Dorothea McAreavey

Long-term results of dual-chamber (DDD) pacing in obstructive hypertrophic cardiomyopathy. Evidence for progressive symptomatic and hemodynamic improvement and reduction of left ventricular hypertrophy.

BackgroundWe previously reported that 6 to 12 weeks of dual-chamber (DDD) pacing results in clinical and hemodynamic improvement in obstructive hypertrophic cardiomyopathy (HCM). This study examines the long-term results of DDD pacing in obstructive HCM. Methods and ResultsDDD devices were implanted in 84 patients (mean age, 49 ± 16 years) with obstructive HCM and severe drug-refractory symptoms. At a mean follow-up of 2.3 ± 0.8 years (maximum, 3.5 years), the New York Heart Association (NYHA) functional class had improved significantly (1.6 ± 0.6 versus 3.2 ± 0.5, P < .00001). Symptoms were eliminated in 28 patients (33%), improved in 47 patients (56%), but remained unchanged in 7 patients (8%). Two patients died suddenly (97% cumulative 3-year survival rate). In 74 patients with significant left ventricular outflow tract (LVOT) obstruction at rest, the LVOT gradients were significantly reduced at follow-up (27 ± 31 versus 96 ± 41 mm Hg, P < .00001). Symptoms and provokable LVOT gradients were also reduced in all 10 patients without significant resting but with provokable LVOT obstruction. Persistence of the LVOT obstruction and symptoms was attributed to inability to pre-excite the interventricular septum (n = 8) and onset of atrial fibrillation (n = 7). Fifty patients had two cardiac catheterization evaluations, 3 ± 1 and 16 ± 4 months after implantation of a pacemaker. In this subgroup, the NYHA functional class improved from 3.2 ± 0.5 at baseline to 1.8 ± 0.7 at the initial evaluation (P < .00001), but with a further significant improvement at the second evaluation: 1.4 ± 0.6, P < .001. This symptomatic improvement was associated with progressive reduction of LVOT gradient at the two evaluations: baseline, 100 ± 47 mm Hg; first evaluation, 41 ± 36 mm Hg (P < .0001); and second evaluation, 29 ± 34 mm Hg (P < .01). Despite the presence of left bundle branch block, DDD pacing reduced LVOT obstruction significantly in 15 patients (LVOT gradient, baseline 89 ± 36 mm Hg versus 18 ± 26 mm Hg at follow-up, P < .0001). There was a weak but significant correlation between the reduction in LVOT gradients accomplished by AV pacing before implantation of DDD device and the eventual reduction in LVOT gradients recorded at the follow-up evaluation (r = .38, P = .0017). Echocardiography demonstrated significant thinning of the anterior septum and distal anterior LV wall in the absence of deterioration of LV systolic function. Conclusions(1) Although most of the improvement of symptoms and hemodynamic indexes occurs during the first few months of DDD pacing, further changes are often observed a year later; (2) DDD pacing is associated with an excellent prognosis in a subgroup of severely disabled patients, many of whom present with syncope or presyncope; (3) baseline pacing studies are not essential to identify patients who may benefit from pacing; (4) preexisting left bundle branch block is compatible with severe LVOT obstruction, and DDD pacing is also beneficial in this subgroup; (5) DDD pacing reduces both resting and provokable LVOT obstruction; (6) additional therapy, for example, radiofrequency ablation of the AV node, may be necessary in some patients either to preexcite the interventricular septum or to control atrial fibrillation; and (7) although LV hypertrophy has been considered a primary feature of HCM, pacing appears to reverse LV wall thickness in a significant subset of adult HCM patients.

Prognostic determinants in hypertrophic cardiomyopathy. Prospective evaluation of a therapeutic strategy based on clinical, Holter, hemodynamic, and electrophysiological findings.

BackgroundPatients with hypertrophic cardiomyopathy (HCM) frequently have arrhythmias and hemodynamic abnormalities and are prone to sudden death and syncope. An important need exists for improved risk stratification and definition of appropriate investigation and therapy. Methods and ResultsThe relation of 31 clinical, Holter, cardiac catheterization, and electrophysiological (EP) variables to subsequent cardiac events in 230 HCM patients was examined by multivariate analysis. Studies were for cardiac arrest (n=32), syncope (n=80), presyncope (n=52), ventricular tachycardia (VT) on Holter (n=36), a strong family history of sudden death (n=9), and palpitations (n=21). Nonsustained VT on Holter was present in 115 patients (50%). Sustained ventricular arrhythmia was induced in 82 patients (36%). Seventeen cardiac events (eight sudden deaths, one cardiac arrest, and eight syncope with defibrillator discharges) occurred during a follow-up of 28±19 months. The 1-year and 5-year event-free rates were 99%, and 79%, respectively. Two variables were significant independent predictors of subsequent events: sustained ventricular arrhythmia induced at EP study (β, 3.5; p=0.002) and a history of cardiac arrest or syncope (β 2.9; p<0.05). Only two of 66 patients without symptoms of impaired consciousness had a cardiac event (3-year event-free rate, 97%). In contrast, nonsustained VT on Holter was associated with a worse prognosis only in patients with symptoms of impaired consciousness: 11 of 79 symptomatic patients with VT on Holter (14%) had events versus only four of 85 symptomatic patients without VT on Bolter (5%) (p=0.057). Notably, none of 51 patients without symptoms of impaired consciousness in whom VT was not induced at EP study had a cardiac event. ConclusionsIn HCM, VT on Holter is of benign prognostic significance in the absence of symptoms of impaired consciousness and inducible VT, and sustained VT induced at EP study, especially when associated with cardiac arrest or syncope, identifies a subgroup at high risk for subsequent cardiac events.

Myocardial Perfusion Scans Projected Population Cancer Risks From Current Levels of Use in the United States

Background— Myocardial perfusion scans contribute up to 20% of the estimated annual collective radiation dose to the US population. We estimated potential future cancer risk from these scans by age at exposure and current frequency of use in the United States. Methods and Results— Usage patterns were determined from national survey data, and radionuclide dosage was based on current guidelines. Cancer risk projection models were generated on the basis of the National Research Council Biological Effects of Ionizing Radiation VII report, under the assumption that risk has a linear relationship with radiation exposure even at low doses. The mean projected number of radiation-related incident cancers and 95% uncertainty intervals were estimated with the use of Monte Carlo simulations. Estimated risks for a scan performed at age 50 years ranged from 2 cancers per 10 000 scans (95% uncertainty interval, 1 to 5) for a positron emission tomography ammonia-13 test to 25 cancers per 10 000 scans (95% uncertainty interval, 9 to 58) for a dual-isotope (thallium-201 plus technetium-99m) scan. Risks were 50% lower at age 70 years but were similar for men and women. The combination of cancer risk estimates and data on frequency of use suggests that the 9.1 million myocardial perfusion scans performed annually in the United States could result in 7400 (95% uncertainty interval, 3300 to 13 700) additional future cancers. Conclusions— The lifetime cancer risk from a single myocardial perfusion scan is small and should be balanced against likely benefit and appropriateness of the test. The estimates depend on a number of assumptions, including life expectancy. They apply directly to asymptomatic individuals with life expectancies similar to those of the general population. For individuals with a symptomatic clinical profile, on whom such scans are typically performed, the risks will be lower because of shorter life expectancy.Background— Myocardial perfusion scans contribute up to 20% of the estimated annual collective radiation dose to the US population. We estimated potential future cancer risk from these scans by age at exposure and current frequency of use in the United States. Methods and Results— Usage patterns were determined from national survey data, and radionuclide dosage was based on current guidelines. Cancer risk projection models were generated on the basis of the National Research Council Biological Effects of Ionizing Radiation VII report, under the assumption that risk has a linear relationship with radiation exposure even at low doses. The mean projected number of radiation-related incident cancers and 95% uncertainty intervals were estimated with the use of Monte Carlo simulations. Estimated risks for a scan performed at age 50 years ranged from 2 cancers per 10 000 scans (95% uncertainty interval, 1 to 5) for a positron emission tomography ammonia-13 test to 25 cancers per 10 000 scans (95% uncertainty interval, 9 to 58) for a dual-isotope (thallium-201 plus technetium-99m) scan. Risks were 50% lower at age 70 years but were similar for men and women. The combination of cancer risk estimates and data on frequency of use suggests that the 9.1 million myocardial perfusion scans performed annually in the United States could result in 7400 (95% uncertainty interval, 3300 to 13 700) additional future cancers. Conclusions— The lifetime cancer risk from a single myocardial perfusion scan is small and should be balanced against likely benefit and appropriateness of the test. The estimates depend on a number of assumptions, including life expectancy. They apply directly to asymptomatic individuals with life expectancies similar to those of the general population. For individuals with a symptomatic clinical profile, on whom such scans are typically performed, the risks will be lower because of shorter life expectancy. # Clinical Perspective {#article-title-38}

Temporal repolarization lability in hypertrophic cardiomyopathy caused by β-myosin heavy-chain gene mutations

BACKGROUND Certain genetic mutations associated with hypertrophic cardiomyopathy (HCM) carry an increased risk of sudden death. QT variability identifies patients at a high risk for sudden death from ventricular arrhythmias. We tested whether patients with HCM caused by beta-myosin heavy-chain (beta-MHC) gene mutations exhibit labile ventricular repolarization using beat-to-beat QT variability analysis. METHODS AND RESULTS We measured the QT variability index and heart rate-QT interval coherence from Holter monitor recordings in 36 patients with HCM caused by known beta-MHC gene mutations and in 26 age- and sex-matched controls. There were 7 distinct beta-MHC gene mutations in these 36 patients; 9 patients had HCM caused by the malignant Arg(403)Gln mutation and 8 patients had HCM caused by the more benign Leu(908)Val mutation. The QT variability index was higher in HCM patients than in controls (-1.24+/-0.17 versus -1. 58+/-0.38, P<0.01), and the greatest abnormality was detected in patients with the Arg(403)Gln mutation (-0.99+/-0.49 versus -1. 46+/-0.43 in controls, P<0.05). In keeping with this finding, coherence was lower for the entire HCM group than for controls (P<0. 001). Coherence was also significantly lower in patients with the Arg(403)Gln mutation compared with controls (P<0.05). CONCLUSIONS These findings suggest that (1) patients with HCM caused by beta-MHC gene mutations exhibit labile repolarization quantified by QT variability analysis and, hence, may be more at risk for sudden death from ventricular arrhythmias, and (2) indices of QT variability may be particularly abnormal in patients with beta-MHC gene mutations that are associated with a poor prognosis.

Cerebellar Ataxia, Seizures, Premature Death, and Cardiac Abnormalities in Mice with Targeted Disruption of the Cacna2d2 Gene

CACNA2D2 is a putative tumor suppressor gene located in the human chromosome 3p21.3 region that shows frequent allelic imbalances in lung, breast, and other cancers. The alpha2delta-2 protein encoded by the gene is a regulatory subunit of voltage-dependent calcium channels and is expressed in brain, heart, and other tissues. Here we report that mice homozygous for targeted disruption of the Cacna2d2 gene exhibit growth retardation, reduced life span, ataxic gait with apoptosis of cerebellar granule cells followed by Purkinje cell depletion, enhanced susceptibility to seizures, and cardiac abnormalities. The Cacna2d2(tm1NCIF) null phenotype has much in common with that of Cacna1a mutants, such as cerebellar neuro-degeneration associated with ataxia, seizures, and premature death. A tendency to bradycardia and limited response of null mutants to isoflurane implicate alpha2delta-2 in sympathetic regulation of cardiac function. In summary, our findings provide genetic evidence that the alpha2delta-2 subunit serves in vivo as a component of P/Q-type calcium channels, is indispensable for the central nervous system function, and may be involved in hereditary cerebellar ataxias and epileptic disorders in humans.

Altered cardiac hemodynamic and electrical state in normal sinus rhythm after chronic dual-chamber pacing for relief of left ventricular outflow obstruction in hypertrophic cardiomyopathy

Dual-chamber (DDD) pacing relieves left ventricular (LV) outflow tract obstruction in patients with hypertrophic cardiomyopathy. The reduction in LV outflow gradient persists in some patients after cessation of pacing. Twelve-lead and signal-averaged electrocardiograms were obtained before and after 12 weeks of DDD pacing in 18 patients with obstructive hypertrophic cardiomyopathy to determine whether the altered hemodynamic state after chronic pacing is accompanied by electrical changes. Hemodynamic studies were performed at baseline and at follow-up. Signal-averaged electro-cardiograms were obtained using a Corazonix Predictor and bidirectional filters at 25 Hz to a noise level of less than 0.5 microV. At follow-up, LV outflow tract gradients were reduced significantly during DDD pacing and with cessation of pacing in sinus rhythm by 56 +/- 10 and 47 +/- 10 mm Hg, respectively (p less than 0.001). There was no simple relation between changes in LV outflow tract gradient and in the electrocardiogram. For example, amplitude of the R wave in V5,6 was reduced by greater than or equal to 0.5 mv in 4 patients, unchanged in 12 and increased in 2. Similarly, the S wave in leads V1,2 was reduced in 7 patients, unchanged in 7 and increased in 4. The T wave became more negative (greater than or equal to 0.1 mv) in leads II, III, aVF and V5,6 in 13 patients and more positive in leads I and aVL in 12.(ABSTRACT TRUNCATED AT 250 WORDS)

Radiofrequency Catheter Atrioventricular Node Ablation in Patients with Permanent Cardiac Pacing Systems

Following successful BF ablation of the atrioventricular node (AVN), temporary pacing is necessary prior to insertion of a permanent pacemaker. The risks and inconvenience of temporary pacing could be avoided if a permanent pacemaker is already in place. This study reports the feasibility of RF ablation of the AVN in 27 patients (age 55 ± 17 years, 15 males) with hypertrophic cardiomyopathy and pacemakers, Indications for AVN ablation were drug refractory atrial fibrillation in 24 patients, and rapid AVN conduction preventing septal pre‐excitation by DDD pacemaker, inserted for relief of left ventricular outflow obstruction, in three cases. Sixteen patients had DDD devices and 11 patients had VVI devices. During RF ablation, each pacemaker was programmed to VVI at 50 beats/min. The ablation catheter was manipulated with fluoroscopic control to avoid close contact with or disturbance of the pacing leads. In 16 patients, RF ablation was performed immediately following pacemaker implantation but in the remaining patients, the AVN was ablated 6–32 months after pacemaker implantation. The power applied was 25–50 watts for a duration of 15–60 seconds. AV block was achieved in all cases but required 34 ± 36 applications for 16.5 ± 17.8 min/case. RF ablation consistently caused reversion to magnet rate in one patient and temporarily inhibited appropriate pacemaker discharge in another. However, no other pacemaker or lead malfunction was detected so that temporary pacing was not required in any case. At 6 ± 3 months follow‐up, all pacemakers were functioning normally without alteration in pacing parameters from baseline. Thus. RF ablation of the AVN can be performed safely in the presence of a recently implanted permanent pacemaker, without temporary pacing.

Ventilatory efficiency and resting hemodynamics in hypertrophic cardiomyopathy.

PURPOSE In patients with systolic heart failure, the ability of cardiopulmonary exercise testing (CPX) variables to reflect pathophysiology is well established. The relationship between CPX and pathophysiology has, however, not been thoroughly investigated in patients with nonobstructive hypertrophic cardiomyopathy (NHCM). The objective of this study was to assess the ability of CPX variables to reflect resting hemodynamics in patients with nonobstructive hypertrophic cardiomyopathy NHCM. METHODS We performed CPX and right heart catheterization on 83 subjects with NHCM (51 male/32 female, mean age = 38 +/- 10 yr, NYHA I-III mean = 1.7). Peak oxygen consumption ( O2) and minute ventilation/carbon dioxide ratio (V E/VCO2) at peak exercise were compared to resting hemodynamics including pulmonary artery systolic, diastolic and mean pressures (PASP, PADP and MPAP), and pulmonary capillary wedge pressure (PCWP). RESULTS Elevations in PCWP (> or = 15 mm Hg), PASP (> or =30 and > or = 40 mm Hg), PADP (> 15 mm Hg) and MPAP (> or = 20 mm Hg) were detected in 22, 33, 10, and 23% of subjects, respectively. Peak V E/VCO2 (positive correlation) and peak VO2 (negative correlation) correlated modestly with all pressure measurements (r = 0.33-0.51, P < 0.01 for all measurements). By receiver operating curve analysis, a V E/VCO2 >35.5 exhibited the best diagnostic accuracy with a curve areas of 0.81 for PAP > or = 30 mm Hg (sensitivity/specificity = 86%/67%), 0.87 for PAP > or = 40 mm Hg (77%/100%), 0.86 for MPAP > 20 mm Hg (83%/79%), and 0.84 for PCWP > or = 15 mm Hg (80%/76%). CONCLUSIONS CPX can accurately identify abnormal resting hemodynamics in patients with NHCM. Further testing of this modality in other forms of diastolic dysfunction may be warranted.

Identification of patients with hypertrophic cardiomyopathy at high risk for sudden death.

Patients with hypertrophic cardiomyopathy are at increased risk for sudden death. Recent studies have improved our ability to risk-stratify such patients and have elucidated several potential mechanisms of sudden death and syncope. Certain noninvasive tests, such as signal-averaged electrocardiography and measurements of cardiac autonomic function and QT/QT dispersion, are often abnormal in hypertrophic cardiomyopathy, but are not useful for risk stratification. Myocardial ischemia determined by exercise thallium scintigraphy, however, identifies young patients with hypertrophic cardiomyopathy who are at high risk for cardiac arrest and syncope. Nonsustained ventricular tachycardia on ambulatory Holter monitoring in the absence of symptoms of impaired consciousness is associated with a benign prognosis and is not predictive of sudden death. Conversely, ventricular tachycardia induced at electrophysiologic study identifies adult patients with hypertrophic cardiomyopathy who subsequently experience sudden death. Finally, characterization of the natural history of the genetic defects will increasingly become an integral part of risk evaluation in hypertrophic cardiomyopathy.

Hypertrophic Cardiomyopathy: valuation and Treatment of Patients at High Risk for Sudden Death

Hypertrophic cardiomyopathy (HCM) is a heritable disease characterized by LV hypertrophy with markedly variable clinical, morphological, and genetic manifestations. It is the most common cause of sudden death in otherwise healthy young individuals. HCM patients often have disabling symptoms and are prone to arrhythmias. Frequently, there is associated LV systolic and diastolic dysfunction, LV outflow obstruction, and myocardial ischemia. Over the past decade, progress has been made in identifying patients who are at high risk for sudden death, in elucidating potential mechanisms of sudden death, and in defining therapeutic algorithms that may improve prognosis. It has also been possible to determine the genetic defect in some of the patients and to correlate clinical findings with the molecular defects. An exciting development has been the use of the dual chamber pacemaker as an alternative to cardiac surgery to improve symptoms and relieve LV outflow obstruction.