Cardiovascular Surgery

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1 Cardiovascular Surgery Predictors of Long-Term Outcomes in Symptomatic Hypertrophic Obstructive Cardiomyopathy Patients Undergoing Surgical Relief of Left Ventricular Outflow Tract Obstruction Milind Y. Desai, MD; Aditya Bhonsale, MD; Nicholas G. Smedira, MD; Peyman Naji, MD; Maran Thamilarasan, MD; Bruce W. Lytle, MD; Harry M. Lever, MD Background We report the predictors of long-term outcomes of symptomatic hypertrophic cardiomyopathy patients undergoing surgical relief of left ventricular outflow tract obstruction. Methods and Results We studied 699 consecutive patients who have hypertrophic cardiomyopathy with severe symptomatic left ventricular outflow tract obstruction (47±11 years, 63% male) intractable to maximal medical therapy, who were referred to a tertiary hospital between January 1997 and December 2007 for the surgical relief of left ventricular outflow tract obstruction. We excluded patients <18 years of age, those with an ejection fraction <50%, those with hypertensive heart disease of the elderly, and those with more than mild aortic or mitral stenosis. Clinical, echocardiographic, and Holter data were recorded. A composite end point of death, appropriate internal cardioverter defibrillator discharges, resuscitated from sudden death, documented stroke, and admission for congestive heart failure was recorded. During a mean follow-up of 6.2±3 years, 86 patients (12%) met the composite end point with 30-day, 1-year, and 2-year event rates of 0.7%, 2.8%, and 4.7%, respectively. The hard event rate (death, defibrillator discharge, and resuscitated from sudden death) at 30 days, 1 year, and 2 years was 0%, 1.5%, and 3%, respectively. Stepwise multivariable analysis identified residual postoperative atrial fibrillation (hazard ratio, 2.12; confidence interval, ; P=0.001) and increasing age (hazard ratio, 1.49; confidence interval, ; P=0.001) as independent predictors of long-term composite outcomes. Conclusions Symptomatic adult hypertrophic cardiomyopathy patients undergoing surgery for the relief of left ventricular outflow tract obstruction have low event rates during long-term follow-up; worse outcomes are predicted by increasing age and the presence of residual atrial fibrillation during follow-up. (Circulation. 2013;128: ) Key Words: cardiomyopathy, hypertrophic outcome assessment (health care) Hypertrophic cardiomyopathy (HCM) is a heterogeneous and often unpredictable inherited cardiomyopathy with variable clinical expression and natural history that ranges from asymptomatic status in the vast majority to heart failure related symptoms to sudden death, which occurs in <1%. 1 3 Based on previous reports, up to 70% HCM patients have demonstrable left ventricular outflow tract (LVOT) obstruction, 4 with a significant proportion requiring a surgical myectomy (with or without concomitant mitral valve procedures) to relieve intractable symptoms despite maximal medical therapy, with excellent long-term outcomes It has also been previously suggested that surgical myectomy alters the natural course of HCM patients with severe symptomatic LVOT obstruction, and most patients have a lifespan similar to an age-matched population. 5 However, we frequently encounter patients who require more than an isolated myectomy to optimally relieve LVOT obstruction (ie, concomitant mitral valve repair/replacement). In addition, many patients require concomitant coronary artery bypass grafting (CABG). There are limited data on the long-term outcomes of such HCM patients. 11,12 We sought to assess short- and long-term outcomes in HCM patients who underwent surgery to relieve symptomatic severe LVOT obstruction. In addition, we sought to determine the predictors of long-term outcomes in these patients. Editorial see p 193 Clinical Perspective on p 216 Methods Population The study population is part of an ongoing institutional review board approved registry of HCM patients at a single tertiary care center (Cleveland Clinic, Ohio), with the initial visit between January 1997 Received September 27, 2012; accepted May 20, From the Heart and Vascular Institute, Cleveland Clinic, Cleveland, OH. Correspondence to Milind Y. Desai, MD, Tomsich Department of Cardiovascular Medicine, Heart and Vascular Institute, Cleveland Clinic, 9500 Euclid Ave, Desk J1-5, Cleveland, OH desaim2@ccf.org 2013 American Heart Association, Inc. Circulation is available at DOI: /CIRCULATIONAHA

2 210 Circulation July 16, 2013 and December 2007 (the registry initiation date approximately coincided with the availability of detailed electronic medical records at our institution). In the current study, we only included 699 symptomatic HCM patients who underwent surgical relief of LVOT obstruction at our institution. The diagnosis of HCM was based on typical clinical, electrocardiographic, and echocardiographic features, with ventricular myocardial hypertrophy occurring in the absence of any other cardiac or systemic disease that could cause the hypertrophy. 3 The degree of left ventricular (LV) hypertrophy in the study population was deemed significantly out of proportion to the duration and degree of hypertension; this decided after a thorough clinical evaluation by experienced physicians. We excluded the following patients: (1) patients <18 years and >65 years of age, (2) those with hypertensive heart disease of the elderly and concomitant LVOT obstruction, (3) those with an ejection fraction <50%, and (4) those with the presence of more than mild aortic or mitral stenosis on the initial echocardiogram. Patients with hypertensive heart disease and concomitant LVOT obstruction were defined as those >65 years of age with a long-standing history of hypertension and characteristic sigmoid-shaped basal septal hypertrophy identified on echocardiography. These patients were excluded because they have a different pathophysiological and genetic profile from the typical HCM patients Additionally, we eliminated the potentially confounding effects of end-stage disease (manifesting as depressed LV function) on outcomes by excluding such patients. Clinical Data Demographic, clinical (including standard and HCM-related risk factors, detailed family history, and examination), medication use (including antiarrhythmics and anticoagulation), and electrocardiographic data obtained at the time of the initial and follow-up visits were recorded from electronic records. All patients were intractably symptomatic during the initial visit. New York Heart Association (NYHA) class was ascertained during the initial visit and follow-up. The history and presence of residual atrial fibrillation (AF) were ascertained, based on clinical record review (ECG, 24- to 48-hour Holter monitoring, loop recording, pacemaker/defibrillator interrogations, and telephonic transmissions) obtained during the initial and standard follow-up examinations. AF was defined as paroxysmal when it self-terminated and was considered permanent when it became established, according to established guidelines. 17 To be classified as paroxysmal, only AF documented for 30 seconds at a time was included. AF occurring only in the 30-day postoperative window was not included in the definition of residual postoperative AF. Ventricular tachycardia (VT) was defined as nonsustained if a wide complex tachycardia lasted >3 beats but <30 seconds (at a rate of 120 beats/min). If it lasted >30 seconds, it was deemed sustained VT. The presence of an implantable cardioverter-defibrillator (ICD) and permanent pacemaker (at baseline and during follow-up, as well) was ascertained. Echocardiography All patients underwent comprehensive echocardiograms with the use of commercially available instruments (HDI 5000, Philips Medical Systems, NA, Bothell, WA, and Acuson Sequoia, Siemens Medical Solution USA Inc, Malvern, PA) as part of standard clinical diagnostic and pre open heart surgery workup. Maximal chamber dimensions, including left atrial dimension and end-diastolic LV wall thickness, were measured in a standard fashion according to American Society of Echocardiography guidelines. 18 LV ejection fraction was measured according to previously described criteria. 18 Resting LVOT peak velocity was measured by continuous-wave Doppler echocardiography, and resting LVOT pressure gradient was estimated by using a simplified Bernoulli equation. 19 Care was taken to avoid contamination of the LVOT waveform by the mitral regurgitation jet. In patients with resting LVOT gradients <30 mm Hg, provocative maneuvers, including Valsalva and amyl nitrite, were also used to measure a provocable LVOT gradient. In patients with resting gradients <100 mm Hg, we also performed exercise echocardiography to assess the postexercise LVOT gradient, because it is a more objective assessment of patients functional capacity. 20 In patients with resting peak LVOT gradient >100 mm Hg, provocative maneuvers were not used. The maximal LVOT gradient was recorded and defined as the highest recorded gradient (either resting or provoked, including exercise) in a given patient. 21 The degree of resting mitral regurgitation was assessed, on a scale of 0 to 4+ (0, none; 1+, mild; 2+, moderate; 3+, moderately severe; and 4+, severe) by using multiple different Doppler criteria. 22 Diastolic function was assessed, based on multiple standard 2-dimensional, Doppler, and tissue Doppler criteria, according to guidelines. 23 In addition, all patients had a predischarge echocardiogram in a manner described above to record the LV ejection fraction, basal LV thickness, residual maximal (resting+provocation with Valsalva and amyl nitrite) LVOT obstruction, and postoperative mitral regurgitation. Cardiac Surgery The type of HCM surgery (myectomy±mitral valve repair/ replacement±coronary artery bypass grafting) was decided based on expert consensus, following a thorough evaluation, between experienced cardiologists and cardiothoracic surgeons, taking into account the findings on preoperative imaging evaluation and intraoperative findings. However, the final decision regarding the specific operative technique was made by the attending cardiothoracic surgeon. The surgeries were divided into the following subgroups: (1) isolated myectomy, (2) myectomy plus mitral valve repair/replacement, (3) myectomy plus CABG, and (4) myectomy plus CABG plus mitral valve repair/replacement. The approach was transaortic through a standard median sternotomy. Specific issues taken into consideration included basal septal thickness, mitral valve morphology, and the presence of obstructive coronary artery disease on preoperative coronary angiography. Additionally, at the discretion of the evaluation cardiologist and cardiac surgeon at the time of preoperative evaluation, patients with concomitant AF also underwent concomitant surgical therapies including maze procedure/pulmonary vein isolation and left atrial appendage exclusion/ligation. Detailed techniques have been described previously. 10,12,24 Follow-Up and Outcomes Death notification was obtained from the electronic medical record (including phone conversations with family members) or from the US Social Security Death Index database, and survival was also ascertained during follow-up by a review of medical records. Follow-up was ascertained between the date of surgery and May The end point was a composite of all deaths, appropriate ICD discharges, resuscitated from sudden death, documented stroke, and the onset of congestive heart failure (CHF) requiring inpatient hospitalization. Where feasible, the cause of death was ascertained as sudden death, death as a result of progressive CHF, or other. Sudden death was defined as unexpected sudden collapse occurring <1 hour from the onset of symptoms in patients who had previously experienced a relatively stable or uneventful clinical course. 25 In addition, we recorded potentially lethal cardiovascular events in which patients were either successfully resuscitated from cardiac arrest or received appropriate defibrillation shocks (appropriateness documented in medical records) from implanted cardioverter-defibrillators because they were regarded as equivalents of sudden death. 25 Stroke was defined as transient or permanent neurological impairment and disability resulting from vascular causes, including episodes lasting <24 hours that were regarded as transient ischemic attacks. Cause of stroke was ascertained as either ischemic or embolic. In addition, we also recorded the date of onset of CHF requiring inpatient hospitalization. We also separately analyzed hard outcomes (death, appropriate ICD discharges, and revival from sudden death). Statistical Analyses Continuous variables are expressed as mean±standard deviation or median and compared with the use of the Student t test or analysis of

3 Desai et al Surgery for HOCM and Outcomes 211 variance (for parametric variables) or Mann-Whitney test (for nonparametric variables). Categorical data are expressed as the percentage frequency and compared with χ 2 test. Hazard ratios (HRs) and 95% confidence intervals were calculated from Cox proportional hazards models for composite and hard end points, respectively. A total of 1000 bootstrapped models were generated (to increase the reliable assessment of risk factors by improving the precision of estimate); variables that entered the model at least 75 times were considered significant. Univariate HRs for various predictors of outcomes were generated initially. A stepwise multivariable Cox proportional hazards model was subsequently developed to determine the independent predictors of the primary end point. Only those predictors with a probability values <0.10 on univariate analysis were considered for stepwise multivariable adjustment. Data are reported as HRs with confidence intervals. Additionally, cumulative event rates as a function over time were obtained by the Kaplan-Meier method, and different event curves of outcomes were compared by using the log-rank test. Statistical analysis was performed by using SPSS version 11.5 (SPSS Inc). A probability value of <0.05 was considered significant. Results The baseline characteristics are shown in Table 1. By study design, all patients were symptomatic at presentation and were on maximally tolerated medications for the relief of LVOT obstruction. As shown in the table, this was a relatively young, predominantly male population with a mean age of 47±11 years (63% male). Although a little over one-third of the population had a history of hypertension, it was not clinically deemed severe enough to cause the degree of ventricular hypertrophy seen in the patients. Traditional HCM-related risk factors for sudden death were seen only in a minority of patients. Echocardiographic variables are shown in Table 2. In the current study population, the maximal LV thickness was noted in the basal septum in all patients. Within the study population, 203 (29%) patients had maximal basal septal Table 1. Baseline Clinical Characteristics of the Study Population Total n=699 Age, y 47±11 Male sex, n (%) 441 (63) Hypertension, n (%) 257 (37) Diabetes mellitus, n (%) 81 (12) Obstructive coronary artery disease, n (%) 116 (17) Family history of HCM, n (%) 134 (19) History of sudden death, n (%) 8 (1) History of syncope, n (%) 147 (21) History of stroke, n (%) 31 (4) Atrial fibrillation, n (%) 180 (26) Ventricular tachycardia, n (%) 68 (18) Implantable cardioverter defibrillator, n (%) 72 (10) Pacemaker, n (%) 98 (14) β-blockers, n (%) 465 (67) Calcium channel blocker, n (%) 188 (27) Disopyramide, n (%) 47 (7) HCM indicates hypertrophic cardiomyopathy. Table 2. Baseline Echocardiographic Characteristics of the Study Population Total n= 699 Left ventricular ejection fraction, % 61±5 Maximal left ventricular thickness, cm 2.21±0.5 Posterior wall thickness, cm 1.44±0.3 Diastolic function, n (%) Abnormal relaxation 416 (59) Pseudonormal 278 (40) Restrictive 5 (0.7) Left atrial dimension, cm 4.6±0.8 Resting mitral regurgitation (0 4 +) 1.53±0.8 Resting left ventricular outflow tract gradient, mm Hg 61±41 Maximal left ventricular outflow tract gradient, mm Hg 103±39 thickness <2 cm, whereas all patients had a maximal LVOT gradient 50 mm Hg preoperatively. The distribution of cardiac surgeries was as follows: (1) isolated myectomy in 454 (65%) patients, (2) myectomy plus mitral valve repair/replacement in 159 (23%), (3) myectomy plus CABG in 64 (9%), and (4) myectomy plus CABG plus mitral valve repair/replacement in 22 (3%) patients. Within subgroups 2 and 4, only 25 (16%) and 2 (9%) patients, respectively, had mitral valve replacement; the rest underwent mitral valve repair. The rate of additional mitral valve procedures in patients with basal septal thickness <2 cm versus 2 cm was significantly higher (74/181 or 41% versus 129/518 or 25%, P<0.01). Of the study group, 17 (2.4%) patients were undergoing a redo cardiac surgical procedure. Pulmonary vein isolation, at the time of surgery (n=23) or surgical maze (n=56) was performed in 79 (11%) patients. Left atrial appendage ligation/excision was performed in 101 (14%) patients. The postoperative characteristics of the study population are shown in Table 3. Following cardiac surgery, 667 patients (96%) remained asymptomatic or minimally symptomatic (NYHA class I or II) during long-term follow-up. Also, there was a significant improvement in residual LVOT gradient and the degree of mitral regurgitation. Residual maximal LVOT gradient (including the use of provocation) was <50 mm and 30 mm Hg in a majority of patients (84% and 71%, respectively). Without provocation, resting LVOT gradients postoperatively were <30 mm Hg in 688 (98%) patients. At or following the initial visit, of the entire population, 378 patients (55%) had Holter monitoring performed at our institution. Episodes of nonsustained ventricular tachycardia and sustained VT (on Holter monitoring) were noted in 71 and 3 patients, respectively, during follow-up. During follow-up, there were additional 48 (7%) and 134 (19%) patients with pacemaker and ICD implantation, respectively. Hence, there were a total of 146 (21%) and 206 (29%) patients with pacemaker and ICDs in follow-up. In addition, 24 (3.4%) patients have required redo cardiac surgeries during follow-up to relieve residual symptomatic LVOT obstruction. The breakdown of the procedures was as follows: 5 repeat myectomies, 16 mitral valve replacements, and

4 212 Circulation July 16, 2013 Table 3. Clinical and Echocardiographic Characteristics After Surgery in the Study Population Total n=699 Postoperative NYHA class, n (%) I 565 (81) II 102 (14.5) III 32 (4.5) IV 0 New postoperative ICD, n (%) 134 (19) ICD discharges, n (%) 10 (1) New postoperative pacemaker, n (%) 48 (7) Residual postoperative atrial fibrillation, n (%) 137 (20) Amiodarone, n (%) 137 (20) β-blockers, n (%) 465 (67) Calcium channel blockers, n (%) 188 (27) Anticoagulation, n (%) 120 (17) LV ejection fraction, % 58±6 Residual maximal LV thickness, cm 1.7±0.5 Residual mitral regurgitation (I IV) 1±0.6 Residual maximal LV outflow tract gradient, mm Hg 32±31 Residual maximal LV outflow tract gradient 30 mm Hg, n (%) 203 (29) Residual maximal LV outflow tract gradient 50 mm Hg, n (%) 111 (16) ICD indicates implantable cardioverter defibrillator; LV, left ventricle; and NYHA, New York Heart Association. 3 myectomies+mitral valve replacements. In addition, 1 patient has undergone cardiac transplantation. This translates into a 97% freedom from reoperation during follow-up. Because of the complexity of this disease, all patients were routinely followed up at least once and, in most cases, on multiple occasions at our tertiary care center postoperatively. Outcomes and Survival Analysis The mean follow-up time for the study population was 6.2±3 years. Number of patients, with a follow-up of 1, 2, 3, 4, 5, 6, and >6 years postoperatively, were 662, 653, 595, 494, 392, 382 and 317, respectively. During the follow-up, 86 patients (12%) met the composite end point of death, successful resuscitation from sudden death, appropriate ICD discharges, documented stroke, and CHF-related admission. Of these, 52 patients (7%) met the hard end point of death, appropriate ICD discharge, and revival from sudden death. In the same patients with multiple composite end points, time to the first event was used as a censoring cutoff. The breakdown of individual end points was as follows: 10 patients (1.4%) experienced appropriate ICD discharges, 11 (1.6%) had successful resuscitation from sudden death, 13 (1.9%) had a stroke, 41 (6%) died, and 29 (4%) progressed to CHF, requiring a hospital admission. All strokes were embolic in nature (10 strokes occurred in patients that could not be anticoagulated, whereas the remaining strokes occurred in those with documented subtherapeutic anticoagulation). Within the group of patients who died, the breakdown was as follows: 32 sudden deaths, 3 deaths attributable to progressive CHF, and 6 attributable to uncertain causes. The 30-day, 1-year, and 2-year composite event rates were as follows: 0.7%, 2.8%, and 4.7%, respectively. Similarly, the 30-day, 1-year, and 2-year hard event rates were as follows: 0%, 1.5%, and 3%, respectively. The breakdown of individual events at 30 days was as follows: 0% mortality, 5 (0.7%) patients with a stroke (1 in surgical subgroup 1, 2 in subgroup 2, and 2 in subgroup 4); and 0 admissions for CHF. At 1 year postoperatively, additional events were observed in 15 (2%) patients (3 additional strokes [0.4%], 9 deaths [1.3%], 2 appropriate ICD discharges [0.3%], and 1 CHF-related admission [0.2%]). Similarly, at 2 years postoperatively, there were 13 additional events (2 strokes [0.3%], 9 deaths [1.3%], and 2 revived sudden deaths [0.3%]). For the composite end point, the data on univariable Cox Proportional Survival analysis is shown in Table 4. Subsequently, variables with a probability value of <0.1 on univariable analysis were entered into a stepwise multivariable model, which is shown in Table 5. Stepwise multivariable analysis identified residual postoperative AF in (2.12 [ ], P=0.001), and increasing age (1.04 [ ], P=0.001) as independent predictors of long-term composite outcomes. We also performed Cox Proportional Survival analysis by using only the hard end point of death, appropriate ICD discharge, and revival from sudden death. Similarly, in this analysis, residual postoperative AF (HR 1.59 [ ], P=0.03) and age (HR 1.04 [ ], P=0.002), also emerged as independent predictors of hard outcomes. The outcomes data on various clinically relevant subgroups are shown in Table 6. Composite events in patients older than the median age (50 years) were twice as frequent as in those aged younger than or equal to the median age (17% versus 8%, P<0.001). Composite event rates of patients with an isolated myectomy or a myectomy+mitral valve repair/replacement were much lower (both 11%) in comparison with those undergoing myectomy+cabg (19%) or myectomy+mitral valve repair/replacement+cabg (32%). There was no difference in the proportion of patients who had residual maximal LVOT gradient 50 mm Hg within various NYHA classes (16% in NYHA class I, 15% in NYHA class II, and 22% in NYHA class III, P=0.6). The composite event rate in patients with residual postoperative AF was more than twice the composite event rate of those without residual AF (23% versus 10%, P=0.001). Kaplan-Meier curves demonstrating differences in outcomes between subgroups separated on the basis of age and residual AF are shown in Figures 1 and 2. Discussion The current study is one of the largest contemporary singlecenter studies to describe the long-term outcomes and their predictors in HCM patients undergoing surgical relief of LVOT obstruction. All patients were intractably symptomatic on maximally tolerated medical therapy with severe resting or provocable LVOT obstruction. Following the initial cardiac surgery, the residual maximal LVOT gradient was <50 mm Hg in the vast majority (84%) of the patients, which is lower than previously reported. 5,11 However, unlike in the current study, these previous studies only reported postoperative LVOT gradient in a resting state, without the use of provocation. Indeed, in the current study, resting LVOT gradient was <30 mm Hg in

5 Desai et al Surgery for HOCM and Outcomes 213 Table 4. Univariable Cox Proportional Hazard Analysis for the Composite End Point Univariable Hazard Ratio P Value Age (10-y increment) 1.49 ( ) Sex 0.69 ( ) 0.1 Hypertension 1.23 ( ) 0.3 Diabetes mellitus 1.46 ( ) 0.3 Obstructive CAD 1.70 ( ) 0.03 Family history of HCM 1.30 ( ) 0.4 History of syncope 1.07 ( ) 0.8 History of AF (preoperative) 2.55 ( ) NSVT or VT 1.21 ( ) 0.7 Medical treatment after initial visit 1.22 ( ) 0.4 Pacemaker 2.00 ( ) Maximal LV thickness (1-mm increment) 1.14 ( ) 0.6 Maximal LVOT gradient (10 mm Hg increment) 0.99 ( ) 0.3 LV ejection fraction (5% increment) 0.89 ( ) 0.3 Diastolic dysfunction 0.87 ( ) 0.5 Mitral regurgitation 1.23 ( ) 0.14 Surgery for atrial fibrillation 1.15 ( ) 0.7 Left atrial appendage ligation/excision 1.13 ( ) 0.7 Concomitant cardiac surgeries 1.36 ( ) Redo cardiac surgery 2.23 ( ) 0.4 Anticoagulation 0.76 ( ) 0.4 Amiodarone 0.70 ( ) 0.2 Residual maximal postoperative LVOT 0.99 ( ) 0.8 gradient (10 mm Hg increment) Residual postoperative AF 2.33 ( ) Because appropriate defibrillator discharge was considered an event, the presence of ICD was not included in the survival analysis. AF indicates atrial fibrillation; CAD, coronary artery disease; HCM, hypertrophic cardiomyopathy; ICD, implantable cardioverter defibrillator; LV, left ventricle; LVOT, left ventricular outflow tract; NSVT, nonsustained ventricular tachycardia; and VT, ventricular tachycardia. 98% patients. Importantly, 96% patients remained in NYHA class I or II, with a 97% freedom from reoperation during follow-up. Almost 80% of the reoperations involved mitral valve replacements. Over a long-term follow-up, we demonstrate a low composite and hard event rate of 12% and 7%, respectively, Table 5. Stepwise Multivariable Cox Proportional Hazards Analysis for the Composite End Point Stepwise Multivariable Hazard Ratio P Value Age (10-y increment) 1.49 ( ) Residual postoperative AF 2.12 ( ) Obstructive CAD, permanent pacemaker, and concomitant cardiac surgeries did not remain significant in stepwise multivariable analysis. Because of the significant interaction between preoperative and postoperative residual AF, only residual AF was entered in the stepwise multivariable model. χ 2 for the final model 25, P< AF indicates atrial fibrillation; and CAD, coronary artery disease. translating into event-free rates of 88% and 93%, respectively. We further demonstrate a very low short-term (30- day and 1-year) composite event rate of 0.7% and 2.8%, respectively. In fact, the short-term (30-day and 1-year) hard event rate was even lower at 0% and 1.5%, respectively. The frequency of permanent pacemaker implantation during follow-up in the study population was also low (7%). Although the presence of obstructive coronary artery disease and the type of cardiac surgery performed (myectomy along with concomitant CABG or mitral valve surgery) predicted composite outcomes on univariable analysis, only age at surgery and residual postoperative AF independently predicted long-term composite outcomes. In fact, composite events occurred twice as frequently in patients >50 years of age versus those 50 years of age, and in those patients with residual postoperative AF versus those without, as well. As shown in Table 5, there was no significant difference in composite or hard event rates in the study population, when divided into subgroups on basis of standard and HCM-related risk factors. Over the years, multiple prior studies have reported excellent outcomes following surgical myectomy for the relief of LVOT obstruction in HCM patients with the abolition of LVOT gradient and symptom relief in the vast majority of patients In fact, it has been suggested that surgical myectomy alters the natural course of HCM and most patients have a lifespan similar to an age-matched population. 5 However, there are only a few reports of outcomes in patients that also underwent concomitant mitral valve surgery or CABG, 11,12 because most of these studies reported outcomes of only those patients that underwent isolated surgical myectomy. Also, of the published studies, only a few reported predictors of long-term outcomes in these patients. 5,11 The strengths of the current study are a large population, with the inclusion of patients who had concomitant surgeries performed (along with myectomy), and the report of predictors of long-term outcomes. The long-term outcomes in the current study were excellent and comparable to similar reports. 11,12 Similar to a prior observation, 11 increasing age and AF predicted longterm outcomes in the current study. However, unlike in that study, female sex was not predictive of outcomes. This is likely attributable to the possibility that, in the current study, we excluded older patients (based on clinical and echocardiographic evaluation) with a diagnosis of hypertensive heart disease of the elderly. It is well known that these typically tend to be older women Multiple other studies have also addressed the issue of AF in HCM patients, but none specifically in a large population undergoing surgery for the relief of LVOT obstruction. 5,26 31 In 1 study of 1337 HCM patients, of which only 22% underwent myectomy, the incidence of AF was 20%, which is identical to our population. 5 However, in that study, AF did not predict outcomes on multivariable analysis, likely because of a much smaller sample size and a slightly different surgical population, because, in that study, patients who underwent concomitant procedures in addition to myectomy were excluded. Another study of 480 HCM patients that combined 2 different cohorts to study the impact of AF in HCM patients observed frequencies of AF similar to our group and demonstrated that

6 214 Circulation July 16, 2013 Table 6. Frequency of Events and in Various Clinically Relevant Subgroups During Follow-Up Frequency of Composite Events (n=86) Frequency of Hard Events (n=52) Age 50 y (median) 29/355 (8) 17/355 (5) > 50 y 57/344 (17) 35/344 (10) Sex Male 48/441 (11) 30/441 (9) Female 38/258 (15) 22/258 (7) Hypertension Yes 34/257 (13) 17/257 (8) No 52/442 (12) 35/442 (8) Diabetes mellitus Yes 75/618 (12) 42/618 (7) No 11/81 (14) 10/81 (12) Obstructive CAD Yes 21/116 (18) 16/116 (14) No 65/583 (11) 36/583 (6) Family history of HCM Yes 14/134 (10) 10/134 (7) No 72/565 (13) 43/565 (8) History of syncope Yes 19/147 (13) 11/147 (8) No 67/552 (12) 41/552 (7) Pacemaker Yes 29/146 (20) 14/146 (10) No 57/553 (10) 38/553 (7) History of prior cardiac surgery Yes 1/17 (6) 1/17 (6) No 85/682 (12) 51/682 (8) Type of cardiac surgery Myectomy 49/454 (11) 28/454 (6) Myectomy + MV repair/replacement 18/159 (11) 8/159 (5) Myectomy + CABG 12/64 (19) 10/64 (16) Myectomy + MV repair/replacement 7/22 (32) 6/22 (27) + CABG Residual postoperative maximal LVOT gradient 50 mm Hg Yes 15/203 (7) 6/111 (5) No 37/496 (8) 46/588 (8) Residual postoperative AF Yes 31/137 (23) 19/137 (14) No 55/562 (10) 33/562 (6) The values displayed in parentheses are percentages. AF indicates atrial fibrillation; CABG, coronary artery bypass grafting; CAD, coronary artery disease; HCM, hypertrophic cardiomyopathy; LVOT, left ventricular outflow tract; and MV, mitral valve. the presence of AF was associated with worse outcomes. 26 However, of the 107 patients with AF, only 14% underwent surgery for the relief of LVOT obstruction. Similarly, in another study of 277 HCM patients, those with AF showed Figure 1. Kaplan Meier curve demonstrating the composite outcomes of patients separated on the basis of median age. worse survival on unadjusted Kaplan-Meier method, 29 but only 28 patients underwent surgical relief of LVOT obstruction. The mechanistic link between AF and outcomes, particularly in the setting of HCM, is not entirely understood. Although it would be expected that residual AF would be associated with CHF and stroke-related composite outcomes, our study also demonstrates its association with hard events. Indeed, in some previous reports, residual AF has been shown to trigger VT There might be a direct link whereby a rapid ventricular rate during an AF episode could directly reduce ventricular refractoriness. In addition, the irregular rhythm of AF leads to short-long-short sequences that could be intrinsically proarrhythmic. 35 AF also results in the reduction of cardiac output through the loss of atrial mechanical function and decreased diastolic filling time, which might increase preload and, via mechanoelectric coupling, increase susceptibility to VT. 36 The hemodynamic effects of atrial tachyarrhythmias may also cause a reflex increase in sympathetic tone and a Figure 2. Kaplan Meier curve demonstrating the composite outcomes of patients with and without residual postoperative atrial fibrillation (AF).

7 Desai et al Surgery for HOCM and Outcomes 215 decrease in parasympathetic tone, which favors the development of VT. 37 From a viewpoint of clinical implications, in HCM patients undergoing surgery for symptom relief, every effort should be made to relieve LVOT obstruction, with the understanding that, in some patients, it might be necessary to perform concomitant mitral valve surgeries to achieve optimal results. In the current study, the frequency of concomitant mitral valve procedures was significantly higher than in previous reports. This is probably because a sizable proportion of our study population had a maximal basal septal thickness of <2 cm, where we feel that an additional mitral valve procedure would be the optimal approach to relieve LVOT obstruction. Also, if patients remain symptomatic despite optimal relief of LVOT obstruction, alternative treatments like cardiac transplantation should potentially be considered early. It also appears that the identification of AF and attempts to abolish it are important. However, 1 dilemma is that the data for the invasive cure of AF are limited. 24 In such patients, an additional step to consider is the exclusion/excision of the left atrial appendage at the time of surgery to reduce the incidence of future strokes. Although commonly practiced, this strategy requires further validation. Our data support the need for closer surveillance of HCM patients for the presence of residual AF in recognition of their increased risk of worse outcomes. If there is evidence of AF, these patients should be adequately anticoagulated. Our study could have the following potential limitations. This was an observational experience from a single tertiary care center, which could have potential referral bias, such that only the highest-risk patients are evaluated at our center. In the current study, we excluded elderly patients with hypertensive heart disease and concomitant LVOT obstruction (defined as patients >65 years of age with a long-standing history of hypertension and characteristic sigmoid-shaped basal septal hypertrophy, identified on echocardiography), because these patients have a different pathophysiological and genetic profile from the typical HCM patients On the other hand, we included patients <65 years of age with hypertension, because the degree and duration of hypertension was not deemed significant to result in the amount of LV hypertrophy seen in these patients. Additionally, we excluded patients with reduced LV systolic function to eliminate the potential independent confounding effects of end-stage disease on outcomes. Because paroxysmal AF can be very brief, and can occasionally happen without symptoms, we might potentially be underestimating its frequency and duration. The technology for monitoring arrhythmias has evolved over the years with the ability to perform continuous monitoring enabling us to recognize and treat more instances of AF. Ascertaining the actual cause of death, especially sudden death in HCM patients, can be very difficult, and we acknowledge that as a limitation of the current study. In conclusion, we demonstrate that symptomatic adult HCM patients undergoing surgery for the relief of LVOT obstruction have a high rate of successful relief of symptoms and outflow tract obstruction, with a very low rate of reoperation and very low event rates during long-term follow-up. Increasing age and the presence of AF during follow-up were independent predictors of long-term outcomes. None. Disclosures References 1. Maron BJ. Hypertrophic cardiomyopathy: a systematic review. JAMA. 2002;287: Elliott P, McKenna WJ. Hypertrophic cardiomyopathy. 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Facilitation of ventricular tachycardia induction with abrupt changes in ventricular cycle length. Am J Cardiol. 1984;53: Lerman BB. Mechanoelectrical feedback: maturation of a concept. J Cardiovasc Electrophysiol. 1996;7: Lown B, Verrier RL. Neural activity and ventricular fibrillation. N Engl J Med. 1976;294: Clinical Perspective We report long-term outcomes in 699 symptomatic hypertrophic cardiomyopathy patients (47±11 years, 63% male) undergoing surgical relief of left ventricular outflow tract obstruction (myectomy±mitral valve surgery), along with their potential predictors. During a mean follow-up of 6.2±3 years, 86 patients (12%) met the composite end point (death, appropriate internal cardioverter defibrillator discharges, resuscitated sudden death, documented stroke, and admission for congestive heart failure) with 30-day, 1-year, and 2-year event rates of 0.7%, 2.8%, and 4.7%, respectively. There was 0% mortality at 30 days postoperatively. Residual postoperative atrial fibrillation or AF (hazard ratio 2.12 [ ], P=0.001), and increasing age (hazard ratio 1.49 [ ], P=0.001) as independent predictors of long-term composite outcomes. In a contemporary population of symptomatic adult hypertrophic cardiomyopathy patients undergoing surgery for relief of left ventricular outflow tract obstruction, there are excellent surgical results and a very low event rate during long-term follow-up. Worse outcomes were predicted by increasing age and presence of residual AF during follow up.