Valvular heart disease associated with benfluorex therapy: results from the French multicentre registry.

AIMS: The aim of this paper is to report clinical characteristics, consequences, echocardiographic features, and pathological findings encountered in patients suffering from valvular disease associated with benfluorex exposure in a multicentre French registry. METHODS AND RESULTS: Forty patients suffering from unexplained restrictive valvular disease with a previous exposition to benfluorex, a fenfluramine derivative, were identified from eight French university hospitals. Patients were mostly women (87.5%) with a mean age of 57 ± 9 years and high body mass index of 30 ± 7 kg/m²; 37.5% of them presented with severe heart failure symptoms (NYHA class III and IV). Benfluorex mean daily dose was 415 ± 131 mg with total therapy duration of 72 ± 53 months. Resulting cumulative dose was 910 ± 675 g. Common echocardiographic findings were leaflets and sub-valvular apparatus thickening and retraction. Aortic and mitral valve regurgitations resulting from leaflets loss of coaptation were the most frequent findings (87.5 and 82.5%) and were severe in 29 patients (72.5%). Multiple valve involvements were present in 31 cases (77.5%). Pulmonary arterial hypertension was identified in 20 cases (50%). Histopathological examination demonstrated abundant extra cellular matrix encasing the leaflets without modification of valve architecture. Fifteen patients (37.5%) underwent valvular surgery. CONCLUSION: Benfluorex-related valvulopathy shares numerous characteristics with other drug-induced valvular disease. Clinical consequences may be serious with severe heart failure symptoms that may lead to surgical treatment.

Mitral and aortic valvular disease associated with benfluorex use.

Fenfluramine has been associated with an increased risk of pulmonary hypertension and valvular disease. Benfluorex is a fenfluramine derivative approved for the treatment of metabolic syndrome and type 2 diabetes mellitus. To date, only three isolated clinical cases of valvular disease and two recent case-control studies have been reported in patients exposed to benfluorex. Herein, the case is described of a patient with mitral and aortic valvular disease, with both echocardiographic and histopathological findings, who had been receiving benfluorex for several years, without any other etiology of valvular disease. The case is suggestive of toxic valvular lesions, similar to those observed previously during treatment with fenfluramine, pergolide, and cabergolide.

Is "hyper response" to cardiac resynchronization therapy in patients with nonischemic cardiomyopathy a recovery, a remission, or a control?

BACKGROUND AND OBJECTIVES: Some patients treated by cardiac resynchronization therapy (CRT) recover "normal" left ventricular (LV) function and functional status. However, whether this "normalization" persists or reverts over time remains unknown. The aim of the present study was to evaluate the long-term outcomes of LV function in patients hyper responder to CRT. METHODS: Eleven consecutive patients with nonischemic dilated cardiomyopathy, sinus rhythm, left bundle branch block (LBBB), New York Heart Association (NYHA) class III or IV, and optimal pharmacological treatment were hyper responder as they fulfilled concurrently the two following criteria: functional recovery (NYHA class I or II) and normalization of LV ejection fraction (LVEF). RESULTS: After a mean follow-up of 65 ± 30 months between CRT implantation and last evaluation LVEF improved from 26 ± 9 to 59 ± 6% (P < 0.0001). One patient died from pulmonary embolism 31 months after implantation. Three patients exhibited LVEF ≤ 50% at their last follow-up visit (two at 40% and one at 45%). In eight patients, brief cessation of pacing was feasible (three were pacemaker-dependent). Mean QRS duration decreased from 181 ± 23 ms to 143 ± 22 ms (P = 0.006). In one patient, pacing was interrupted for 2 years and LVEF decreased markedly (from 65% to 31%) but returned to normal after a few months when pacing was resumed. CONCLUSION: In hyper responder patients, "normalization" of LV function after CRT persists as long as pacing is maintained with an excellent survival.

Patients with non-ischaemic dilated cardiomyopathy and hyper-responders to cardiac resynchronization therapy: characteristics and long-term evolution.

AIMS: In some patients with non-ischaemic dilated cardiomyopathy (NIDCM), left bundle branch block (LBBB), and severe cardiac failure, cardiac resynchronization therapy (CRT) has been shown to reverse almost completely left ventricular (LV) function. These patients thus eligible to be qualified 'hyper-responders' are exclusively recruited in patients with NIDCM. Evaluate proportion of 'hyper-responders' among patients with NIDCM and try to determine their profile before implantation of CRT. METHODS AND RESULTS: Consecutive patients with DCM [LV ejection fraction (LVEF) <35%, LV end-diastolic diameter >60 mm], sinus rhythm, LBBB, and New York Heart Association (NYHA) class III and IV implanted with a CRT were prospectively followed. Patients were considered 'hyper-responders' if they fulfilled after a minimum period of 6 months the following criteria: functional recovery (NYHA class I or II) and LVEF >or=50%. Among the 51 NIDCM patients, 11 (21.5%) were 'hyper-responders' following CRT (LVEF increased from 26 +/- 9 to 59 +/- 6%, P < 0.01). In the 40 (78.5%) remaining patients, there was no or minimal functional improvement and only a modest increase in LVEF from 21 +/- 9 to 26 +/- 12% (P = 0.03). Comparison between 'hyper-responders' and remaining patients showed that baseline parameters of 'hyper-responders' were less severely deteriorated. CONCLUSION: In a significant subset of patients with CRT for NIDCM, a 'complete' functional recovery associated with normalization of LV function was observed. This observation suggests that LBBB could be the causative factor of DCM in this subgroup of patients. There was not a unique discriminating factor at baseline between 'hyper-responders' and remaining patients.

Cardiac resynchronization therapy: "nonresponders" and "hyperresponders".

BACKGROUND: Cardiac resynchronization therapy (CRT) is a recognized treatment modality for patients with dilated cardiomyopathy (DCM), left bundle branch block, and severe cardiac failure. However, 30% of patients are "nonresponders." Intriguingly, the opposite case has not been reported until recently: Do some patients treated with CRT have a "complete" recovery and thus can be considered "hyperresponders"? OBJECTIVE: The purpose of this study was to investigate patients treated with CRT who have a "complete" functional recovery, with normalization of left ventricular function after therapy. METHODS: Eighty-four consecutive patients with DCM, sinus rhythm, and left bundle branch block in New York Heart Association functional class III and IV who were implanted with a CRT device were prospectively followed. Patients were considered to be "hyperresponders" if they concurrently fulfilled two criteria: functional recovery and left ventricular ejection fraction > or = 50%. RESULTS: Among the 84 patients with DCM, 11 (13%) were "hyperresponders" within 6 to 24 months after CRT (left ventricular ejection fraction increased from 25% +/- 8% to 60% +/- 6.5%, P = .001). Comparison of baseline parameters between "hyperresponders" and the remaining patients showed that only etiology of the DCM was statistically discriminative. All "hyperresponders" belonged to the group of patients with nonischemic DCM (18% vs 0%, P = .05). CONCLUSION: In a subset of patients successfully implanted with a CRT device, "complete" functional recovery associated with normalization of LV function was observed, giving rise to the concept of "hyperresponders." This finding is observed exclusively in the subgroup of patients with nonischemic DCM and suggests that left bundle branch block may be the causal factor of DCM in this subgroup of patients.

Primary failure of cardiac resynchronization therapy: what are the causes and is it worth considering a second attempt? A single-centre experience.

AIMS: Cardiac resynchronization therapy (CRT) has been validated as an effective treatment for patients with drug-refractory congestive heart failure and left bundle branch block. Failure of implantation of the left ventricular (LV) lead has been reported in 10-15% of patients. The goal of our study was to determine the causes of failure and the success rate following a repeat procedure by the same operators. METHODS AND RESULTS: We reviewed our last 100 consecutive cases of CRT before July 2007. The procedure was considered as unsuccessful if it had to be interrupted before the placement of the LV lead in an appropriate position, because of patient's haemodynamic status or if the procedure duration exceeded 3 h. Cardiac resynchronization therapy was unsuccessful in 10 patients (5 men, mean age: 72 +/- 11 years). The causes of failure of CRT were as follows: no target vein other than the great cardiac vein (n = 5), coronary sinus dissection (n = 1), and a lateral vein too small to provide a stable location for the LV lead (n = 4). A second procedure was attempted in four patients and was successful in all cases. CONCLUSION: In our study results, failure of CRT was observed in 10% of the patients. A second procedure can be attempted in a selected group of patients and is associated with a high success rate.

Left ventricular pacing in patients with congestive heart failure.

Cardiac resynchronisation therapy (CRT) using biventricular (BIV) pacing has proved its effectiveness to correct myocardial asynchrony and improve clinical status of patients with severe congestive heart failure (CHF) and widened QRS. Despite a different effect on left ventricular electrical dispersion, left univentricular (LV) pacing is able to achieve the same mechanical synchronisation as BIV pacing in experimental studies and in humans. This results in clinical benefits of LV pacing at mid-term follow-up, with significant improvement in functional class, quality of life and exercise tolerance at the same extent as those observed with BIV stimulation in non randomised studies. Furthermore these benefits are obtained at lesser costs and with conventional dual-chamber devices. However, LV pacing has to be compared to BIV pacing in randomised trials before being definitely considered as a cost-effective alternative to BIV pacing.

Drug-Induced- or Rheumatic- Valvular Heart Disease in Patients Exposed to Benfluorex?

There is a risk of misdiagnosis between benfluorex-induced VHD and acute rheumatic fever (ARF)-related VHD due to common characteristics of both etiologies. We aimed at estimating the probability for a patient exposed to benfluorex presenting with VHD to have, at the same time, a history of ARF-related VHD. Such epidemiological approach could help at reducing the risk of misdiagnosis. We used INSEE data and related literature as well as various modeling hypotheses to drive and test a formula for calculating the probability of a patient presenting with VHD and a history of benfluorex intake to have a prior history of ARF-related VHD. Different scenarios were estimated by a Markov model on the life course of people born in France between 1940 and 1960. Sensitivity analyses were performed under these scenarios. According to the different scenarios and gender, the probability that a patient born between 1940 and 1960 presenting with VHD and a history of benfluorex intake would have had a prior history of ARF-related VHD varied from 0.2% to 2.7%. The probabilities by the year of birth were as follows: 0.8%-2.7% for a patient born in 1940, < 0.5% in all scenarios for patients born after 1955, and < 0.2% in all scenarios for patients, born in 1960. Our results indicate that the burden of ARF-related VHD is low in the patient population exposed to benfluorex. The probability of ARF related VHD should not be over-estimated in the diagnostic procedure of VHD.

Midterm benefits of left univentricular pacing in patients with congestive heart failure.

BACKGROUND: Resynchronization therapy by simultaneous pacing of the right and left ventricles has gained wide acceptance as a useful treatment for patients with severe congestive heart failure. Several short-term hemodynamic studies in humans and animals failed to demonstrate any benefit of biventricular pacing over left univentricular pacing, but long-term studies on this pacing mode are lacking. The objective of this study was to assess the outcome over a 1-year period of patients paced exclusively in the left ventricle. METHODS AND RESULTS: Clinical, angiographic, echocardiographic, and ergometric data were collected at baseline and after 12 months in 22 patients (age, 69.3+/-6.5 years) with NYHA class III or IV (10 patients), sinus rhythm, left bundle-branch block, and no bradycardia indication for pacing. After 12 months, compared with baseline values, NYHA class improved significantly by 40% (P<0.0001), 6-minute walk distance by 30% (P=0.01), peak VO2 by 26% (P=0.01), left ventricular end-diastolic diameter by 5% (P=0.02), ejection fraction by 22% (P=0.07), mitral regurgitation area by 40% (P=0.01), and norepinephrine level by 37% (P=0.04). CONCLUSIONS: In patients with severe congestive heart failure, sinus rhythm, and left bundle-branch block despite optimal pharmacological treatment, left univentricular pacing is feasible and results in significant midterm benefit in exercise tolerance and left ventricular function.

The use of epicardial electrogram as a simple guide to select the optimal site of left ventricular pacing in cardiac resynchronization therapy.

Cardiac resynchronization therapy (CRT) has been demonstrated to improve symptoms and survival in patients with left ventricular (LV) systolic dysfunction and dyssynchrony. To achieve this goal, the LV lead should be positioned in a region of delayed contraction. We hypothesized that pacing at the site of late electrical activation was also associated with long-term response to CRT. We conducted a retrospective study on 72 CRT patients. For each patient, we determined the electrical delay (ED) from the onset of QRS to the epicardial EGM and the ratio of ED to QRS duration (ED/QRS duration). After a followup of 30 ± 20 months, 47 patients responded to CRT. Responders had a significantly longer ED and greater ratio of ED/QRS duration than nonresponders. An ED/QRS duration ≥0.38 predicted a response to CRT with 89% specificity and 53% sensitivity.

Clinical spectrum, treatment, and outcome of patients with type II mixed cryoglobulinemia without evidence of hepatitis C infection.

OBJECTIVE: The clinical spectrum, etiologies, and best therapeutic approaches of type II mixed cryoglobulinemia (MC) not associated with hepatitis C virus (HCV) infection have been poorly described to date. We studied the clinical presentation and outcome of patients with type II MC with no evidence of HCV. METHODS: This was a multicenter retrospective study on the clinical presentation and outcome of patients with type II MC without evidence of HCV infection. Only patients with symptomatic MC were included. RESULTS: Thirty-three patients were included (median followup 67.2 mo). Extensive investigations for associated diseases were performed at presentation. MC was related to an autoimmune disease in 14 patients, to a lymphoid malignancy in 4 patients, and to an infectious disease in 2 patients, while MC was classified as essential (primary) in 13. Essential MC tended to be more severe than secondary disease with, in particular, more frequent renal and peripheral nerve involvement. Most patients were treated with steroid with or without immunosuppressive agents, mainly cyclophosphamide. These treatments were unable to induce sustained remission. One patient was successfully treated with lenalidomide. Seven patients with nonmalignant MC were treated with rituximab; 2 had a sustained complete remission, 3 improved greatly but relapsed within 5 months, and 2 experienced a disease flare. CONCLUSION: An important proportion of non HCV-related type II MC remains essential. Efforts should be made to find other etiologies than HCV, because treatments with steroid and immunosuppressants are not satisfactory, especially in severe forms. In these situations anti-CD20 therapy may present the best option but should be used with caution. New agents such as lenalidomide remain to be evaluated.

Benfluorex and unexplained valvular heart disease: a case-control study.

BACKGROUND: Recent case reports suggest that benfluorex, a fenfluramine derivative used in the management of overweight diabetic patients and dyslipidemia, is associated with cardiac valve regurgitation. METHODS: We conducted a case-control study. Eligible patients were those admitted in the cardiology or the cardiac surgery units of our hospital between January, 1(st) 2003 and June 30(th) 2009, with mitral insufficiency diagnostic codes (ICD-10 I340 and I051). Patients with either a primary cause (degenerative, known rheumatic heart disease, infectious endocarditis, congenital, radiation-induced valvular disease, associated connective and/or vasculitis disease, trauma, tumor) or a secondary (functional) cause were considered as having an "explained" mitral regurgitation. Other patients were considered as having an "unexplained" mitral regurgitation and were included as cases. For each case, two controls were matched for gender and for the closest date of birth, among a list of patients with an "explained" mitral regurgitation. Drug exposures were assessed blindly regarding the case or control status, through contacts with patients, their family and/or their physicians. RESULTS: Out of the 682 eligible patients, 27 cases and 54 matched controls were identified. The use of benfluorex was reported in 22 patients: 19 of the 27 cases, versus 3 of the 54 controls, odds-ratio 17.1 (3.5 to 83), adjusted for body mass index, diabetes and dexfenfluramine use. CONCLUSION: The use of benfluorex is associated with unexplained mitral regurgitation.

Cardiac multislice spiral computed tomography as an alternative to coronary angiography in the preoperative assessment of coronary artery disease before aortic valve surgery: a management outcome study.

BACKGROUND: Conventional coronary angiography (CA) is still recommended before valvular surgery. Preliminary studies suggest that multislice spiral computed tomography coronary angiography (MSCT-CA) can be used to rule out coronary artery disease (CAD). AIM: To assess prospectively the safety of ruling out CAD before surgery solely on the basis of normal MSCT-CA in patients with severe aortic valve disease. METHODS: We included all consecutive patients scheduled for aortic valve surgery. We first estimated the calcium score (Agatston score equivalent [ASE]). Patients underwent injected MSCT if the ASE was<1000. CA was cancelled when MSCT-CA quality was sufficient and showed no significant CAD. Our primary endpoint was the occurrence of perioperative myocardial infarction in patients who underwent surgery with no prior CA. RESULTS: Between 1st July 2005 and 30th June 2008, we included 199 patients with severe aortic valve disease: 118 men (59%); mean age 69+/-12 years; 63 patients (32%) underwent CA directly because the ASE was > or =1000. Of 136 patients who underwent MSCT-CA, 106 (78%) had a normal MSCT-CA and underwent aortic valve surgery without prior CA; CA was performed in 30 patients because of abnormal (n=18) or bad quality (n=12) MSCT-CA. One patient of the 106 (0.94%, 95% confidence interval 0.17-5.15) had a perioperative myocardial infarction. CONCLUSIONS: When the ASE is <1000, MSCT is safe and may be recommended instead of CA as a first-line means of ruling out CAD in patients with severe aortic valve disease.

Evaluation of left bundle branch block as a reversible cause of non-ischaemic dilated cardiomyopathy with severe heart failure. A new concept of left ventricular dyssynchrony-induced cardiomyopathy.

OBJECTIVES: We sought to determine if amelioration of left bundle branch block (LBBB)-induced contraction disturbances achieved by left ventricular (LV)-based pacing could result in sustained reversal of severe LV dysfunction in certain patients with chronic heart failure due to non-ischaemic cardiomyopathy. BACKGROUND: It has been shown that LBBB induces asynchronous contraction of LV. However, whether such a functional contraction disturbance, if present for an extended period of time, could account for a dilated cardiomyopathy remains unknown. METHODS: The study population comprised 29 patients with dilated cardiomyopathy, sinus rhythm, LBBB and severe heart failure (14 patients in New York Heart Association (NYHA) class III and 15 in class IV). Patients were followed prospectively after resynchronization therapy. LV function was considered to be normalized when ejection fraction (EF) was >50% at 1 year. RESULTS: Five among the 29 patients (17%: group 1) demonstrated both complete normalization of LV function following resynchronization therapy (EF: from 19+/-6 to 55+/-3%, P = 0.001) and clinical improvement (mean NYHA class: 3.4+/-0.5 to 1.8+/-0.4, P = 0.02; 6-min walk distance: 300+/-136 to 444+/-75 m, P = 0.12; peak VO2: 11.9+/-4 to 15.8+/-2 ml/min/kg, p = 0.03). Among the remaining 24 patients (83%: group 2) EF improved but did not normalize (from 21+/-8 to 23+/-11%, ns). Baseline clinical features could not predict which patients would exhibit the reversal of LV dysfunction. CONCLUSIONS: Normalization of LV function 1 year after resynchronization therapy in a small but important number of patients suggests that long-standing LBBB may be a newly identified reversible cause of cardiomyopathy.

Assessment of upgrading to biventricular pacing in patients with right ventricular pacing and congestive heart failure after atrioventricular junctional ablation for chronic atrial fibrillation.

AIMS: Effects of cardiac resynchronization therapy (CRT) in patients with right ventricular pacing and congestive heart failure (CHF) have only been reported in limited series. CRT in patients with atrial fibrillation remains controversial. Patients with AV junctional ablation offer a unique opportunity to study the effects of CRT in patients with right ventricular pacing combined with atrial fibrillation. The aims of the present study were to evaluate the effects of upgrading to biventricular pacing patients with CHF, permanent atrial fibrillation, and prior ablation of the atrioventricular (AV) junction followed by conventional right ventricular pacing. METHODS AND RESULTS: We studied 16 consecutive patients with permanent atrial fibrillation treated by AV junctional ablation. After a mean follow-up of 20+/-19 months (6 weeks to 5 years) they were successfully upgraded to biventricular pacing for severe CHF. Parameters were prospectively evaluated at baseline and at 6 months. The 14 surviving patients at 6 months demonstrated significant improvement (P<0.02) in New York Heart Association class but the exercise test parameters remained unchanged. Cardiothoracic ratio decreased by 5% (P=0.04), end-systolic diameter by 8% (P=0.001), end-diastolic diameter by 4% (P=0.08), systolic pulmonary artery pressure by 17% (P<0.0001) and mitral regurgitation area by 40% (P<0.05). Ejection fraction increased by 17% (P=0.11) and fractional shortening by 24% (P=0.01). CONCLUSION: CRT improves left ventricular performance and functional status in patients with permanent atrial fibrillation and prior remote right ventricular pacing.