Markers of responsiveness to disopyramide in patients with hypertrophic cardiomyopathy.

BACKGROUND: Significant left-ventricular outflow tract obstruction (LVOTO) in hypertrophic cardiomyopathy (HCM) may result in symptoms and is associated with adverse outcomes. Although disopyramide can reduce resting gradients, nearly 30% of HCM patients do not respond. We sought to study the clinical and echocardiographic variables associated with disopyramide-induced LVOT-gradient reduction. METHODS: Forty-one disopyramide-treated HCM patients (average daily-dose 305 mg) were subdivided into two groups: (1) nineteen responders, with a reduction of LVOT-gradients of at least 30% from baseline, and (2) twenty-two non-responders, in whom LVOT-gradients did not change or increased following treatment. All patients had a thorough clinical and echocardiographic assessment pre- and post-treatment initiation. RESULTS: Patients who responded to disopyramide had better pretreatment left ventricular (LV) systolic function (LV ejection fraction of 67.9 ±â€¯5.6% vs. 59.7 ±â€¯5.8%, p = 0.0001), better LV global longitudinal strain (-17.9 ±â€¯2.3% vs. -16.1 ±â€¯2.5%, p = 0.048), less mitral regurgitation, smaller LV size (indexed LV end-systolic volume of 16.2 ±â€¯5.1 ml/m2 vs. 23.2 ±â€¯6.8 ml/m2, p = 0.001), and lower LV maximal wall thickness (17.2±3 mm vs.19.2 ±â€¯3.4 mm, p = 0.046). Baseline left atrial (LA) volumes were significantly lower in the responders, with higher indices of LA ejection fraction (62 ±â€¯11.2% vs. 50.5 ±â€¯12.2%, p = 0.005), systolic LA strain (34 ±â€¯12.4% vs. 25.8 ±â€¯10.6%, p = 0.04), and LA strain-rate (1.34 ±â€¯0.49%/sec vs. 0.99 ±â€¯0.24%/sec, p = 0.012). In multivariable analysis, the presence of reduced LV systolic function and systolic LA strain-rate remained independently associated with poor response to disopyramide. CONCLUSIONS: Obstructive HCM patients with more severe disease at baseline tend to respond less to disopyramide treatment. In those patients, early referral for alcohol septal ablation or myectomy surgery should be considered.

Theophylline as an adjunct to control malignant ventricular arrhythmia associated with early repolarization.

Early repolarization (ER) has been associated with an increased risk of sudden cardiac arrest. Interestingly, ventricular arrhythmias seem to be triggered by parasympathetic stimulation. In the present case report, we describe complete control of highly frequent malignant ventricular arrhythmias after adding theophylline to ineffective oral hydroquinidine and high-rate pacing in a patient suffering from malignant ER. We hypothesize that the theophylline-mediated enhanced beta-adrenergic stimulation could reduce the transmural myocardial voltage discrepancy by increasing the inward ICa,L current.

Can pharmacologic gradient reduction decrease mortality in hypertrophic cardiomyopathy?

Pharmacologic therapy is the first line approach to relieve symptoms in obstructive hypertrophic cardiomyopathy. There are no randomized trials to evaluate their effect on prognosis. Gradient reduction by surgical septal myectomy is associated with excellent prognosis, but not all patients have symptoms severe enough to require surgery; and, guidelines recommend operation only for patients with high gradients and symptoms unresponsive to pharmacologic therapy. The combination of disopyramide and beta-blockade is effective in reducing resting gradients (though not to the extent of surgery). This review examines the question of whether pharmacologic reduction of gradient in asymptomatic patients or those with milder symptoms might decrease HCM-related mortality.

In vivo effects of mutant HERG K+ channel inhibition by disopyramide in patients with a short QT-1 syndrome: a pilot study.

INTRODUCTION: Quinidine has been evaluated in patients with a short QT-1 syndrome caused by an IKr gain-of-function mutation of HERG. Recently, in vitro data with disopyramide showed an even stronger effect on the N588K mutant current. The aim of the present study was to test the in vivo effects of disopyramide in patients with short QT-1 syndrome caused by a N588K mutation in HERG. METHODS AND RESULTS: Repetitive ECGs were recorded in two female patients with short QT-1 syndrome with a N588K-HERG mutation off drugs, on oral quinidine, and on oral disopyramide. One patient underwent exercise testing on drugs to determine the QT interval to heart rate relation, whereas the QT interval was calculated to the peak of the T wave in lead V3. In the same patient, drug-induced changes in ventricular effective refractory periods were determined by programmed ventricular stimulation via the ICD lead. Disopyramide increased the QT interval from QTc 329 ms/QTc 315 ms, respectively, off drugs to QTc 358 ms/QTc 333 ms in both patients and restored the heart rate dependence of the QT interval toward normal subjects (-0.39 ms/bpm off drugs, -0.58 ms/bpm on disopyramide vs. 1.29 +/- 0.33 ms/bpm in normal subjects). The ventricular effective refractory period increased under disopyramide by 40 ms. CONCLUSION: These preliminary observations suggest that oral disopyramide may be a suitable alternative to quinidine for prolonging the QT interval and ventricular effective refractory periods in patients with short QT-1 syndrome. Further studies of this pharmacologic approach are warranted.

Phase I and pharmacokinetic study of amrubicin, a synthetic 9-aminoanthracycline, in patients with refractory or relapsed lung cancer.

Amrubicin is a novel synthetic 9-aminoanthracycline derivative and is converted enzymatically to its C-13 hydroxy metabolite, amrubicinol, whose cytotoxic activity is 10-100 times that of amrubicin. We aimed to determine the maximum tolerated dose (MTD) of amrubicin and to characterize the pharmacokinetics of amrubicin and amrubicinol in previously treated patients with refractory or relapsed lung cancer. The 15 patients were treated with amrubicin intravenously at doses of 30, 35, or 40 mg/m(2) on three consecutive days every 3 weeks for a total of 43 courses. Neutropenia was the major toxicity (grade 4, 67%). The MTD was 40 mg/m(2), with the specific dose-limiting toxicities being grade 4 neutropenia persisting for >4 days, febrile neutropenia, or grade 3 arrhythmia in the three patients treated at this dose. A patient with non-small-cell lung cancer showed a partial response, and ten individuals experienced a stable disease. The area under the plasma concentration versus time curve (AUC) for amrubicin and that for amrubicinol increased with amrubicin dose. The amrubicin AUC was significantly correlated with the amrubicinol AUC. The recommended phase II dose of amrubicin for patients with lung cancer refractory to standard chemotherapy is thus 35 mg/m(2) once a day for three consecutive days every 3 weeks.

[Atrial flutter and fibrillation]. / Vorhofflimmern und Vorhofflattern.

This article summarizes current understandings and therapies for both arrhythmias. Atrial flutter is most often arising from a macroreentry circuit in the right atrium or around scar tissue in case or previous cardiothoracic surgery. As a macroreentrant tachycardia it is regular and can lead to higher heart rates, especially if occurring with 1:1 conduction. In contrast atrial fibrillation, especially when occurring paroxysmal at the beginning, is arising from triggers within the pulmonary veins. Ablation strategies to electrically isolate those triggers have a treatment success rate of 80%, which is much more than can be achieved with antiarrhythmic medication (success rates 30-50%). Emergency treatment of both arrhythmias include cardioversion and pacemaker implantation with AV node ablation if necessary.

Pharmacological treatment of reflex syncope.

Patient education, identification of possible triggers of syncope and reassurance are a central feature of the management of patients with reflex syncope. Patients should be advised as to the importance of adequate hydration and taught physical countermaneuvers to enhance cardiac venous return. These maneuvers are sufficient for most patients, however, for a small number of patients who continue to have recurrent syncopal events, pharmacological intervention may be considered. Volume expansion can be enhanced with salt and fludrocortisone. Agents from diverse pharmacological classes have been used to attenuate the reflex response, enhance vasoconstriction and attenuate vagal outflow. Alpha adrenoreceptor agonists, anticholinergic agents, theophylline, beta adrenoreceptor antagonists, serotonin reuptake inhibitors and disopyramide are the most widely studied. None of these agents has shown a consistent therapeutic benefit in clinical trials.

Strategy for the management of vasovagal syncope.

The disorders of autonomic control associated with orthostatic intolerance are a diverse group of syndromes that can result in syncope and near-syncope. A basic understanding of the pathophysiology of these disorders is essential to diagnosis and proper treatment. It is especially important to recognise the difference between the effect of prolonged upright posture on a failing autonomic nervous system (a hyposensitive or dysautonomic response) and the vasovagal response (which may be a hypersensitive response). Vasovagal syncope is the most common abnormal response to upright posture and occurs in all age groups. The advent of tilt table testing has helped define a population with an objective finding during provocative testing that has enabled researchers to study the mechanism of vasovagal syncope and to evaluate the efficacy of treatments. In most patients, vasovagal syncope occurs infrequently and only under exceptional circumstances and treatment is not needed. Treatment may be indicated in patients with recurrent syncope or with syncope that has been associated with physical injury or potential occupational hazard. Based on study data, patients with vasovagal syncope can now be risk stratified into a high-risk group likely to have recurrent syncope and a low-risk group. Many patients with vasovagal syncope can be effectively treated with education, reassurance and a simple increase in dietary salt and fluid intake. In others, treatment involves removal or avoidance of agents that predispose to hypotension or dehydration. However, when these measures fail to prevent the recurrence of symptoms, pharmacological therapy is usually recommended. Although many pharmacological agents have been proposed and/or demonstrated to be effective based on nonrandomised clinical trials, there is a remarkable absence of data from large prospective clinical trials. Data from randomised placebo-controlled studies support the efficacy of beta-blockers, midodrine, serotonin reuptake inhibitors and ACE inhibitors. There is also considerable clinical experience and a consensus suggesting that fludrocortisone is effective. Encouraging new data suggest that a programme involving tilt training can effectively prevent vasovagal syncope. For patients with recurrent vasovagal syncope that is refractory to these treatments, implantation of a permanent pacemaker with specialised sensing/pacing algorithms appears to be effective. A number of larger clinical trials are underway which should help further define the efficacy of a number of different treatments for vasovagal syncope.

Medical therapy of neurocardiogenic syncope.

Neurocardiogenic syncope, alternatively called vasovagal, vasodepressor, or neurally mediated syncope, is a clinical syndrome faced by many clinicians. Its pathophysiology is complicated and not fully understood. Multiple pharmacologic therapies have been evaluated, with no clear ideal agent. Decisions regarding tilt-table testing, selection of pharmacotherapy, and assessment of drug efficacy are not straightforward. This article attempts to assess these issues.

Fibrilaçäo atrial: papel dos antiarrítmicos convencionais na reversäo das crises e prevençäo de recorrências / Atrial fibrilation: role of conventional antiarrythmic drugs in reversion and prevention of recurrences

A fibrilaçäo atrial é a taquiarritmia supraventricular mais comum da clínica e sua sintomatologia está relacionada com a ausência da contraçäo atrial, a irregularidade da resposta ventricular, a frequência ventricular e o estado da funçäo ventricular. O restabelecimento do ritmo sinusal pode ser feito por meio da cardioversäo química ou elétrica, precedida ou näo de anticoagulaçäo, na dependência dos fatores de risco do paciente para a formaçäo de trombos ou da duraçäo da arritmia. Provavelmente a cardioversäo da fibrilaçäo atrial está indicada na maioria dos casos; entretanto, o perfil clínico do paciente que deve ser submetido a esta conduta ainda näo foi identificado. A reversäo química da fibrilaçäo atrial pode ser realizada ambulatorialmente, utilizando-se fármacos dos grupos IA, IC ou III, cuja escolha é feita em bases clínicas. Mais recentemente, o emprego de propafenona e amiodarona vem submetendo aumentando devido à razoável eficácia e baixo risco de pró-arritmia mais comum com fármacos do grupo I, particularmente a quinidina. Uma vez restaurado o ritmo sinusal a prevençäo de recorrências é necessária de preferência com o mesmo agente que causou a reversäo. Nos pacientes sem indicaçäo para reversäo ou naqueles nos quais näo se pretende reverter (fibrilaçäo atrial permanente), está indicado o controle da resposta ventricular com fármacos que retardam a conduçäo nodal, associado à anticoagulaçäo em pacientes de alto risco para tromboembolismo.

Dynamic outflow obstruction due to the transient extensive left ventricular wall motion abnormalities caused by acute myocarditis in a patient with hypertrophic cardiomyopathy: reduction in ventricular afterload by disopyramide.

A 65-year-old woman was admitted to the coronary care unit because of acute pulmonary edema. Immediate 2-dimensional and Doppler echocardiograms revealed extensive left ventricular wall motion abnormalities and left ventricular hypertrophy with extreme outflow obstruction. Although an ECG showed ST-segment elevation in the anterolateral leads, a coronary arteriogram revealed normal epicardial arteries. Heart failure was relieved after diminishing the dynamic outflow obstruction with disopyramide administration. An endomyocardial biopsy from the right ventricle on the 8th hospital day showed borderline myocarditis. Wall motion abnormalities gradually normalized within 2 weeks. It is speculated that her pulmonary edema would not have been relieved so readily without the immediate reduction in ventricular afterload by disopyramide. These clinical changes over time were observed with serial echo-Doppler examinations.

Management of vasovagal syncope.

Vasovagal syncope is a common disorder of autonomic cardiovascular regulation that can be very disabling and result in a significant level of psychosocial and physical limitations. The optimal approach to treatment of patients with vasovagal syncope remains uncertain. Although many different types of treatment have been proposed and appear effective based largely on small nonrandomized studies and clinical series, there is a remarkable absence of data from large prospective clinical trials. However, based on currently available data, the pharmacologic agents most likely to be effective in the treatment of patients with vasovagal syncope include beta blockers, fludrocortisone, and alpha-adrenergic agonists. In this article, we provide a summary of the various therapeutic options that have been proposed for vasovagal syncope and review the clinical studies that form the basis of present therapy for this relatively common entity.

Disopyramide improves hypoxia in patients with tetralogy of Fallot through a negative inotropic action.

The hemodynamic and right ventricular volumetric effects of disopyramide were investigated in patients with tetralogy of Fallot (TF). Intracardiac pressure and oxygen saturation were measured, before and after intravenous administration of disopyramide (2 mg/kg) in 7 patients who had not had previous surgery. Right ventricular volume and the diameter of its outflow tract were analyzed in these 7 and in a further 4 patients with a previous shunt. Aortic oxygen saturation increased from 90.4+/-7.5 (mean+/-SD) to 94.1+/-5.5% (p<0.05) with an increase in pulmonary blood flow and pressure. The systolic pressure gradient between the main pulmonary artery and the right ventricle decreased from 59+/-8 to 42+/-9 mmHg (p<0.01). Aortic pressure fell from 77+/-5 to 67+/-4 mmHg (p<0.05). Systemic vascular resistance increased from 15.3+/-2.2 to 19.4+/-3.3 u x m2 (p<0.05). Pulmonary vascular resistance remained unchanged. The diastolic and systolic diameter indices of the right ventricular outflow tract increased from 17.8+/-3.8 to 20.5+/-3.4 and from 6.5+/-3.0 to 10.4+/-2.2 mm/m2, respectively (p<0.01), whereas the right ventricular ejection fraction decreased. Disopyramide improves systemic oxygen saturation in patients with TF through its negative inotropic action on the right ventricle.

Efficacy and safety of clonazepam in refractory neurally mediated syncope.

Neurally mediated syncope is a complex syndrome that is often difficult to manage using currently available treatment strategies. The efficacy and safety of clonazepam was evaluated in 35 patients with refractory neurally mediated syncope. All patients had syncope (n = 33) or disabling presyncope (n = 2) and a positive head-up tilt table test (HUTT) despite treatment with one or more of the following therapies: beta-blocker, high-salt diet, fludrocortisone, elastic compression stockings, and disopyramide. Clonazepam was initiated at 0.5 mg/day and titrated in 0.25-0.5 mg/day increments for symptom control. Early (first 8 weeks) symptomatic response was achieved in 31 of 35 (89%) patients. Early HUTT reverted to negative in 29 of 35 (83%) patients. Two patients discontinued clonazepam during early follow-up due to side effects. Thirty-three patients received long-term clonazepam therapy. Twenty-five patients had late HUTT with 21 remaining negative. Of the eight patients who did not have late HUTT, one patient discontinued clonazepam prior to HUTT due to side effects. Seven patients refused late HUTT. All seven patients achieved symptomatic control on clonazepam with two requiring dose titration. Of the 21 patients with a negative late HUTT, 18 achieved symptomatic control with two of these patients requiring dose titration. Two patients who had only partial symptom control despite dose titration achieved total symptomatic control with the addition of disopyramide and beta-blockers. Two patients with a negative late HUTT discontinued clonazepam due to side effects. One patient had been symptomatically controlled while the other had recurrent symptoms with dose limiting side effects occurring after clonazepam dose titration. In the 4 patients with a positive late HUTT, 2 patients were symptomatically controlled, 1 patients required combination therapy with a beta-blocker to achieve symptomatic control, and 1 patient discontinued therapy due to side effects. Overall, 29 of 35 (83%) patients continue to receive clonazepam with symptom control. Based on intention-to-treat HUTT results, 21 of 35 (60%) patients were responders. Four patients required clonazepam dose titration and three required combination therapy with clonazepam plus disopyramide and/or a beta-blocker to achieve control. Clonazepam was discontinued in 6 patients, 5 for side effects and 1 following a transient ischemic attack. Clonazepam appears to be an effective therapeutic alternative in patients with refractory neurally mediated syncope. Based on our preliminary findings, a placebo controlled evaluation of clonazepam in neurally mediated syncope is warranted.

Unexplained syncope: clinical management.

The management of unexplained syncope begins with the patient's history and physical examination, which are oriented to help separate benign from serious causes. Malignant etiologies are more likely to occur with exertional syncope. Cardiac causes should be considered, particularly cardiomyopathy, postoperative congenital heart disease, right ventricular dysplasia, anomalous coronary artery, pulmonary artery hypertension, myocarditis, long QT syndrome, and Wolff-Parkinson-White syndrome. Neurological and metabolic disorders may underlie a syncope episode. After malignant causes of syncope have been excluded and the diagnosis of neurocardiac syncope has been established, treatment strategies include behavior modification, salt and increased fluids, and pharmacological agents. Efficacious agents include beta-blockers, dysopyramide, fludrocortisones, and alpha agents. Yet, behavior modification alone may be as effective as salt or pharmacological therapy. Because the natural history of neurocardiac syncope in children is spontaneous resolution, it is appropriate to try the simple measures before introducing drug therapy.