David Begley

Targeted left ventricular lead placement to guide cardiac resynchronization therapy: the TARGET study: a randomized, controlled trial.

OBJECTIVES This study sought to assess the impact of targeted left ventricular (LV) lead placement on outcomes of cardiac resynchronization therapy (CRT). BACKGROUND Placement of the LV lead to the latest sites of contraction and away from the scar confers the best response to CRT. We conducted a randomized, controlled trial to compare a targeted approach to LV lead placement with usual care. METHODS A total of 220 patients scheduled for CRT underwent baseline echocardiographic speckle-tracking 2-dimensional radial strain imaging and were then randomized 1:1 into 2 groups. In group 1 (TARGET [Targeted Left Ventricular Lead Placement to Guide Cardiac Resynchronization Therapy]), the LV lead was positioned at the latest site of peak contraction with an amplitude of >10% to signify freedom from scar. In group 2 (control) patients underwent standard unguided CRT. Patients were classified by the relationship of the LV lead to the optimal site as concordant (at optimal site), adjacent (within 1 segment), or remote (≥2 segments away). The primary endpoint was a ≥15% reduction in LV end-systolic volume at 6 months. Secondary endpoints were clinical response (≥1 improvement in New York Heart Association functional class), all-cause mortality, and combined all-cause mortality and heart failure-related hospitalization. RESULTS The groups were balanced at randomization. In the TARGET group, there was a greater proportion of responders at 6 months (70% vs. 55%, p = 0.031), giving an absolute difference in the primary endpoint of 15% (95% confidence interval: 2% to 28%). Compared with controls, TARGET patients had a higher clinical response (83% vs. 65%, p = 0.003) and lower rates of the combined endpoint (log-rank test, p = 0.031). CONCLUSIONS Compared with standard CRT treatment, the use of speckle-tracking echocardiography to the target LV lead placement yields significantly improved response and clinical status and lower rates of combined death and heart failure-related hospitalization. (Targeted Left Ventricular Lead Placement to Guide Cardiac Resynchronization Therapy [TARGET] study); ISRCTN19717943).

Efficacy of implantable cardioverter defibrillator therapy for primary and secondary prevention of sudden cardiac death in hypertrophic cardiomyopathy

Risk stratification and effectiveness of implantable cardioverter‐defibrillator (ICD) therapy are unresolved issues in hypertrophic cardiomyopathy (HCM), a cardiac disease that is associated with arrhythmias and sudden death. We assessed ICD therapy in 132 patients with HCM: age at implantation was 34 ± 17 years , and 44 (33%) patients were aged ≤ 20 years . Indications were sustained ventricular tachycardia (VT) or cardiac arrest (secondary prevention) in 47 (36%) patients, and clinical features associated with increased risk for sudden death (primary prevention) in 85 (64%) patients. There were 6 deaths and 55 appropriate interventions in 27 (20%) patients during a mean follow‐up period of 4.8 ± 4.2 years : 5‐year survival and event‐free rates were 96%± 2% and 75%± 5% , respectively. ICD intervention‐free rates were significantly less for secondary than for primary prevention: 64%± 7% versus 84%± 6% at 5 years, P = 0.02 . Notably, 59 of 67 events (cardiac arrest and therapeutic ICD interventions), or 88%, occurred during sedentary or noncompetitive activity. Incidence of therapeutic shocks was related to age but not to other reported risk factors, including severity of cardiac hypertrophy, nonsustained VT during Holter monitoring, and abnormal blood pressure response to exercise. ICD related complications occurred in 38 (29%) patients, including 60 inappropriate ICD interventions in 30 (23%) patients. However, 8 (27%) of the patients with inappropriate shocks also had therapeutic interventions. ICD is effective for secondary prevention of sudden death in HCM. However, selection of patients for primary prevention of sudden death, and prevention of device related complications require further refinement. (PACE 2003; 26:1887–1896)

Myocardial bridging does not predict sudden death in children with hypertrophic cardiomyopathy but is associated with more severe cardiac disease

OBJECTIVES We sought to examine the association between systolic compression of sections of epicardial coronary vessels (myocardial bridging) with myocardial perfusion abnormalities and clinical outcome in children with hypertrophic cardiomyopathy (HCM). BACKGROUND It has recently been suggested that myocardial bridging is an important cause of myocardial ischemia and sudden death in children with HCM. METHODS Angiograms from 57 children with HCM were reviewed for the presence of bridging (50% or more maximum systolic arterial compression). QT interval indices, echocardiographic and cardiac catheterization findings, treadmill exercise tests, exercise thallium scintigraphy, Holter monitoring and electrophysiologic study findings were compared in children with and without bridging. The findings were also related to the presence or absence of compression of septal branches of the left anterior descending artery (LAD). RESULTS Bridging was present in 23 (40%) of the children. Multiple coronary arteries were involved in four children. Bridging involved the LAD in 16 of 28 (57%) affected vessels. Myocardial perfusion abnormalities were present in 14 of 30 (47%) children without bridging and in 17 of 22 (94%) children with bridging, p = 0.002. However, bridging was associated with more severe septal hypertrophy (19+/-8 mm vs. 28+/-8 mm, p < 0.001), a higher septum:posterior wall thickness ratio (2.7+/-1.2 vs. 1.8+/-0.9, p < 0.001), and higher left ventricle (LV) outflow gradient (45+/-37 mm Hg vs. 16+/-28 mm Hg, p = 0.002). Compression of septal LAD branches was present in 37 (65%) of the children and was significantly associated with bridging, severity of LV hypertrophy and outflow obstruction. Multivariate analysis demonstrated that LV septal thickness and septal branch compression, and not bridging, were independent predictors of thallium perfusion abnormalities. There was a 90% power at 5% significance to detect an effect of bridging on thallium abnormalities at an odds ratio of 3. Bridging was also not associated with significantly greater symptoms, increased QT and QTc intervals and QTc dispersion, ventricular tachycardia on Holter or induced at EP study, or a worse prognosis. CONCLUSIONS Bridging and compression of septal branches of the LAD are common in HCM children and are related to magnitude of LV hypertrophy. Left ventricular hypertrophy and compression of intramyocardial branches of the epicardial coronary arteries may contribute to myocardial perfusion abnormalities. Our findings suggest that bridging does not result in myocardial ischemia and may not cause arrhythmias or sudden death in HCM children.

Effect of Low-Amplitude Two-Dimensional Radial Strain at Left Ventricular Pacing Sites on Response to Cardiac Resynchronization Therapy

BACKGROUND Left ventricular (LV) lead placement to areas of scar has detrimental effects on response to cardiac resynchronization therapy (CRT). Speckle-tracking radial two-dimensional strain offers assessment of the extent of regional myocardial deformation. The aim of this study was to assess the impact of LV lead placement at areas of low-amplitude strain on CRT response. METHODS The optimal cutoff of radial strain amplitude at the LV pacing site associated with an unfavorable CRT response was determined in a derivation group (n = 65) and then tested in a second consecutive validation group (n = 75) of patients with heart failure. Patients had concordant LV leads if placed at the most delayed site, and dyssynchrony was defined as anteroseptal to posterior delay ≥ 130 msec. CRT response was defined as a ≥15% reduction in LV end-systolic volume at 6 months. RESULTS In the derivation group, a derived cutoff for radial strain amplitude of <9.8% defined low-amplitude segments (LAS) and had a high specificity but low sensitivity for predicting LV reverse remodeling, suggesting a strong negative predictive value. In the validation group, compared with patients without LAS at the LV pacing site, in patients with LAS (n = 16), CRT response was significantly lower (62.7% vs 31.3%, P < .05). By multivariate analysis, LV lead concordance and the absence of an LAS at the LV pacing site but not dyssynchrony were significantly related to CRT response. CONCLUSION LV lead placement over segments with two-dimensional radial strain amplitudes <9.8% is associated with poor outcomes of CRT.

Utility of Genetic Screening in Hypertrophic Cardiomyopathy: Prevalence and Significance of Novel and Double (Homozygous and Heterozygous) β-Myosin Mutations

Genetic screening of the beta-myosin heavy chain gene (MYH7) was evaluated in 100 consecutive unrelated patients with hypertrophic cardiomyopathy (HCM) and 200 normal unrelated subjects. Seventeen beta-myosin mutations were identified in 19 patients. Notably, 13, or 76%, were novel. Mutations were detected in both alleles in two patients: homozygous for Lys207Gln in one, and heterozygous for Pro211 Leu and Arg663His in another. No mutation was detected in the controls. MYH7-associated HCM was associated with more marked left atrial enlargement and syncope than non-MYH7-related HCM. Our findings indicate that: (1) screening methods should allow identification of novel mutations; and (2) more than one sarcomeric mutation may be present in a patient more commonly than is appreciated. Further studies are necessary to ascertain the clinical consequences of the novel and compound gene abnormalities, and to determine whether correlating functional domain to phenotype provides more useful information about the clinical significance of the molecular defects.

The Impact of the Right Ventricular Lead Position on Response to Cardiac Resynchronization Therapy

Introduction: Left ventricular (LV) lead placement to the latest contracting area (concordant LV lead) is associated with better response to cardiac resynchronization therapy (CRT) compared to a discordant LV lead. However, the effect of the right ventricular (RV) lead site on CRT response is unclear. We investigated the relationship of the RV and LV lead positions on CRT response.

Cardiac resynchronisation therapy: pacemaker versus internal cardioverter-defibrillator in patients with impaired left ventricular function

Objective Studies have shown beneficial effects of cardiac resynchronisation therapy (CRT) on mortality among patients with heart failure. However the incremental benefits in survival from CRT with a defibrillator (CRT-D) are unclear. The choice of appropriate device remains unanswered. Method This is a single-centre observational study in a tertiary cardiac centre. Patients (n=500) implanted with a CRT device with pacing alone (CRT-P) (n=354) and CRT-D (n=146) were followed for at least 2 years (mean 29 months, SD 14 months). The primary end point was all-cause mortality. Results A total of 116 deaths (23.2%) were recorded: 88 (24.8%) and 28 (19.2%), in the CRT-P and CRT-D groups, respectively. At 1 year there was a trend favouring CRT-D (HR 0.54, 95% CI 0.27 to 1.07, p=0.08) but this was attenuated by the 2nd year and became insignificant at the end of follow-up (HR 0.76, 95% CI 0.50 to 1.170, p=0.21). There was no survival benefit from having an internal cardioverter-defibrillator if patients were deemed non-responders to CRT. 27% of the CRT-P patients with ischaemic cardiomyopathy met indications for potential internal cardioverter-defibrillator implantation for primary prevention. These were older patients with poorer baseline function in comparison with CRT-D patients with devices for primary prevention. Once these differences were adjusted for, there was no difference in outcome between the groups. Conclusions CRT-D did not offer additional survival advantage over CRT-P at longer-term follow-up, as the clinical benefit of a defibrillator attenuated with time. Further work is needed to define which subset of patients benefit from CRT-D.

Cardioverter-defibrillator implantation and generator replacement in the octogenarian

AIMS Increase in life expectancy has led to increased rate of implantable cardioverter-defibrillator (ICD) implantation in patients in their 80s, but there are no current formal recommendations to guide physicians when elderly patients with ICDs require elective unit replacement (EUR). This study aims at assessing survival and rates of ICD therapies in patients who have had ICD implantation or EUR above the age of 80, focusing on the latter. METHODS AND RESULTS Retrospective analysis of a prospectively kept database of all ICD-related procedures carried out in a single tertiary centre. Patients 80 years of age or older submitted to ICD implantation (n = 42) or EUR (n = 34) between November 1991 and May 2012 were included. Using collected baseline and outcome data from this cohort, we assessed survival of these patients and the rates of ICD therapies. Median additional years of life after ICD implantation and ICD EUR in patients who died before data retrieval was 2.5 and 1.2, respectively, and while 65% of deceased patients after ICD implantation died in the first 3 years after the procedure, 50% of deceased post-ICD EUR patients died within the first year. Mortality rates at 1 and 2 years post-EUR were 23.1 and 38.1%, respectively. Furthermore, ventricular tachycardia occurred in a small minority of patients after EUR (16.7%) and no ventricular fibrillation-triggered ICD therapies were reported in both groups. CONCLUSION In octogenarians who are due for an ICD EUR, careful thought should be given to the current clinical status, comorbidities, and general frailty prior to considering them for the procedure. A survival benefit from ICD EUR in this age stratum is not likely.

Dual Chamber Pacemaker Therapy for Mid‐Cavity Obstructive Hypertrophic Cardiomyopathy

BEGLEY, D., et al.: Dual Chamber Pacemaker Therapy for Mid‐Cavity Obstructive Hypertrophic Cardiomyopathy. Intracavitary LV obstruction is an important determinant of clinical outcome in hypertrophic cardiomyopathy (HCM). In a minority of patients the obstruction is at the level of the papillary muscles. Mid‐cavity obstructive HCM may be associated with a distal LV aneurysm and a worse prognosis. It is often not amenable to standard cardiac surgery for LV outflow obstruction. The long‐term effects (mean follow‐up 4.8 ± 2.9 years) of dual chamber (DDD) pacemaker therapy in 14 patients with mid‐cavity obstructive HCM (mean age 34 ± 16 years, range 15–65 years) were studied. Patients were evaluated by cardiac catheterization at baseline and 6 months to 1 year after receiving DDD pacemakers off all drug therapy. Symptoms were improved in all patients and NYHA functional class reduced from 2.8 ± 0.1 to 1.9 ± 0.4 (P < 0.0005). Intracavitary LV pressure gradients was reduced significantly (43 ± 36 vs 84 ± 31 mmHg at baseline, P < 0.0005). There was a significant associated reduction in apical LV systolic pressure (152 ± 37 vs 188 ± 34 mmHg, P < 0.001). In addition, there was a trend towards increased exercise tolerance (445 ± 123 vs 396 ± 165). Cardiac output and LV filling pressures were unchanged. In conclusion, chronic DDD pacing results in significant symptomatic and hemodynamic improvement in this uncommon but important subset of patients with obstructive HCM in whom the role of cardiac surgery is less well defined compared with the more typical outflow tract location of LV obstruction.

Impact of VV optimization in relation to left ventricular lead position: an acute haemodynamic study

AIMS Left ventricular (LV) lead placement to the most delayed segment offers the greatest potential benefit to cardiac resynchronization therapy (CRT). We assessed the impact of interventricular (VV) optimization on acute changes in cardiac output (CO) in patients with and without LV pacing of the most delayed segment. METHODS AND RESULTS In 124 patients, the most delayed segment was defined by speckle tracking radial strain and the LV lead position by biplane fluoroscopy. Patients were classified as either a concordant (LV lead at latest site), adjacent (within one segment), or remote (two or more segments away) LV lead. Atrioventricular (AV) and VV delays were optimized by echocardiography. Cardiac output was measured non-invasively and a >20% increase in CO from baseline (intrinsic) defined acute response. Changes in CO in patients with concordant, adjacent, or remote LV leads were recorded following atrioventricular optimization alone (AV OPT) and after combined AV and VV optimization (AV/VV OPT). Compared with AV OPT pacing, AV/VV OPT produced a greater rise in CO (5.45 ± 1.1 vs. 5.76 ± 1.2 L/min, P< 0.001) and higher acute response rates (48.4 vs. 61.3%, P= 0.041). In adjacent patients, compared with AV OPT pacing, AV/VV OPT settings increased the response rate from 36.4 to 63.6% (P= 0.037). VV optimization had no effect on acute response rates in patients with remote (26.7 vs. 33.3%, P = 0.581) or concordant LV leads (65.6 vs. 72.1%, P = 0.438). CONCLUSION VV optimization overcomes some but not all of the deleterious effects of a suboptimal LV lead position.