Is implantable defibrillator indicated in all patients on cardiac resynchronization therapy?

Implantable cardioverter defibrillator (ICD) and cardiac resynchronization therapy (CRT) have been introduced during the recent years to improve survival, decrease hospital readmissions and mortality, and to improve functional status and quality of life for patients with heart failure and left ventricular systolic dysfunction (LVSD). Studies which evaluated the use of CRT or ICD alone or compared CRT with CRT-ICD in patients with heart failure and LVSD are listed in this article. The results obtained are already influencing clinical practice in the US, where it has been estimated that 90% of patients receiving a CRT device now are being implanted with an ICD component. However, it is still today debated whether patients with LVSD and heart failure should be routinely offered a CRT-ICD. In fact, there are some issues that still should be solved before to establish indication for CRT-D in all heart failure patients with an indication for CRT: 1) a non complete agreement among the different societies which wrote recommendations for guidelines (a comparative table is reported); 2) a better identification of implantable patients and an amelioration of utilized devices; 3) economic and ethical ramifications of this therapy. Anyway still now the crucial question is: ''Can resynchronization be done in isolation or must be accompanied by an ICD device?''. To answer to this question we can only express which is, in our opinion, the actual position of many physicians who work in the field of pacing and electrophysiology: ''The lesson to be learned is that we still can not predict surely which patient will die of sudden death. Until a method of identifying the high risk patients can be developed, the safest strategy should be to advise a combined ICD-CRT device for patients with indication for CRT''.

COX-2 expression in canine and feline invasive mammary carcinomas: correlation with clinicopathological features and prognostic molecular markers.

Cyclooxygenase (COX)-2 is an inducible enzyme linked to tumor growth and angiogenesis. Its expression occurs in a wide range of preneoplastic and neoplastic conditions in humans, including colon and breast carcinomas. We evaluated the role of COX-2 as a mediator of angiogenesis in feline and canine invasive carcinomas (IMCs) and its role as a prognostic indicator. COX-2 expression was assessed in neoplastic samples and healthy mammary glands by immunohistochemistry, and related to the following clinicopathological parameters: age, tumor size, histologic type, tumor grading, vessel invasion, estrogen (ER) and progesterone receptor (PR) status, Ki-67, HER-2 overexpression, microvessel density (MVD), VEGF expression and overall survival (OS). In both species, COX-2 immunoreactivity was not observed in healthy tissues, whereas 96% of feline and 100% of canine invasive carcinomas scored positive. In queens, COX-2 overexpression was significantly correlated to ER-negative status (p=0.04) and to increased PR (p=0.038) expression, and angiogenesis assessed by VEGF expression (p=0.002). In bitches an increased COX-2 expression was significantly correlated to HER-2 overexpression (p=0.013) and to tumor dedifferentiation (p=0.03). In both species increased levels of COX-2 were correlated to poorer prognosis (p=0.03 in dogs and p=0.002 in cats). COX-2 is expressed in mammary tissues during tumorigenesis and its expression is associated with a poorer prognosis in bitches and queens. The correlation of COX-2 expression and angiogenesis provides support for a potential role of COX-2 inhibitors for the prevention and the treatment of feline IMCs via their anti-angiogenic properties. In the canine species, moreover, COX-2 may be important for mediating HER-2 induced mammary tumors.

Resynchronization of mitral valve annular segments reduces functional mitral regurgitation in cardiac resynchronization therapy.

AIM: Cardiac resynchronization therapy (CRT) reduces the severity of functional mitral regurgitation (FMR) in patients with heart failure and left bundle branch block. Our hypothesis was that the induction of a more synchronous mitral valve anulus contraction can be a mechanism of FMR reduction in CRT patients. METHODS: An echo tissue Doppler imaging (TDI) examination was performed at baseline and 6 months after biventricular pacing system implant in 30 patients (4 females and 26 males, 74.1+/-6.1 years) with dilatative or ischemic chronic heart failure, NYHA class = or >III, ejection fraction (EF) = or <35% and QRS = or >140 ms. EF, Myocardial Performance Index (MPI), left end-diastolic and systolic volumes (LVEDV, LVESV), mitral regurgitation jet area/left atrial area (JA/LAA), effective regurgitant orifice area (EROA), mitral anulus contraction (MAC) were evaluated. Using TDI, at the 6 left ventricle (LV) basal segments the time to the peak myocardial sustained systolic velocity (Ts) and the standard deviation (SD) of TS were evaluated. RESULTS: At 6 months follow-up NYHA class, EF, MPI were significantly improved, LV volumes were reduced. FMR degree, evaluated both as JA/LAA and EROA, was significantly reduced. This effect was associated with the 6 basal segments resynchronization and with a more effective annular contraction. CONCLUSIONS: Our data show that CRT by resynchronizing left ventricular basal segments produces a more effective mitral valve annulus contraction and contributes to FMR improvement. Further studies need to evaluate if this could be taken into account as new therapeutic perspective of functional mitral valve regurgitation.

Short term microgravity effect on isometric hand grip and precision pinch force with visual and proprioceptive feedback.

Experiments executed on the upper limb are assuming increasing significance in the frame of the Human Physiology in space, for at least two reasons: the upper limb is the principal means of locomotion for the subject living in a space station; furthermore, fatigue can have a significant effect on the hand, for the ordinary work on board, and in particular for the extra-vehicular activities. The degradation of the performances affecting the muscular-skeletal apparatus can be easily recognized on the upper limb, by exerting specific scientific protocols, to be repeated through the permanence of the subject in weightlessness conditions. Another aspect relevant to the effect of microgravity on the upper limb is associated with the alteration of the motor control programs due to the different gravity factor, affecting not only the bio-mechanics of the subject, but in general all his/her psycho-physical conditions, induced by the totally different environment. Specific protocols on the upper limb can facilitate the studies on learning mechanisms for the motor control. The results of such experiments can be transferred to the Earth, useful for treatment of subjects with local traumas or diseases of the Central Nervous System.

Randomized crossover comparison of right atrial appendage pacing versus interatrial septum pacing for prevention of paroxysmal atrial fibrillation in patients with sinus bradycardia.

BACKGROUND: New atrial pacing techniques and overdrive pacing algorithms have been introduced to prevent atrial fibrillation. This study was designed to test the hypotheses that (1) interatrial septum pacing (IASP) at the triangle of Koch would be more effective than right atrial appendage pacing (RAAP) in preventing paroxysmal atrial fibrillation (PAF) in patients with sinus bradycardia and (2) an algorithm (CAP) designed to achieve constant atrial capture would increase the efficacy of rate-responsive atrial pacing. METHODS: We studied 46 patients with PAF and sinus bradycardia implanted with a DDD(R) (Medtronic Thera) pacemaker. Twenty-four patients (6.0 +/- 10.1 PAF episodes/month within 3 months before study) were randomized to RAAP and 22 patients (5.4 +/- 7.1, not significant) to IASP. Within each arm 2 randomized crossover periods of CAP-OFF and CAP-ON function were programed. RESULTS: The PAF episodes per month significantly decreased in the RAAP (CAP-OFF: 2.1 +/- 4.2, P <.05; CAP-ON: 1.9 +/- 3.8, P <.05) and in the IASP group (CAP-OFF: 0.2 +/- 0.5, P <.05; CAP-ON: 0.2 +/- 0.5, P <.05). Values were significantly lower in the IASP group than in the RAAP group in both CAP-OFF (0.2 +/- 0.5 vs 2.1 +/- 4.2, P <.05) and CAP-ON (0.2 +/- 0.5 vs 1.9 +/- 3.8, P <.05) conditions. PAF burden was significantly lower in the IASP than in the RAAP group in CAP-OFF (47 +/- 84 min/d vs 140 +/- 217, P <.05) and in CAP-ON (41 +/- 72 vs 193 +/- 266, P <.05) conditions. No differences were observed within each arm in PAF burden between the 2 crossover CAP programing periods. CONCLUSIONS: Rate-adaptive IASP at the triangle of Koch is more effective than RAAP in preventing PAF in patients with sinus bradycardia. In our sample of patients no additional clinical benefit is furnished by the CAP algorithm.

Fibrillin-1 (FBN1) gene frameshift mutations in Marfan patients: genotype-phenotype correlation.

Marfan syndrome (MFS) is a multisystemic disease associated with mutations in the fibrillin-1 gene. Most of the reported mutations are missense substitutions mainly affecting the epidermal growth factor (EGF)-like protein domain structure and the calcium-binding (cb) site. The aim of our study was to investigate the correlation between fibrillin-1 frameshift mutations and the clinical phenotype in patients affected by MFS. In 48 out of 66 Marfan patients a pathogenetic mutation was found. We detected novel mutations causing premature termination codon in exons 19, 37, 40 and 41 of four Italian patients. The first mutation in exon 19 (cbEGF #8 domain) results in a clinical phenotype involving mainly the skeletal and cardiovascular systems. Interestingly, we noticed that, while mutations in exons 37 and 41 (eight cysteine domains #4 and #5) are milder, the mutation in exon 40 (cbEGF #24 domain) is more severe and causes major cardiovascular involvement with thoracic and abdominal aortic aneurysms. It is noteworthy that the degree of the severity in the phenotype of one of our patients and another from the literature carrying a mutation in exon 41 could be explained with alterations in mRNA expression.

Should stimulation therapy for congestive heart failure be combined with defibrillation backup?

Biventricular pacing has been proposed to resynchronize ventricular contraction in patients with congestive heart failure (CHF) and interventricular conduction delay. However, the sudden death rate is still high despite the improvement in cardiac performance. Devices combining biventricular pacing with implantable cardioverter defibrillator (ICD) backup are now under clinical investigation to demonstrate whether they can decrease sudden death. From the first implant of an ICD with biventricular transvenous pacing on August 1998 to April 2000, 96 patients underwent such implants: 67 (70%) received pacemakers alone and 29 (30%), who had class I ICD indications, received combined pacemaker/ICD systems. During a mean follow-up of 283 +/- 170 days, 13 (14%) patients died: 5 of 29 (17%) in the ICD group and 8 of 67 (12%) in the pacemaker group. A total of 15 patients (52%) had ICD shocks and 6 patients (21%) had 113 episodes of ventricular tachyarrhythmias, of which 96 (85%) were converted to sinus rhythm with antitachypacing. The echocardiograms showed a narrowing of the delay between the onset of right and left ventricular outflow from 40 +/- 37 msec to 17 +/- 16 msec (p = 0.03) and a reduction of the mitral regurgitation area from 7 +/- 3.8 cm2 to 5 +/- 4 cm2 (p = 0.04) at 3 months. Functional class improved from 2.8 +/- 0.7 to 1.6 +/- 0.5 (p <0.001) 3 months after implant. Thus, ischemic patients with reduced left ventricular ejection fraction and ventricular tachyarrhythmias seem good candidates for biventricular pacing with ICD backup. The sudden death risk for those with idiopathic dilated cardiomyopathy, however, is difficult to stratify, and the choice of ICD backup has to be considered on the basis of patient safety, as well as of costs.

Prevention of short term reversible chronic atrial fibrillation by permanent pacing at the triangle of Koch.

OBJECTIVES: The purpose of this study was to investigate if single lead interatrial septum pacing could be effective in maintaining sinus rhythm in patients in whom restoration of sinus rhythm was only possible for a period of 2-24 hours after one or more previous electrical cardioversions, and in whom a sinus bradycardia was documented before arrhythmia restarted. The two hours limit was chosen because it was considered a sufficient time to implant a dual chamber pacemaker. BACKGROUND: Alternative atrial pacing techniques have been demonstrated to be successful in preventing recurrences of atrial fibrillation (AF) in patients with sinus bradycardia. Excluding the AF occurring after only a few sinus beats, at 24 hours from electrical cardioversion an early restart of chronic AF has been reported in 12% to 17% of the patients. METHODS: After sinus rhythm was restored by internal electrical cardioversion, 17 patients, 7 ablated at the AV junction, underwent a dual chamber rate response (DDDR) pacemaker implantation with a screw-in atrial lead placed in the interatrial septum. RESULTS: After a follow-up period of 17+/-5 months (range 12 to 27 months) persistence of sinus rhythm was observed in 11 patients (65%). Six patients (35%) had recurrences of paroxysmal attacks, while five (30%) were totally free of AF. Recurrence of chronic AF was observed in six cases (35%) after 2 days-12 months from implantation. No dislodgements of the atrial lead and no complications were observed at implantation and during follow-up. CONCLUSIONS: Interatrial septum pacing is a safe and feasible technique with a satisfying success rate (65%) in long-term maintaining sinus rhythm in previously unsuccessfully cardioverted patients.

Atrioventricular interval optimization in the right atrial appendage and interatrial septum pacing: a comparison between echo and peak endocardial acceleration measurements.

Interatrial septum pacing (IASP) reduces interatrial conduction time and consequently may interfere with atrioventricular delay (AVD) optimization. We studied 14 patients with an implanted BEST Living system device able to measure peak endocardial acceleration (PEA) signal. The aims of our study were to compare the (1) optimal AVD (OAVD) in right atrial appendage pacing (RAAP) and IASP, and (2) OAVD derived by the PEA signal versus OAVD derived by Echo/Doppler evaluation of the left ventricular filling time (LVFT) and cardiac output (CO). Measurements were performed in DDD VDD modes Eight patients (group A) had RAAP and six patients (group B) had IASP. In group A, OAVD measured by LVFT, CO, and PEA was 185 +/- 23 ms, 177 +/- 19 ms, and 192 +/- 23 ms in DDD and 147 +/- 19 ms, 135 +/- 27 ms, and 146 +/- 20 ms in VDD, respectively. OAVD measured by LVFT, CO, and PEA was significantly longer in DDD mode than in VDD (P < 0.01, P < 0.01, P < 0.001). In group B, OAVD measured by LVFT, CO, and PEA was 116 +/- 19 ms, 113 +/- 10 ms, and 130 +/- 30 ms in DDD and 106 +/- 16 ms, 96 +/- 15 ms, and 108 +/- 26 ms in VDD, respectively. No statistical differences were observed between DDD and VDD. Significant correlations between OAVDs PEA derived and OAVDs LVFT and CO derived were observed (r = 0.71, r = 0.69, respectively). When new techniques of atrial stimulation, as IASP, are used an OAVD shorter and similar in VDD and DDD has to be considered. The BEST Living system could provide a valid method to ensure, in every moment, the exact required OAVD to maximize atrial contribution to CO.

Electrophysiologic procedures and activation of the hemostatic system.

BACKGROUND: Thromboembolism occurs in 0.4% to 2% of the subjects undergoing radiofrequency ablation (RFA), but its mechanisms remain unclear. Our aim was to evaluate several parameters of the hemostatic system in relation to the electrophysiologic procedure. METHODS: Thirty consecutive patients were enrolled in the study. Fifteen underwent electrophysiologic study and 15 underwent radiofrequency ablation. Before the ablation procedure, all subjects were given an intravenous heparin bolus (2500 IU). Blood samples were drawn immediately before, at the end of, and 24 hours after the procedures. Spontaneous platelet aggregation in whole blood and in platelet-rich plasma, markers of clotting activation (prothrombin fragment 1+2 and the thrombin-antithrombin complex) and the fibrinolytic system (plasminogen activator inhibitor and D-dimer) levels were evaluated. RESULTS: At the end of the procedure, spontaneous platelet aggregation in whole blood, prothrombin fragment 1+2, thrombin-antithrombin complex, and D-dimer levels increased significantly in all patients. The hemostatic changes were more marked after RFA than after electrophysiology. Spontaneous aggregation in whole blood, prothrombin fragment 1+2, and thrombin-antithrombin complex levels at 24 hours after the procedure were similar to those observed before the procedure in both groups; D -dimer levels were still elevated with respect to preprocedure levels, with a trend toward higher levels in patients undergoing RFA rather than electrophysiology. A significantly more marked activation of coagulation (prothrombin fragment 1+2, P <.005) was found in patients in whom the mean duration of energy application was higher than 23.5 seconds. CONCLUSIONS: Our data suggest that antithrombotic prevention with a prolonged administration of heparin and/or the association of antiplatelet agents should be considered in patients undergoing RFA.

Interatrial septum pacing: a new approach to prevent recurrent atrial fibrillation.

BACKGROUND: There are a variety of approaches to the prevention of atrial fibrillation (AF) with pacing. Aim of this study was to test the safety and feasibility of interatrial septum pacing at the posterior triangle of Koch for AF prevention and to exclude potential arrhythmic effects. MATERIAL AND METHODS: Interatrial septum pacing was performed in 34 patients (21 males, 13 females, mean age 69 +/- 12 years): 9 without a history and clinical evidence of atrial fibrillation (AF) (6 with sinus bradycardia, 2 with second-degree AV block, and 1 with carotid sinus hypersensitivity) and 25 with sinus bradycardia and paroxysmal atrial fibrillation (PAF) (mean symptomatic episodes/month 6.2 +/- 10). In all patients a screw-in bipolar lead was positioned in the interatrial septum superiorly to the coronary sinus. RESULTS: At implant the mean P wave amplitude was 2.5 +/- 1.5 mV, the pacing threshold was 1 +/- 0.6 V and the impedance was 907 +/- 477 Ohm. Mean P wave duration was 118 +/- 17 ms in sinus rhythm and 82 +/- 15 during interatrial septum pacing (p < 0.001). During a mean follow-up period of 10 +/- 7 months, no patients without atrial tachyarrhythmias before implantation experienced AF. During a 9 +/- 6 months follow-up we observed only 2 symptomatic arrhythmia recurrences between AF patients (mean symptomatic episodes/month 0.006 +/- 0.0022) (p < 0.01 vs before implant period). CONCLUSIONS: Our data indicate that interatrial septal pacing is safe and feasible. A significant less incidence of arrhythmic episodes has been observed during follow-up. Further controlled randomized prospective studies are necessary to establish the exact role of this technique respect to conventional or multisite stimulation when patients with paroxysmal AF need to be permanently paced.

A major involvement of the cardiovascular system in patients affected by Marfan syndrome: novel mutations in fibrillin 1 gene.

The aim of our study was to characterize the molecular defect in Italian Marfan patients, thus contributing to the effort of correlating the genotype with the phenotype. In particular, our ultimate goal was to identify the region(s) of the fibrillin 1 (FBN1) gene mainly involved in the health of the heart and of the aorta in terms of the cardiovascular system. We searched for a molecular defect in three patients with classic Marfan syndrome (MFS). The mutations were detected applying heteroduplex analysis to each of the 65 exons of the FBN1 gene amplified by polymerase chain reaction (PCR). Exons containing heteroduplex bands were sequenced directly from PCR products. This study reports the detection of three unique missense mutations in the FBN1 gene in three Italian patients: a 44-year-old adult male and 36-year-old female affected by classic MFS (with all the cardinal manifestations in the cardiovascular, ocular and skeletal systems), and an 11-year-old male affected by infantile (earlier onset) classic MFS. The first two are sporadic cases and present a Cys-->Arg amino acid substitution (T-->C substitution at nucleotide 7729) in exon 62 and a Cys-->Tyr amino acid substitution (G-->A substitution at nucleotide 6695) in exon 54. The third is a familial case which presents a Cys-->Trp aminoacidic substitution (C-->G substitution at nucleotide 3546) in exon 28. Our data confirm that cysteine substitutions in calcium binding epidermal growth factor (cbEGF)-like domains cause severe Marfan phenotype. Exon 24-32 cluster seems to produce an even more severe phenotype. The early characterization may be of clinical relevance for prevention and early surgical treatment of aortic aneurysm or dissection.

Influence of age, lead axis, frequency of arrhythmic episodes, and atrial dimensions on P wave triggered SAECG in patients with lone paroxysmal atrial fibrillation.

Signal-averaged P wave of 42 patients with lone paroxysmal atrial fibrillation (PAF) and 29 normal subjects (N) were recorded, using three orthogonal leads and analyzed in the time and frequency (entire P wave or a 100-ms segment ranging from 75 ms before to 25 ms after the end of P wave) domains. PAFs were divided into a group of 12 having > or = 2 attacks a month (HF) and a group of 30 having < or = 2 attacks a year (LF). Statistically significant differences were absent with regard to ages of PAF and N; ages of HF, LF, and N at the time of signal-averaged ECG; ages of HF and LF at the time of the first arrhythmic episode; and elapsed times from the first episode. Length of P wave and some frequency-domain parameters were found to be significantly correlated with age. PAF showed a significantly longer duration of P wave in the frontal plane using the time-domain analysis. Frequency analysis was found to be useful in evaluating the influence of attack frequency. HF showed significantly higher values of some frequency-domain parameters than LF and N, while the three groups did not differ for time-domain analysis. P wave duration and frequency content of the three orthogonal leads proved to be significantly different in PAF and N. Right and left atrial echocardiographic dimensions proved to be higher (even if within normal limits) in HF than in LF and N. Results suggest that frequency analysis should be performed on the entire P wave.

Wavelength index at three atrial sites in patients with paroxysmal atrial fibrillation.

The purpose of this study was to evaluate the wavelength index (WLI) at three atrial sites in a group of 23 patients with recurrent episodes of lone paroxysmal atrial fibrillation (LPAF) and a control group (n = 20). All patients underwent programmed atrial stimulation (paced cycle length = 600 ms) at high, medium, and low lateral right atrial wall. P wave duration, sinus cycle length, and corrected sinus node recovery time were not significantly different between the two study groups. WLI was calculated according to the following formulas: atrial effective refractory period (AERP)/duration of atrial extrastimulus electrogram (A2) or AERP/A2 + atrial latency; and atrial functional refractory period (AFRP)/A2. WLI was significantly shorter in LPAF than in the control group at each of the paced atrial sites independently of the formula used. Duration of premature atrial electrogram appeared to play the major role in determining the difference in WLI between patients with paroxysmal atrial fibrillation and the control group.