hour heart‐to‐mediastinum ratio <1.8) and regional sympathetic integrity and washout rate (from 15‐minute ¹²³I‐MIBG uptake). Relative QT variability was defined from a continuous 5‐minute ECG in the supine position (n = 31) and standing position (subgroup; n = 15) by the log ratio of absolute QT variability (QT variance divided by the mean QT interval squared) to heart rate (HR) variability (HR variance divided by the mean HR squared). Patients with (n = 16; 52%) versus without cardiac sympathetic dysinnervation demonstrated higher relative QT variability in the supine position (P < 0.001), owing to lower HR variability. However, on standing, absolute QT variability was significantly raised in these patients (P = 0.009) despite similar HR variability in the 2 groups. Correlations of heart‐to‐mediastinum ratio with standing QT variability (relative [r =?0.63, P = 0.013] and absolute [r =?0.79, P = 0.001]) were superior to corresponding supine measures (relative [r =?0.47, P = 0.008] and absolute [P = NS]). No associations of QT variability with washout rate or regional ¹²³I‐MIBG uptake were identified. Conclusion: Elevated QT variability is associated with cardiac sympathetic dysinnervation in type 2 diabetes and may contribute to adverse prognosis. Moreover, QT variability may be more specific for cardiac sympathetic innervation when measured in the context of sympathetic activation. (J Cardiovasc Electrophysiol, Vol. 24, pp. 305‐313, March 2013)     

Chronic beta-adrenoceptor blockade prevents the development of beta-adrenergic subsensitivity in experimental right-sided congestive heart failure in dogs.

BACKGROUND. The reductions of myocardial beta-adrenergic receptor density and responsiveness to catecholamines in congestive heart failure are associated with excessive sympathetic stimulation. The purpose of this study was to determine whether the myocardial changes could be prevented by beta-receptor blockade. METHODS AND RESULTS. We administered the oral beta-receptor blocking agent nadolol (40 mg/day) to dogs during an early stage of experimental right heart failure and to sham-operated dogs for 5 weeks. Animals receiving no nadolol were studied concurrently. Nadolol treatment did not prevent right ventricular hypertrophy or elevated concentrations of plasma norepinephrine that occurred in right heart failure, nor did it affect the decrease in myocardial norepinephrine content and norepinephrine uptake activity, suggesting that the hemodynamic stress imposed on the right ventricle of dogs with right heart failure was similar regardless of the presence or absence of beta-receptor blockade. Resting heart rate, right atrial pressure, aortic pressure, cardiac output, right ventricular dP/dt, and left ventricular dP/dt and dP/dt/P measured 5 days after discontinuation of nadolol did not differ significantly from those without nadolol treatment in either right heart failure or sham-operated animals. Sham-operated dogs also showed no changes in myocardial beta-receptor or adenylate cyclase activity after nadolol treatment. However, nadolol treatment prevented the reduction of myocardial beta-receptor density and attenuated the decrease in the cardiac beta-adrenergic sensitivity that occurred in right heart failure. CONCLUSIONS. Excessive sympathetic stimulation may play an important role in the development of beta-receptor downregulation and beta-adrenergic subsensitivity in right heart failure.     

Increased myocardial [123I]-metaiodobenzylguanidine uptake after enalapril treatment in patients with chronic heart failure.

OBJECTIVE: To assess non-invasively the effect of enalapril on cardiac sympathetic neuronal uptake function in patients with congestive heart failure, by using [123I]-metaiodobenzylguanidine (MIBG), which is a noradrenaline analogue. Cardiac MIBG uptake was visualised by single photon emission tomography (SPET). In addition, plasma noradrenaline concentration, indicating systemic sympathetic activity, was measured to see whether it was related to cardiac MIBG uptake. DESIGN: Consecutive patients were treated with enalapril and served as their own controls. SETTING: Cardiac unit of a tertiary care centre. PATIENTS: 23 Patients with chronic, mild to moderate, stable congestive heart failure, and a left ventricular ejection fraction less than 40%. Heart failure was caused by ischaemic heart disease or was idiopathic. INTERVENTIONS: Cardiac MIBG SPET was performed and plasma noradrenaline concentration was measured before and after 6 weeks treatment with enalapril. MAIN OUTCOME MEASURES: Cardiac uptake of MIBG was measured by using the left ventricular cavity and a venous blood sample as a reference. RESULTS: Cardiac uptake of MIBG increased significantly after enalapril treatment, indicating improved cardiac neuronal uptake function. Plasma noradrenaline concentration did not decrease significantly. Cardiac MIBG uptake was not related to plasma noradrenaline concentration. CONCLUSIONS: Cardiac MIBG SPET can be used to assess changes in cardiac sympathetic neuronal uptake function caused by pharmacological intervention. Enalapril seemed to improve cardiac sympathetic neuronal uptake function but did not significantly affect plasma noradrenaline concentrations in a group of patients with predominantly moderate heart failure. These results accord with the hypothesis that restoration of cardiac neuronal uptake of noradrenaline is one of the beneficial effects of enalapril in such patients.     

Relationship between cardiac metaiodobenzylguanidine uptake and hemodynamic, functional and neurohormonal parameters in patients with heart failure.

BACKGROUND: Sympathetic activation plays a pivotal role in heart failure attributing to the disease process and symptoms of the patient. Myocardial sympathetic activity can be visualized using radioiodinated metaiodobenzylguanidine 123I-MIBG, a structural analogue of norepinephrine (NE). AIM OF THE STUDY: We investigated whether a relation exists between myocardial MIBG uptake and different functional, hemodynamic and neurohormonal parameters in patients with chronic heart failure. METHODS AND RESULTS: The study comprised 52 patients with stable congestive heart failure functional class II or III and left ventricular ejection fractions of <35%. The heart/mediastinum ratio (H/M ratio) was calculated to quantify myocardial MIBG uptake. A significant correlation was found between peak oxygen consumption and maximal exercise duration as exercise parameters and H/M ratio of MIBG (R, respectively, 0.36 and 0.4, P<0.05). From all other measured parameters, only plasma NE showed a significant correlation with the H/M ratio of MIBG. CONCLUSION: Cardiac sympathetic activity, as measured by myocardial MIBG uptake, is correlated with peak exercise parameters.     

Carotid sinus baroreceptor reflex in dogs with experimental heart failure

We have previously demonstrated a decrease in baroreceptor discharge sensitivity in dogs with experimental heart failure. In the present study, we determined the sensitivity of the carotid sinus baroreceptor reflex in dogs with pacing-induced heart failure. The carotid sinus baroreceptor reflex sensitivity was determined by pressurizing one carotid sinus with all other baroreceptor and cardiopulmonary receptor inputs removed. The data were analyzed by plotting carotid sinus pressure-mean arterial pressure curves and carotid sinus pressure-renal sympathetic nerve activity curves in the two groups of dogs. The peak arterial pressure during carotid hypotension was significantly depressed in dogs with heart failure compared with normal dogs (107.1 +/- 5.7 versus 139.8 +/- 7.0 mm Hg, p less than 0.001). Mean arterial pressure range, renal sympathetic nerve activity range, and peak slope were significantly decreased in the heart-failure group. To determine if this depression was completely due to depression of baroreceptor discharge per se, or to alterations in central or end-organ responsiveness, similar experiments were performed by stimulating the carotid sinus nerve and evaluating frequency, voltage, and duration of stimulation on the resultant mean arterial pressure and renal sympathetic nerve activity. As was the case with carotid sinus pressurization, electrical stimulation caused a significantly smaller change in mean arterial pressure in heart-failure dogs compared with the normal dogs. However, there was no significant difference between normal and heart-failure dogs for the renal sympathetic nerve activity-electrical stimulation curves. These data strongly suggest that the depressed carotid sinus baroreceptor reflex in heart failure is not solely the result of depressed baroreceptor responsiveness but may be related to poor end-organ responses and normal central control of renal sympathetic outflow.     

Analysis of baroreflex control of heart rate in conscious dogs with pacing-induced heart failure

The autonomic components of the baroreflex control of heart rate were evaluated in conscious mongrel dogs before and after 4-6 weeks of ventricular pacing (250 beats/min). Arterial baroreflex sensitivity (BRS) was determined by the slopes of linear regression of pulse interval versus the preceding systolic arterial pressure in response to bolus injections of either phenylephrine or nitroglycerin. BRS was significantly depressed in the heart failure state [nitroglycerin slope, 5.0 +/- 2.7 (mean +/- SD) versus 16.6 +/- 5.1 msec/mm Hg, p less than 0.005; phenylephrine slope, 15.0 +/- 14.8 versus 32.0 +/- 26.7 msec/mm Hg, p less than 0.005]. There was no depression in BRS in dogs that were used as time controls or were acutely paced for 30 minutes. After beta 1-adrenergic blockade with metoprolol, the resting heart rate in the heart failure state was depressed more than in the normal state (-17.0 +/- 5.0% versus -3.2 +/- 3.4%, p less than 0.001). Atropine significantly increased resting heart rate more in the normal state than in the heart failure state (115.8 +/- 36.7% versus 25.4 +/- 14.5%, p less than 0.005). Thus, dogs in the heart failure state appear to have high resting cardiac sympathetic tone and low resting vagal tone. For nitroglycerin administration, metoprolol depressed BRS by 47.6 +/- 26.3% in the normal state and by 63.6 +/- 58.5% in the heart failure state. Atropine decreased the BRS by 86.7 +/- 7.8% in the normal state and by 39.5 +/- 30.2% in the heart failure state.(ABSTRACT TRUNCATED AT 250 WORDS)     

Myocardial norepinephrine, epinephrine and dopamine concentrations after cardiac autotransplantation in dogs

Myocardial norepinephrine is markedly reduced after cardiac transplantation because of interruption of postganglionic cardiac sympathetic nerves. There are also substantial stores of dopamine in the myocardium, but the influence of cardiac denervation on dopamine remains unknown. The effect of cardiac transplantation was determined and, thus, the effect of denervation on myocardial norepinephrine, dopamine and epinephrine. Myocardial catecholamines were measured with high-performance liquid chromatography with electrochemical detection in five dogs 6 to 8 weeks and in four dogs 8 to 12 years after cardiac autotransplantation and in six sham-operated dogs with intact cardiac innervation. Norepinephrine, dopamine and epinephrine levels were determined from samples obtained from the right and left atria and ventricles. Samples from the left ventricular apex and base were analyzed separately. There was a striking depletion of norepinephrine in all cardiac chambers after short-term autotransplantation. The norepinephrine content of the left atrium in sham-operated dogs (1,659 +/- 219 ng/g) was significantly higher than that of dogs with long-term autotransplanted hearts (754 +/- 372 ng/g). Sham-operated dogs and dogs with long-term autotransplanted hearts had statistically significant (p less than 0.05) differences in norepinephrine content in the left ventricular apex (480 +/- 197 versus 294 +/- 198 ng/g), left ventricular base (876 +/- 2204 versus 654 +/- 156 ng/g) and right ventricle (766 +/- 133 versus 247 +/- 29 ng/g). In contrast to norepinephrine, dopamine concentrations were relatively preserved in the short-term group despite the virtual depletion of myocardial norepinephrine.(ABSTRACT TRUNCATED AT 250 WORDS)     

Ischemic ventricular arrhythmias during heart failure: A canine model to replicate clinical events

BACKGROUND: Development of experimental animal models has played an invaluable role in understanding the mechanisms of ventricular arrhythmias. OBJECTIVES: The purpose of this study was to evaluate a new canine model of myocardial infarction (MI), heart failure, and ischemic ventricular arrhythmias in an attempt to replicate clinical conditions. METHODS: Thirty-six mongrel dogs underwent placement of a permanent ventricular pacemaker and induction of an anterior MI by percutaneous transcatheter embolization of polyvinyl foam particles into the left anterior descending coronary artery (just distal to the first septal branch). After a 2-week recovery period, heart failure was induced by continuous rapid ventricular pacing at 200 to 240 ppm for 3 weeks. Transient (4-minute) myocardial ischemia was induced via balloon occlusion of the proximal left circumflex coronary artery. Echocardiographic and electrophysiologic testing was performed before MI creation and repeated prior to acute ischemia induction. RESULTS: Seven dogs (19%) died within several hours of MI creation. All surviving dogs developed severe left ventricular systolic dysfunction. Significant increases in the intraatrial and intraventricular conduction intervals were observed following MI creation and heart failure induction compared with baseline values, as evidenced by increases in the duration of the P wave and QRS complex. Significant increases in corrected QT interval and ventricular refractoriness were observed. Acute transient ischemia induced sustained ventricular tachycardia or ventricular fibrillation in 21 of 29 dogs (72%). CONCLUSION: This canine model can serve as a useful tool for studying ventricular arrhythmias during the interactions of healed infarction, heart failure, increased sympathetic tone, and myocardial ischemia.     

Effects of metoprolol in chagasic patients with severe congestive heart failure

BACKGROUND: Beta-blockers are the most effective and promising treatment for congestive heart failure secondary to left ventricular dysfunction and sympathetic activation. METHODS: Since chagasic patients with severe congestive heart failure have left ventricular systolic dysfunction and neurohormonal activation, we administered metoprolol to nine chagasic patients who were in severe congestive heart failure. Metoprolol (5 mg p.o. daily) was uptitrated on a weekly basis. RESULTS: Patients were receiving digitalis, diuretics and angiotensin converting enzyme inhibitors and had left ventricular dilatation (6.77+/-0.89 cm), depressed ejection fraction (0.20+/-0.06), low systolic blood pressure (93+/-11 mm Hg), sinus tachycardia (115+/-17 beats/min) and sympathetic activation 400+/-246 pg/ml). One patient was in New York Heart Association Functional class III and eight patients were in functional class IV. At the end of the fifth week of treatment (metoprolol 25 mg), seven patients were in functional class III and two were in functional class II. Heart rate decreased to 85+/-15 beats/min (P<0.05) and the systolic blood pressure increased to 108+/-18 mm Hg (P<0.01). There were no significant changes in left ventricular ejection fraction. By the end of the tenth week of treatment (metoprolol 50 mg), four patients were now in functional class I and five were in functional class II. Left ventricular ejection fraction increased to 0.27+/-0.05 (P<0.01) and the left ventricular systolic diameter decreased from 6.38+/-0.90 at baseline to 5.89+/-0.59 and 5.76+/-0.96 after 25 and 50 mg of metoprolol treatment, respectively (P<0.04). Plasma norepinephrine decreased non-significantly to 288+/-91 pg/ml. CONCLUSION: Beta-blockers improve the clinical status and the left ventricular function of chagasic patients with severe congestive heart failure.     

Congestive heart failure following chronic tachycardia

The mechanics of left ventricular contraction were analyzed in quantitative terms from isovolumic contractions in six dogs in which congestive heart failure developed following 13 to 29 days of chronic pacemaker-induced ventricular tachycardia. Twenty-four hours following cessation of stimulation, heart failure was evidenced in the intact sedated dogs by elevated left ventricular end-diastolic pressures (average, 28 mm. Hg), ascites, and the presence of a protodiastolic gallop sound. Aortic pressure, heart rate, and the ratio of stroke volume to end-diastolic volume were decreased while the ratio of left ventricular mass to body weight was unchanged, and cardiac output was increased, presumably secondary to hypervolemia. Left ventricular function was substantially reduced, contractile element velocity-tension relations were altered, and V_max was significantly reduced (failure 2.37 ± 0.40 circumferences per second vs. control 3.0 ± 0.03). The maximum isovolumic tension development for any given end-diastolic volume also was decreased in five of six animals. Left ventricular myocardial stores of creatine, creatine phosphate, and adenosine triphosphate were significantly depressed. These findings indicate that the syndrome of heart failure following chronic tachycardia, characterized by elevated left ventricular end-diastolic pressure and ascites, is associated with significant depression of the left ventricular contractile state and total energy stores.     

Mechanisms of Arrhythmias in Heart Failure

Mechanisms of Arrhythmias in Heart Failure. The diagnosis of heart failure infers a bad prognosis. Mortality is high and many patients die suddenly. Ventricular arrhythmias, commonly observed in patients with heart failure, are thought to underlie at least some of these sudden deaths. The mechanism of arrhythmias occurring in the setting of heart failure is still unclear. Experimental evidence points to a higher tendency for failing myocardium to develop delayed and early afterdepolarization-induced triggered activity and automaticity. Conditions favoring reentry also have been described in failing hearts. Modulating factors such as sympathetic activation, electrolyte disturbances, and chronic stretch are present in the setting of heart failure and may favor all of the mentioned mechanisms of arrhythmias. Clinical evaluation of arrhythmias in patients and animals with heart failure and the effects of pharmacologic treatment of ventricular arrhythmias in patients with depressed left ventricular function further accentuate that more than one mechanism of arrhythmia may he operating in heart failure and underscore the importance of modulating factors such as sympathetic activation and stretch.