Frequent Implantable Cardioverter-defibrillator Shocks Research Articles

Role of cardiac imaging in patients undergoing catheter ablation of ventricular tachycardia.

Ventricular tachycardia is a major health issue in patients with structural heart disease (SHD). Implantable cardioverter defibrillator (ICD) therapy has significantly reduced the risk of sudden cardiac death (SCD) in such patients, but on the other hand, it has led to frequent ICD shocks as an emerging problem, being associated with poor quality of life, frequent hospitalizations and increased mortality. Myocardial scar plays a central role in the genesis and maintenance of re-entrant arrhythmias, as the coexistence of surviving myocardial fibres within fibrotic tissue leads to the formation of slow conduction pathways and to a dispersion of activation and refractoriness that constitutes the milieu for ventricular tachycardia circuits. Catheter ablation has repeatedly proven to be well tolerated and highly effective in treating VT and in the last two decades has benefited from continuous efforts to determine ventricular tachycardia mechanisms by integration with a wide range of invasive and noninvasive imaging techniques such as intracardiac echocardiography, cardiac magnetic resonance, multidetector computed tomography and nuclear imaging. Cardiovascular imaging has become a fundamental aid in planning and guiding catheter ablation procedures by integrating structural and electrophysiological information, enabling the ventricular tachycardia arrhythmogenic substrate to be characterized and effective ablation targets to be identified with increasing precision, and allowing the development of new ablation strategies with improved outcomes. In this review, we provide an overview of the role of cardiac imaging in patients undergoing catheter ablation of ventricular tachycardia.

Radiofrequency Ablation in Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC).

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a heritable form of cardiomyopathy, typically with autosomal dominant transmission, shown to be a defect in the cardiac desmosomes, with distinct regional and histopathological features. Clinically, this can ultimately result in bi-ventricular failure and/or malignant ventricular tachycardia (VT) via reentrant circuits created by patchy scar formation. We sought to review the current treatment for ventricular arrhythmias in the setting of ARVC, with particular attention to radiofrequency (RF) ablation and its varied techniques, along with potential therapies in the ablation spectrum. There is underwhelming data on the effectiveness of medical therapy for ARVC-related VT, including beta-blockers and antiarrhythmic medication. Primary and secondary prophylactic implantable-cardioverter defibrillator (ICD) implantation in higher-risk patients is recommended. More recently, RF ablation has been used for ARVC-related VT. Endocardial VT ablation in this setting can produce acute success, though recurrence rate is quite high, which may be explained by the more epicardial and patchy nature of the disease. Combined endocardial-epicardial ablation has since been shown to be feasible, safe, and with significantly better acute and long-term success, particularly when combined with scar dechanneling or homogenization of the scar. However, recurrence rates are not insignificant, and ablation does not eliminate the need for ICD placement. Medical therapy for ARVC-related VT is suboptimal. RF ablation techniques including endocardial and epicardial approaches appear to have the highest success rates for ARVC-related VT. Catheter ablation of VT in ARVC patients should be considered a potentially effective strategy for eliminating frequent VT episodes and ICD shocks rather than a curative therapeutic approach, until long-term efficacy has been consistently documented. Research into the optimal mapping and ablation techniques are promising and ongoing.

Off-line analysis of electro-anatomical mapping in ventricular arrhythmias.

Sudden cardiac death due to ventricular tachycardia (VT) is a major health issue in patients with structural heart disease and depressed ejection fraction. If from one side, implantable cardioverter defibrillator (ICD) therapy has significantly improved survival of these patients, on the other hand, it has led to frequent ICD shocks as an emerging problem, being associated with poor quality of life, frequent hospitalizations and increased mortality. Scar-related re-entry due to the coexistence of surviving myocardial fibers within fibrotic tissue is the most common mechanism subtending VT both in ischemic and non-ischemic cardiomyopathies. In the last two decades, continuous efforts to determine VT mechanisms and effectively prevent and treat VT with a substrate-based approach has benefit from off-line analysis of data coming from invasive electroanatomical mapping as well as from noninvasive imaging modalities such as cardiac magnetic resonance able to identify the arrhythmic substrate. In this review, we walk over again established methods for VT substrate characterization and we present possible applications of new emerging technologies.

Abstract 9629: Combination Therapy of Cilostazol and Bepridil Suppresses Recurrent Ventricular Fibrillation Related to J-Wave Syndromes

Introduction: Brugada syndrome (BrS) and idiopathic ventricular fibrillation (VF) associated with infero-lateral early repolarization patterns (early repolarization syndrome (ERS)) are termed “J-wave syndromes”. In such patients, an implantable cardioverter-defibrillator (ICD) is first-line therapy for prevention of sudden cardiac death. However, frequent ICD shocks due to recurrent VF remain serious problems. We investigated if combination therapy using cilostazol and bepridil could suppress recurrent VF. Methods: Our cohort comprised 22 consecutive patients (BrS, 16; ERS, 3; unknown, 3) with J-wave syndromes in whom ICDs were implanted for spontaneous episodes of VF. We enrolled 7 patients with J-wave syndromes who experienced ICD shocks due to recurrent VF after ICD implantation. At first, cilostazol was instituted. In all subjects, palpitations due to sinus tachycardia caused by cilostazol were symptomatic. Addition of bepridil attenuated cilostazol-induced palpitations (87±12 to 66±7 bpm, P<0.01) and maintained the suppressive effect of cilostazol against VF. Results: Prior to the onset of the cilostazol/bepridil combination therapy, all 7 patients had a total of 20 shocks over an accumulated period of 79 months. In contrast, after the onset of therapy, they accumulated a combined follow-up period of 375 months, and during that significantly longer period only one of them received 2 shocks. Three patients underwent replacement of the ICD generator 4-5 years after ICD implantation. Cilostazol was discontinued 2 days before replacement because of its anti-platelet effects. In all 3 patients, temporary discontinuation of cilostazol led to the reappearance of J waves, culminating in VF and an appropriate ICD shock in one of them. J waves disappeared upon re-institution of cilostazol. Conclusions: These data suggest that combination therapy of cilostazol and bepridil may be effective and safe in suppressing VF recurrence in some cases of J-wave syndromes.

Combination therapy of cilostazol and bepridil suppresses recurrent ventricular fibrillation related to J-wave syndromes.

Brugada syndrome and idiopathic ventricular fibrillation (VF) associated with inferolateral early repolarization patterns are termed "J-wave syndromes." In such patients, an implantable cardioverter-defibrillator (ICD) is first-line therapy for prevention of sudden cardiac death. However, frequent ICD shocks due to recurrent VF remain serious problems. The purpose of this study was to ascertain if combination therapy of cilostazol and bepridil could suppress recurrent VF. We enrolled 7 patients with J-wave syndromes who experienced ICD shocks due to recurrent VF after ICD implantation. At first, cilostazol was instituted. In all subjects, palpitations due to sinus tachycardia caused by cilostazol were symptomatic. Addition of bepridil attenuated cilostazol-induced palpitations and maintained the suppressive effect of cilostazol against VF (87 ± 12 bpm to 66 ± 7 bpm, P < .01). Six patients remained free of VF. Three patients underwent replacement of the ICD generator 4-5 years after ICD placement. Cilostazol was discontinued 2 days before replacement because of its antiplatelet effects. In all 3 patients, temporary discontinuation of cilostazol led to the reappearance of J waves, culminating in VF and an appropriate ICD shock in 1 patient. J waves disappeared with reinstitution of cilostazol. These data suggest that combination therapy of cilostazol and bepridil may be effective and safe in suppressing VF recurrence in some cases of J-wave syndromes.

Left Cardiac Sympathetic Denervation in Patients with Heart Failure: a New Indication for an Old Intervention?

Heart failure (HF) is characterized by an autonomic imbalance with withdrawal of vagal activity and increased sympathetic activity. Novel non-pharmacological approaches to HF aimed at increasing vagal activity are being proposed. Left cardiac sympathetic denervation (LCSD) has been shown to modify favorably the outcome of several disorders characterized by life-threatening arrhythmias triggered by increased sympathetic activity. The present manuscript discusses the rationale and the limited experimental and clinical experience suggesting a potential role for LCSD in the treatment of patients with advanced heart failure. Possible future clinical applications of LCSD may include HF patients who are intolerant to β-adrenergic blockade, HF patients who have frequent implantable cardioverter-defibrillator shocks, and HF patients in countries where the likelihood of receiving a device is limited, but the capability to perform a one in a lifetime procedure is present.

Catheter Ablation for Ventricular Tachycardia in Structural Heart Disease

The management of ventricular tachyarrhythmias has changed significantly over the past several decades. The advent of readily available implantable cardioverter defibrillators (ICDs) has had the greatest effect, with important mortality effects in patients with ventricular tachycardia and structural heart disease. ICDs have been shown to reduce sudden death in patients with ischemic and nonischemic cardiomyopathies; evidence of adverse consequences of ICD shocks, however, is mounting. In addition to the negative effects on patient-reported quality of life, anxiety, and depression, frequent ventricular arrhythmias and ICD shocks have also been associated with increased mortality. It is therefore important to identify and implement effective ventricular tachycardia-suppressive strategies. Antiarrhythmic drugs represent one such method, but are challenged by unfavourable side effect profiles and proarrhythmic risk. Catheter ablation of ventricular tachycardia is now a well-accepted intervention, which has been demonstrated to reduce recurrent arrhythmias. Questions persist regarding the optimal role for ablation compared with drug therapy.

Temporary Percutaneous Left Ventricular Support for Ablation of Untolerated Ventricular Tachycardias

Catheter ablation is increasingly recognized as an important option for the treatment of ventricular tachycardia (VT) in the serious clinical settings of frequent implantable cardioverter defibrillator shocks, and arrhythmia storms, in a variety of structural heart diseases.1 The high incidence of VTs that are not hemodynamically tolerated forces challenges to the traditional approaches of using activation and entrainment mapping to localize the ablation target area, in favor of a strategy of substrate modification that can be performed during sinus rhythm. In some patients, however, a clear target cannot be detected during sinus rhythm; this frequently occurs in some forms of nonischemic cardiomyopathies. More recently, interest is growing in the possibility of making VT tolerable through cardiopulmonary support. Article see p 1202 In this issue of Circulation: Arrythmia and Electrophysiology , Ostadal et al2 provide experimental data on the different capabilities offered by 3 commercially available support systems. It should be kept in mind, however, that these systems are Food and Drug Administration–approved only to support temporary high-risk situations. The data offered in this study are limited in that they provide only information related to systemic arterial pressure in healthy animals and do not allow any evaluation of the different levels of perfusion attained at individual critical organs, ie, brain or kidney. The study does, however, offer a comparative evaluation of the performances of these different systems and offers the opportunity to discuss advantages and limitation of their use. Percutaneous left ventricular assist devices (pLVAD) are increasingly used in few high-volume and skilled centers around the world in an attempt to achieve hemodynamic support during previously nontolerated ventricular arrhythmias to allow use of electrophysiological maneuvers to identify the critical isthmus of the circuit where an effective ablation will produce a permanent interruption of the VT. It is hoped that …

Congenital Long QT 3 in the Pediatric Population

There is insufficient knowledge concerning long-QT (LQT) 3 in the pediatric population to determine whether recommendations for more aggressive therapy in these patients are appropriate. An international multicenter review of 43 children with cardiac sodium channel (SCN5A) mutations and clinical manifestations of LQT syndrome without overlap of other SCN5A syndromes was undertaken to describe the clinical characteristics of LQT3 in children. Patients were aged 7.6 ± 5.9 years at presentation and were followed for 4.7 ± 3.9 years. There was significant intrasubject corrected QT interval (QTc) variability on serial electrocardiography. Forty-two percent presented with severe symptoms or arrhythmia and exhibited longer QTc intervals compared to asymptomatic patients. None of the 14 patients who underwent primary prevention implantable cardioverter-defibrillator (ICD) implantation received appropriate shocks in 41 patient-years of follow-up, while 2 of 6 patients who underwent secondary prevention ICD implantation received appropriate shocks in 30 patient-years of follow-up. Half of patients who underwent ICD implantation experienced inappropriate shocks or ICD-related complications. Mexiletine significantly shortened the QTc interval, and QTc shortening was greater in patients with longer pretreated QTc intervals. Two ICD patients with frequent appropriate ICD shocks showed immediate clinical improvement, with elimination of appropriate ICD shocks after mexiletine loading. In conclusion, severe symptoms are common in children with LQT3 and are associated with longer QTc intervals. ICD implantation is associated with significant morbidity. Mexiletine shortens the QTc interval, and it may be beneficial.

Successful catheter ablation of epicardial ventricular tachycardia worsened by cardiac resynchronization therapy

Soon after an upgrade from a single-chamber implantable cardioverter-defibrillator (ICD) to cardiac resynchronization therapy (CRT) with an ICD, a 64-year-old man with non-ischaemic cardiomyopathy began to have increasingly frequent ICD shocks for slow ventricular tachycardia (VT). At electrophysiological study, no clinical VT was induced by endocardial right ventricular pacing, but was easily induced by epicardial left ventricular (LV) pacing via a subxiphoid pericardial approach. The VT was successfully ablated on the LV epicardial surface. This case suggests that epicardial catheter ablation may be an alternative for managing CRT-induced proarrhythmias without the inactivation of LV pacing.

Ten‐Year Follow‐Up of Cardiac Sympathectomy in a Young Woman with Catecholaminergic Polymorphic Ventricular Tachycardia and an Implantable Cardioverter Defibrillator

Current recommendations for therapy of catecholaminergic ventricular tachycardia (CPVT) include beta blockade and implantable cardioverter defibrillators (ICDs). Patients may experience recurrent arrhythmias, ICD shocks and, rarely, sudden death despite optimal medical therapy. We report a young woman with CPVT who received frequent ICD shocks despite beta blockade, who subsequently underwent cardiac sympathectomy with a dramatic reduction in shocks over 10 years of follow-up.

Validity and Reliability of the Chronic Heart Failure Questionnaire Mastery Subscale in Patients With Defibrillators

Reliable, valid measures are needed to assess one's sense of mastery, which has the potential for decreasing anxiety and depressive symptoms among patients with implantable cardioverter-defibrillators (ICDs). This study evaluates the reliability and validity of a measure of mastery, the Chronic Heart Failure Questionnaire (CHQ) mastery subscale. One hundred twenty-two (75% men, mean age 65 years) and 100 patients complete baseline and 12-month face-to-face interviews, respectively. The CHQ mastery subscale is found to have internal consistency reliability (Cronbach's alphas = .79, .84), and its validity is supported. Factor analysis yields a single robust factor. Differences in the CHQ mastery subscale scores by the New York Heart Association (NYHA) classes are found: Patients with NYHA Class III or IV have lower mastery than those with Class I or II. Baseline younger age and less frequent ICD shocks and lower mastery are significant predictors of respectively 12-month anxiety (R( 2) = .37) and depressive symptoms (R(2) = .45).The CHQ mastery subscale has demonstrated satisfactory reliability and validity in this sample.

Simultaneous epicardial and endocardial substrate mapping and radiofrequency catheter ablation as first-line treatment for ventricular tachycardia and frequent ICD shocks in chronic chagasic cardiomyopathy

Slow conduction scarred areas are related with ventricular tachycardia (VT) arrhythmogenesis in nonischemic cardiomyopathy. The purpose of this study was to characterize the substrate in both epicardial and endocardial surfaces of the left ventricle and to evaluate the effectiveness of substrate mapping and ablation for VT in Chagas cardiomyopathy. Seventeen patients were evaluated prospectively using a simultaneous epicardial and endocardial electroanatomical substrate mapping and ablation. With a mean of 201 +/- 94 epicardial and 169 +/- 77 endocardial points, the epicardial voltage areas < or =0.5 mV were 56.8 +/- 40.6 (range 4.4 to 154.8 cm(2)) as compared to 22.5 +/- 15.8 cm(2) (range 5.4 to 61.0 cm(2); p = 0.004) in the endocardium. Analyzing the epicardial surface, there was a strong correlation between the bipolar voltage electrograms and the electrogram duration at the epicardium during sinus rhythm (r = 0.897, p < 0.0001). Acute success was obtained in 83.3% of patients with no serious complications. At the end of follow-up from 14 patients with acute success, 11 (78.6%) had been event-free based on implantable cardioverter defibrillator (ICD) interrogation logs. Chronic Chagas cardiomyopathy patients have larger epicardial as compared to endocardial substrate areas. Combined epicardial endocardial substrate mapping and ablation during sinus rhythm proves effective in preventing VT recurrences and appropriate ICD therapies.

Abstract 5700: Worsening Renal Function and Arrhythmic Event in Implantable Cardioverter Defibrillator Patients with Nonischemic Heart Failure

Purpose: Implantable Cardioverter Defibrillator (ICD) prevents sudden cardiac death in high risk patients with heart failure (HF). Worsening renal function (WRF) is associated with mortality in patients with myocardial infarction or HF, but its effect on lethal arrhythmia is unknown. We evaluated the influence of WRF on the occurrence of arrhythmic events in patients with nonischemic HF and ICD. Methods: A total of 286 nonischemic HF patients who underwent ICD implantation between 1990 and 2007 were studied. Estimated Glomerular Filtration Rate (eGFR) was calculated using the Modification of Diet in Renal Disease. Renal dysfunction was defined as eGFR &lt;60mL/min/1.73m 2 and WRF was defined as 15mL/min/1.73m 2 per year. Differences in arrhythmia recurrences according to the eGFR and WRF were compared by Kaplan-Meier survival curves. Results: During a mean follow-up time of 2.2+/−1.0 years, 94 (33%) of 286 patients (mean age; 57+/−15 years, 72% male) experienced appropriate ICD shock therapy. There was a significantly higher cumulative rate of appropriate ICD shock therapy (p&lt;0.05) and electrical storm (p&lt;0.05) in patients with renal dysfunction than others. The patients with renal dysfunction at baseline experience WRF more frequently than other patients (53% vs. 23%, respectively, p&lt;0.01). After correcting for age, sex, left ventricular ejection fraction (LVEF), indication for ICD implantation, and use of beta-blockers in a Cox regression model, WRF was still an independent predictor of the time to first appropriate shock (HR 2.21, 95% CI 1.32–3.69, p&lt;0.05) and electrical storm (HR 2.22, 95% CI 1.19 – 4.13, p&lt;0.05). The result of subgroup analysis of 147 patients with low LVEF (LVEF&lt;35%) indicated that the patients with WRF experienced electrical storms more frequently (p&lt;0.05). Conclusion: WRF is associated with increased rate of arrhythmic event in nonischemic HF patients. Especially, those patients with low LVEF and WRF experience more frequent ICD shocks.

Suppression of Ventricular Tachycardia Associated with Cardiac Sarcoidosis by Steroid Therapy

In patients with cardiac sarcoidosis, ventricular tachycardia (VT) is observed in some cases. However, effective therapies for the VT are still unknown.Case: A 50‐year old female with cardiac sarcoidosis underwent DDD pacemaker implantation for a high degree atrioventricular block with symptoms of faintness and shortness of breath. One month after the surgery, she was admitted for frequent episodes of non‐sustained VT. In the electrophysiologic study (EPS), sustained monomorphic VT and ventricular fibrillation were induced; therefore pacemaker was replaced with implantable cardioverter‐defibrillator (ICD). Amiodarone was started orally but it couldn't suppress frequent VT episodes, and frequent ICD shocks were delivered. When the oral steroid therapy was initiated for the cardiac sarcoidosis, it not only suppressed the frequent VT but also improved the atrioventricular nodal dysfunction.In conclusion, steroid therapy might be an option to consider in cardiac sarcoidosis with refractory VT.

Abstract 2037: Renal Dysfunction and Appropriate Shock Therapy in Implantable Cardioverter Defibrillator Patients with Nonischemic Heart Failure

Background: Implantable Cardioverter Defibrillator (ICD) prevent sudden cardiac death in high risk patients with heart failure. The presence of coexisting conditions has a substantial effect on the rate of arrhythmic events in heart failure patients. Renal dysfunction is associated with mortality in patients with myocardial infarction or heart failure, but the influence of degrees of renal impairment is less well defined. Methods: A total of 221 patients who underwent ICD implantation were included between 1990 and 2006. Gromerular Filteration Rate (GFR) was estimated using the Modification of Diet in Renal Disease (MDRD) and renal insufficiency was defined as MDRD GFR&lt;60mL/min/1.73m 2 . Differences in arrhythmia recurrences according to the MDRD GFR were compared by Kaplan-Meier survival curves. Results: During a mean follow-up time of 3.7±2.8 years, 82 (37%) of 221 patients (mean age; 4.7±1.3 years, 71% male) experienced appropriate ICD shock therapy. There was a trend of higher cumulative rate of appropriate ICD shock therapies in patients with renal insufficiency than other patients (p&lt;0.10). The result of subgroup analysis of 94 patients with low LVEF (LVEF&lt;35%) indicated that the patients with renal insufficiency experienced electrical storms more frequently (p&lt;0.05). After correcting for age, sex, left ventricular ejection fraction (LVEF), indication for ICD implantation, and use of beta-blockers in a Cox regression model, low MDRD GFR was still an independent predictor of the time to first appropriate ICD shock (hazard ratio [HR] 2.30, 95% confidence interval [CI] 1.13–4.69, p&lt;0.05). Below 60mL/min/1.73m 2 , each reduction of the MDRD GFR by 10 units was associated with a HR for appropriate shock of 1.40 (95% CI, 1.00 to 1.95). Conclusion: Renal insufficiency is associated with increased rate of arrhythmic event in nonischemic HF patients. Especially, those patients with low LVEF and renal dysfunction experience more frequent ICD shocks.

Suppression of Ventricular Tachycardia Associated with Cardiac Sarcoidosis by Steroid Therapy

In patients with cardiac sarcoidosis, ventricular tachycardia (VT) is observed in some cases. However, effective therapies for the VT are still unknown. Case: A 50-year old female with cardiac sarcoidosis underwent DDD pacemaker implantation for a high degree atrioventricular block with symptoms of faintness and shortness of breath. One month after the surgery, she was admitted for frequent episodes of non-sustained VT. In the electrophysiologic study (EPS), sustained monomorphic VT and ventricular fibrillation were induced; therefore pacemaker was replaced with implantable cardioverter-defibrillator (ICD). Amiodarone was started orally but it couldn't suppress frequent VT episodes, and frequent ICD shocks were delivered. When the oral steroid therapy was initiated for the cardiac sarcoidosis, it not only suppressed the frequent VT but also improved the atrioventricular nodal dysfunction. In conclusion, steroid therapy might be an option to consider in cardiac sarcoidosis with refractory VT.

Congenital long QT syndrome: Diagnosis and management in pediatric patients

The long QT syndrome (LQTS) is characterized by electrocardiographic abnormalities and a high incidence of syncope and sudden cardiac death (SCD). The diagnosis is suggested when ventricular repolarization abnormalities result in prolongation of the corrected QT interval. When LQTS is suspected, genetic screening may identify a specific long QT subtype and provide guidance for appropriate therapy. Treatment depends on the relative risk of SCD, which is increased with longer QT durations, prior cardiac events, and a family history of SCD. beta Blockers are considered the initial treatment of choice, with implantable cardioverter-defibrillator (ICD) therapy warranted in high-risk patients. In patients with frequent ICD shocks or in those at high risk for SCD where ICD placement cannot be performed, cardiac pacing and/or left cardiac sympathetic denervation may be indicated.

Successful radiofrequency catheter ablation of idiopathic ventricular fibrillation presented as recurrent syncope and diagnosed by an implanted loop recorder

As a palliative therapy, an implantable cardioverter-defibrillator (ICD) could not prevent the occurrence of ventricular tachycardia or fibrillation (VT, VF), but only suppress it by overdrive pacing or direct current shocks. Recurrent VT or VF followed by frequent ICD shocks might thus put patients in a painful disaster. We presented a case of recurrent syncope diagnosed as recurrent VF by an implanted loop recorder (ILR). The VF was eliminated by radiofrequency catheter ablation (RFCA) of triggering ventricular premature complexes (VPCs).

Effect of treatment of panic disorder in patients with frequent ICD discharges: a pilot study

Anxiety and depression are common in patients receiving an implantable cardioverter defibrillator (ICD). An association between the number of ICD discharges and mood disturbances has been found. We performed a pilot study in ICD patients with frequent ICD shocks having a comorbid diagnosis of panic disorder with agoraphobia and depression, in which we treated them with a combination of a selective serotonin reuptake inhibitor (SSRI) and a behavior program. We hypothesized that this intervention would result in a decrease of ventricular premature beats or arrhythmias and possibly in a reduction of number of shocks. Four of 5 patients treated with such a combination therapy experienced no discharge of the ICD during a 6 month follow-up. The total number of ventricular premature beats decreased significantly after treatment. There was also clear psychiatric improvement. These results warrant larger scale studies on the pathophysiological mechanisms as well as treatment issues.