Adrian K. Almquist

EFFICACY OF IMPLANTABLE CARDIOVERTER-DEFIBRILLATORS FOR THE PREVENTION OF SUDDEN DEATH IN PATIENTS WITH HYPERTROPHIC CARDIOMYOPATHY

BACKGROUND Hypertrophic cardiomyopathy is a genetic disease associated with a risk of ventricular tachyarrhythmias and sudden death, especially in young patients. METHODS We conducted a retrospective multicenter study of the efficacy of implantable cardioverter-defibrillators in preventing sudden death in 128 patients with hypertrophic cardiomyopathy who were judged to be at high risk for sudden death. RESULTS At the time of the implantation of the defibrillator, the patients were 8 to 82 years old (mean [+/-SD], 40+/-16), and 69 patients (54 percent) were less than 41 years old. The average follow-up period was 3.1 years. Defibrillators were activated appropriately in 29 patients (23 percent), by providing defibrillation shocks or antitachycardia pacing, with the restoration of sinus rhythm; the average age at the time of the intervention was 41 years. The rate of appropriate defibrillator discharge was 7 percent per year. A total of 32 patients (25 percent) had episodes of inappropriate discharges. In the group of 43 patients who received defibrillators for secondary prevention (after cardiac arrest or sustained ventricular tachycardia), the devices were activated appropriately in 19 patients (11 percent per year). Of 85 patients who had prophylactic implants because of risk factors (i.e., for primary prevention), 10 had appropriate interventions (5 percent per year). The interval between implantation and the first appropriate discharge was highly variable but was substantially prolonged (four to nine years) in six patients. In all 21 patients with stored electrographic data and appropriate interventions, the interventions were triggered by ventricular tachycardia or fibrillation. CONCLUSIONS Ventricular tachycardia or fibrillation appears to be the principal mechanism of sudden death in patients with hypertrophic cardiomyopathy. In high-risk patients with hypertrophic cardiomyopathy, implantable defibrillators are highly effective in terminating such arrhythmias, indicating that these devices have a role in the primary and secondary prevention of sudden death.

Clinical Outcome and Phenotypic Expression in LAMP2 Cardiomyopathy

CONTEXT Mutations in X-linked lysosome-associated membrane protein gene (LAMP2; Danon disease) produce a cardiomyopathy in young patients that clinically mimics severe hypertrophic cardiomyopathy (HCM) due to sarcomere protein mutations. However, the natural history and phenotypic expression of this newly recognized disease is incompletely resolved and its identification may have important clinical implications. OBJECTIVES To determine the clinical consequences, outcome, and phenotypic expression of LAMP2 cardiomyopathy associated with diagnostic and management strategies. DESIGN, SETTING, AND PATIENTS Clinical course and outcome were assessed prospectively in 7 young patients (6 boys) with defined LAMP2 mutations from the time of diagnosis (age 7-17 years; median, 14 years) to October 2008. Phenotypic expression of this disease was assessed both clinically and at autopsy. MAIN OUTCOME MEASURES Progressive heart failure, cardiac death, and transplant. RESULTS Over a mean (SD) follow-up of 8.6 (2.6) years, and by age 14 to 24 years, the study patients developed left ventricular systolic dysfunction (mean [SD] ejection fraction, 25% [7%]) and cavity enlargement, as well as particularly adverse clinical consequences, including progressive refractory heart failure and death (n = 4), sudden death (n = 1), aborted cardiac arrest (n = 1), or heart transplantation (n = 1). Left ventricular hypertrophy was particularly marked (maximum thickness, 29-65 mm; mean [SD], 44 [15] mm), including 2 patients with massive ventricular septal thickness of 60 mm and 65 mm at ages 23 and 14 years, respectively. In 6 patients, a ventricular pre-excitation pattern at study entry was associated with markedly increased voltages of R-wave or S-wave (15-145 mm; mean [SD], 69 [39] mm), and deeply inverted T-waves. Autopsy findings included a combination of histopathologic features that were consistent with a lysosomal storage disease (ie, clusters of vacuolated myocytes) but also typical of HCM due to sarcomere protein mutations (ie, myocyte disarray, small vessel disease, myocardial scarring). CONCLUSIONS LAMP2 cardiomyopathy is a profound disease process characterized by progressive clinical deterioration leading rapidly to cardiac death in young patients (<25 years). These observations underscore the importance of timely molecular diagnosis for predicting prognosis and early consideration of heart transplantation.

Deaths and cardiovascular injuries due to device-assisted implantable cardioverter–defibrillator and pacemaker lead extraction

Aims An estimated 10 000–15 000 pacemaker and implantable cardioverter–defibrillator (ICD) leads are extracted annually worldwide using specialized tools that disrupt encapsulating fibrous tissue. Additional information is needed regarding the safety of the devices that have been approved for lead extraction. The aim of this study was to determine whether complications due to device-assisted lead extraction might be more hazardous than published data suggest, and whether procedural safety precautions are effective. Methods and results We searched the US Food and Drug Administrations (FDA) Manufacturers and User Defined Experience (MAUDE) database from 1995 to 2008 using the search terms ‘lead extraction and death’ and ‘lead extraction and injury’. Additional product specific searches were performed for the terms ‘death’ and ‘injury’. Between 1995 and 2008, 57 deaths and 48 serious cardiovascular injuries associated with device-assisted lead extraction were reported to the FDA. Owing to underreporting, the FDA database does not contain all adverse events that occurred during this period. Of the 105 events, 27 deaths and 13 injuries occurred in 2007–2008. During these 2 years, 23 deaths were linked with excimer laser or mechanical dilator sheath extractions. The majority of deaths and injuries involved ICD leads, and most were caused by lacerations of the right atrium, superior vena cava, or innominate vein. Overall, 62 patients underwent emergency surgical repair of myocardial perforations and venous lacerations and 35 (56%) survived. Conclusion These findings suggest that device-assisted lead extraction is a high-risk procedure and that serious complications including death may not be mitigated by emergency surgery. However, skilled standby cardiothoracic surgery is essential when performing pacemaker and ICD lead extractions. Although the incidence of these complications is unknown, the results of our study imply that device-assisted lead extractions should be performed by highly qualified physicians and their teams in specialized centres.

Primary Prevention of Sudden Death as a Novel Treatment Strategy in Hypertrophic Cardiomyopathy

Case Report : A 20-year-old asymptomatic man was diagnosed with hypertrophic cardiomyopathy (HCM) after routine physical examination during which a systolic heart murmur was detected. Echocardiography showed massive left ventricular (LV) hypertrophy with ventricular septal thickness of 36 mm extending into the anterolateral wall (30 mm); outflow obstruction was absent. Ambulatory (Holter) ECG showed 3 isolated premature ventricular contractions, and blood pressure response to exercise was normal. Echocardiographic examinations in parents and siblings were negative for HCM. Although 2 centers advised against an implantable cardioverter-defibrillator (ICD) based on the presence of only 1 risk factor for sudden death (ie, extreme hypertrophy), a prophylactic device was recommended by a third cardiac consultant. After an uneventful 16-month period during which the ICD neither detected nor treated arrhythmias, an unprovoked episode of ventricular fibrillation triggered a defibrillation shock that immediately restored sinus rhythm (Figure 1). Figure 1. Primary prevention of sudden death in HCM. Continuous recording of a stored intracardiac ventricular electrogram from a young asymptomatic man with extreme LV hypertrophy (septal thickness 36 mm). The ICD senses ventricular fibrillation and automatically delivers a defibrillation shock (arrow), which restores normal rhythm. HCM is the most common genetic cardiovascular disease, and since its description 45 years ago, sudden death has been its most visible and devastating consequence.1–5 Indeed, HCM is the most common cause of sudden cardiac death in young people (including trained athletes).5 Such events usually occur in previously healthy individuals without significant symptoms or as the initial clinical manifestation of the disease, thus generating considerable anxiety and a sense of vulnerability among patients and families.2–5 Identification of high-risk patients and efforts at prevention of sudden death represent important clinical challenges in HCM.6 The ICD was introduced 25 years ago as a treatment strategy for lethal ventricular tachyarrhythmias.7 …

Prevention of Sudden Cardiac Death With Implantable Cardioverter-Defibrillators in Children and Adolescents With Hypertrophic Cardiomyopathy

OBJECTIVES The aim of this study was to determine the efficacy of implantable cardioverter-defibrillators (ICDs) in children and adolescents with hypertrophic cardiomyopathy (HCM). BACKGROUND HCM is the most common cause of sudden death in the young. The availability of ICDs over the past decade for HCM has demonstrated the potential for sudden death prevention, predominantly in adult patients. METHODS A multicenter international registry of ICDs implanted (1987 to 2011) in 224 unrelated children and adolescents with HCM judged at high risk for sudden death was assembled. Patients received ICDs for primary (n = 188) or secondary (n = 36) prevention after undergoing evaluation at 22 referral and nonreferral institutions in the United States, Canada, Europe, and Australia. RESULTS Defibrillators were activated appropriately to terminate ventricular tachycardia or ventricular fibrillation in 43 of 224 patients (19%) over a mean of 4.3 ± 3.3 years. ICD intervention rates were 4.5% per year overall, 14.0% per year for secondary prevention after cardiac arrest, and 3.1% per year for primary prevention on the basis of risk factors (5-year cumulative probability 17%). The mean time from implantation to first appropriate discharge was 2.9 ± 2.7 years (range to 8.6 years). The primary prevention discharge rate terminating ventricular tachycardia or ventricular fibrillation was the same in patients who underwent implantation for 1, 2, or ≥3 risk factors (12 of 88 [14%], 10 of 71 [14%], and 4 of 29 [14%], respectively, p = 1.00). Extreme left ventricular hypertrophy was the most common risk factor present (alone or in combination with other markers) in patients experiencing primary prevention interventions (17 of 26 [65%]). ICD-related complications, particularly inappropriate shocks and lead malfunction, occurred in 91 patients (41%) at 17 ± 5 years of age. CONCLUSIONS In a high-risk pediatric HCM cohort, ICD interventions terminating life-threatening ventricular tachyarrhythmias were frequent. Extreme left ventricular hypertrophy was most frequently associated with appropriate interventions. The rate of device complications adds a measure of complexity to ICD decisions in this age group.

Failure of impedance monitoring to prevent adverse clinical events caused by fracture of a recalled high-voltage implantable cardioverter-defibrillator lead

BACKGROUND The Medtronic Sprint Fidelis implantable cardioverter-defibrillator high-voltage lead is prone to fracture. The October 2007 safety advisory recommended lead impedance monitoring to aid in identifying lead fractures. OBJECTIVE The aim of this single-center study was to examine the effectiveness of impedance monitoring for detecting Sprint Fidelis lead failures before they caused adverse clinical events such as inappropriate shocks. METHODS Impedance and sensing information were acquired during routine clinic and CareLink follow-up and at the time of lead failure using the Patient Alert, sensing integrity counter, nonsustained episode, and electrogram features in Medtronic pulse generators. RESULTS Between September 2004 and February 2008, 17 of 514 Sprint Fidelis leads (3.3%) followed up at our center failed between 11 and 35 months after implantation (mean 23.0 +/- 8.0 months). Fifteen of these failures (88%) were caused by pace-sense conductor fractures, and 2 (12%) were caused by high-voltage conductor defects. Twelve of 15 patients (80%) with pace-sense conductor fractures received inappropriate shocks; of these, 4 had no significant increase in lead impedance before they were shocked, 2 were shocked <3 hours after their lead impedances exceeded the 1,000 Omega audible alert threshold, and 2 patients did not hear the alarm. All pace-sense conductor failures whose sensing function could be evaluated (13 of 15) had oversensing based on stored data, and oversensing usually (11 of 13) preceded impedances changes. CONCLUSION Impedance monitoring did not prevent inappropriate shocks in two-thirds of our patients. Thus, pace-sense conductor impedance monitoring as currently implemented does not reliably forewarn patients of a lead malfunction. Consequently, patients who have Sprint Fidelis leads remain at risk for adverse clinical events associated with pace-sense conductor fracture.

Cardiac electrophysiologic and hemodynamic correlates of neurally mediated syncope

This study assessed the temporal relation of RR interval, AH interval and systemic blood pressure changes during induced symptomatic bradycardia-hypotension episodes in 14 patients with recurrent syncope suspected of being neurally mediated. Upright tilt with isoproterenol reproduced symptoms in 9 of 14 patients (positive response) and was negative in 5 of 14 (negative response). Isoproterenol alone shortened supine RR intervals in all patients. With tilt, however, isoproterenol prolonged RR intervals in those with positive results (supine 519 +/- 124 ms vs tilt 845 +/- 212 ms, p less than 0.005) while further shortening RR intervals among negative responders (supine 436 +/- 90 ms vs tilt 377 +/- 82 ms, p less than 0.05). Similarly, tilt with isoproterenol prolonged AH intervals in patients with positive responses despite RR prolongation, while shortening AH in negative responders. Additionally, with combined tilt and isoproterenol, systemic arterial pressure decreased significantly in patients with positive responses (systolic 99 +/- 13 vs 57 +/- 13 mm Hg, p less than 0.001, diastolic 62 +/- 17 vs 28 +/- 9 mm Hg, p less than 0.001) but not in patients with negative responses. Further, onset of hypotension (42 +/- 14 seconds after tilt) preceded onset of RR interval prolongation (52 +/- 23 seconds after tilt). Syncope (142 +/- 72 seconds after tilt) coincided closely with nadir of systemic pressure (136 +/- 74 seconds) and both tended to precede maximum RR prolongation (152 +/- 87 seconds). Thus, the bradycardia and hypotension associated with neurally mediated syncope exhibit characteristic but distinctly different time courses, with arterial pressure changes developing earlier and coinciding more closely with symptom development.

Carotid sinus hypersensitivity: evaluation of the vasodepressor component.

The basis of the vasodepressor response in patients with carotid sinus hypersensitivity (CSH) is unknown, and prevention of recurrent vasodepressor-induced hypotension in these patients has not been possible. In this study we assessed the effectiveness of atrioventricular sequential pacing and pharmacologic interventions in the prevention of carotid sinus massage (CSM)-induced vasodepressor responses in eight patients with CSH. Maintenance of constant heart rate (80 beats/min) and atrioventricular synchrony (atrioventricular interval 150 msec) with sequential pacing did not significantly alter mean CSM-induced fall in systolic pressure (CSM control, -60 +/- 12 mm Hg vs CSM with atrioventricular sequential pacing, -48 +/- 19 mm Hg). Similarly, neither pharmacologic muscarinic blockade nor combined muscarinic and beta-adrenergic blockade significantly attenuated CSM-induced fall in systolic pressure (CSM with atropine, -43 +/- 16 mm Hg; CSM with atropine plus propranolol, -47 +/- 18 mm Hg; both p = NS vs atrioventricular sequential pacing alone). On the other hand, intravenous norepinephrine and oral ephedrine blunted the CSM-induced drop in systolic pressure (CSM with norepinephrine, -19 +/- 12 mm Hg; CSM with ephedrine, -21 +/- 11 mm Hg; both p less than .01 vs atrioventricular sequential pacing alone). Thus, vasodepressor responses were not prevented by control of heart rate, maintenance of atrioventricular synchrony, pharmacologic muscarinic blockade, or combined muscarinic and beta-adrenergic blockade, but were attenuated by drugs believed to be predominantly alpha-adrenergic agonists. Consequently, atrioventricular sequential pacing alone may be inadequate to prevent hypotension in patients with pronounced vasodepressor responses, whereas administration of vasoconstrictors such as ephedrine may diminish symptoms.

Lead integrity alert algorithm decreases inappropriate shocks in patients who have Sprint Fidelis pace-sense conductor fractures.

BACKGROUND The Medtronic Sprint Fidelis high-voltage implantable cardioverter-defibrillator (ICD) lead is prone to fracture. The majority of fractures involve the pace-sense (P/S) conductors and may result in multiple inappropriate shocks. The Medtronic lead integrity alert (LIA) algorithm was designed to improve early detection of transient P/S conductor fractures and to decrease the incidence and number of inappropriate shocks. OBJECTIVE The purpose of this prospective single-center study was to assess the effectiveness of the LIA algorithm for warning patients of an impending Sprint Fidelis P/S conductor fracture and for decreasing the incidence and number of inappropriate shocks. METHODS The study population included all patients who had Sprint Fidelis leads and Medtronic ICD pulse generators that were implanted and followed at the Minneapolis Heart Institute. Patients were evaluated in the clinic every 3 to 4 months or by remote monitoring using the Medtronic CareLink system. When the LIA algorithm was released in August 2008, the RAMware was downloaded to the pulse generator of all patients with the Sprint Fidelis lead. Patients and family members received educational materials and were given a demonstration of the audible alerts. RESULTS Between October 2004 and January 2010, 52 (11.3%) of 461 Sprint Fidelis leads failed in the study population. Inappropriate shocks were the first sign of lead failure in 18 (69%) of the 26 patients who did not have the LIA compared to 4 (17%) of 23 patients who had the LIA (P = .0004). Patients who experienced inappropriate shocks without the LIA received an average of 13.2 +/- 13.6 inappropriate shocks (range 2-54) versus 3.0 +/- 2.0 inappropriate shocks (range 2-6) in patients who had the LIA (P = .017). The audible alert was effective in 70% (16/23) and 35% (6/17) of patients with and without the LIA, respectively, whose alerts were programmed ON (P = .053). Overall, 8 (32%) of 25 patients whose audible alerts were triggered did not immediately hear or recognize the tone. CONCLUSION The LIA appears to be an effective method for detecting most Sprint Fidelis lead fractures and for decreasing the incidence and number of inappropriate shocks. However, a better method for alerting patients and caregivers is needed.

Long-term survival after cardiac arrest in hypertrophic cardiomyopathy

BACKGROUND Patients with hypertrophic cardiomyopathy (HCM) and aborted cardiac arrest are generally regarded as a high-risk subgroup susceptible to future major cardiac events and an unfavorable prognosis. However, outcome over extended time periods after major arrhythmic events is unresolved in such HCM patients. OBJECTIVE This study sought to more completely define the natural history of HCM. METHODS Of 916 HCM patients in the Minneapolis Heart Institute registry, 39 experienced either cardiac arrest (n = 21) or an appropriate shock from a prophylactically implanted cardioverter-defibrillator (ICD) (n = 18), and were assessed prospectively. RESULTS Age at initial arrhythmic event was 34 +/- 17 years (range 8 to 68; 67% <40 years). Of the 39 study patients, 32 (82%) survived after their initial cardiac event (for 9.4 +/- 7.6 years; up to 30 years), including 14 patients for >or=10 years (36%) and 4 patients >or=20 years (10%). Of the 32 survivors, 15 (47%) have not experienced subsequent events, and 17 (53%) had >or=1 additional cardiac arrest or appropriate ICD intervention. Annual HCM-related mortality was 1.4%, similar to general HCM populations, and 88% of patients were free of HCM-related death over the follow-up period. Survival from potentially lethal arrhythmias was associated with no or only mild heart failure symptoms in 29 of 32 patients (91%) at most recent evaluation. CONCLUSION In HCM, long-term survival up to 30 years may follow cardiac arrest with or without ICD intervention. Disabling heart failure symptoms were uncommon after these arrhythmic events, at last follow-up. These novel observations regarding the natural history of HCM underscore the unpredictability of the arrhythmogenic substrate, which may remain dormant over extended periods of time.