Structural Heart Live Cases Supported by: Medtronic Inc Bard Inc Acist Medical System Terumo Medical Corp

Disclosures Samin K. Sharma, MD, FACC None for today’s case Speaker’s Bureau – Boston Scientific Corporation, Abbott Vascular Inc, AngioScore, ABIOMED, CSI Annapoorna S. Kini, MD, FACC Nothing to disclose Partho Sengupta, MD, FACC Jagat Narula, MD, MACC Research funding and consulting for Medtronics

October 13th 2015 Structural Heart Live Case #7: KM 79 yr. M Presentation: Pt with known HOCM presented on Sept 9th 2015 with progressive exertional dyspnea and fatigue – NYHA class III. Pt had mild inferior wall ischemia on stress MPI. Pt was placed on multiple medications for HOCM but could not tolerate due to near syncopal episodes and presently taking low dose Calcium channel blocker. Also has loop recorder implanted PMH: Hypertension, Hyperlipidemia, chronic diastolic HF Medications: Aspirin, Verapamil, Irbesartan, Atorvastatin, HCTZ TTE: Normal LV size and localized septal hypertrophy (21mm) with SAM of anterior mitral leaflet, high LVOT gradient (rest 22, valsalva 42 and peak stress 141 mmHg), hyperdynamic LV and mild-mod MR

Cardiac MRI

October 13th 2015 Structural Heart Live Case Contd…. CMR: Moderate asymmetric septal hypertrophy with LV apical cavity obliteration, patchy areas of intra-myocardial enhancement (myocardial necrosis) and moderate to severe MR Cardiac Cath: Non-obstructive CAD except 60% calcified mid LAD lesion, hyperdynamic LV and mild MR. FFR mLAD 0.86 Course: Patient was started on increasing doses of verapamil and HCTZ was discontinued. Remained symptomatic and could not tolerate verapamil Plan Today: Patient is planned for echo guided alcohol septal ablation (ASA) for refractory symptomatic HOCM. SLIDE TO BE EDITED BY JK

Issues Related To The Case Alcohol septal ablation vs. Surgical my(om)ectomy in treatment of HOCM

Background Hypertrophic (obstructive) cardiomyopathy (HOCM/HCM) is characterized by: - hypertrophy of IVS (>12 mm) - narrowed LV outflow tract - systolic anterior motion of MV resulting in dynamic LV outflow obstruction (one third) Is the most common genetic CV disease transmitted as autosomal dominant trait Occurs in 1 in 500 (0.2%) of general population In the USA there are currently 300,000 people with HOCM Most patients are identified in their 30’s and 40’s <1% of patients are referred for echocardiography Probably #1 cause of sudden cardiac death in young athlete More common in men; women likely to be severely disabled

Background HOCM/HCM Asymmetric septal hypertrophic (ASH) without obstruction ( 70%) Asymmetric septal hypertrophic (ASH) with obstruction ( 30%)

Myocardial Changes in HOCM Morphologic Features for Sudden Death Disproportionate thickening of the ventricular septum (VS) with respect to left ventricular (LV) free wall; gross heart specimen from a 13-yr old. Marked disarray of cardiac muscle cells in the disproportionately thickened VS forming typical disorganized architecture of HOCM LV myocardium showing several abnormal intramural coronary arteries with markedly thickened walls and narrowed lumen, dispersed Maron et al. JAMA 2002;287:1308

Clinical Manifestations HOCM Majority of patients are asymptomatic or only mildly symptomatic; Shortness of breath occurs in 90% of symptomatic patients due to increased LVEDP Fatigue, presyncope, syncope Chest pain on exertion in 75% of patients, due to demand-supply imbalance, epicardial coronaries are usually normal Rarely sudden death.

Implications of LV Outflow Tract Obstruction 1,101 consecutive patients with HCM (outflow gradient ≥30 mmHg Maron et al., N Engl J Med 2003;348:298

Effect of LV Outflow Tract Obstruction on Clinical Outcome in HOCM 100 80 60 40 20 No obstruction, <40 yr age No obstruction, 40 yr age Freedom from CHF III-IV & death (%) Obstruction, <40 yr age Obstruction, 40 yr age 0 2 4 6 8 10 Years after gradient measurement No. at Risk No obstruction, <40 yr of age 349 251 206 146 103 80 No obstruction, 40 yr of age 421 306 258 188 128 108 Obstruction, <40 yr of age 106 70 52 37 21 15 Obstruction, 40 yr of age 118 74 51 29 18 10 Maron et al., NEJM 2003;348:295

Evaluation of LVOT Obstruction Brockenbrough-Braunwald phenomenon – reliable sign of dynamic obstruction Mechanism: increased ventricular filling overwhelming by increase in contractility; arterial pulse pressure fails to increase as expected (or decreases) Dynamic obstruction during the strain phase of a Valsalva maneuver

LVOT Obstruction and Symptoms Mitral Regurgitation Atrial Fibrillation Pulmonary Hypertension Low Cardiac Output Intermittent Hypotension (Syncope) Sudden Cardiac Death ASH SAM HOCM Genetic disorder HCM

HOCM Management Goals of Treatment Improve symptoms Heart failure, Angina, Syncope Reduce incidence of SCD Protect the remainder of the family

Primary Treatment Strategies for Subgroups within the HCM Clinical Spectrum Overall Population with Hypertrophic Cardiomyopathy Clinical Spectrum Genotype-Positive Phenotype-Negative Longitudinal FU None or Mild Symptoms No treatment or drugs for HOCM Progressive Heart Failure Symptoms Drug therapy High Risk of Sudden Death Implantable Cardioverter- Defibrillator Atrial Fibrillation Pharmacological rate Control Cardioversion Anticoagulation Drug-refractory Heart Failure Symptoms Maron B. JAMA 2002;287:1308

Primary Treatment Strategies for Subgroups within the HCM Clinical Spectrum Progressive Heart Failure Symptoms Drug therapy Drug-refractory Heart Failure Symptoms Alternatives to Surgery - Alcohol Septal Ablation (ASA) - Chronic Dual- Chamber Pacing Obstructive HOCM (Rest or Provocation) Ventricular Septal Myomectomy-Myotomy Nonobstructive HCM (Rest or Provocation) Heart Transplantation (for end-stage systolic dysfunction)

When to Consider Surgery for HOCM Factors Favoring Myectomy Young age (including pediatric patients and adolescents) Massive myocardial thickening >3.0 cm Intrinsic significant valvular disease or membrane Significant coronary stenoses, unsuitable for PCI Baseline LBBB Midcavity obstruction Large institutional experience with excellent surgical outcomes

Mechanism of Action of ASA in HOCM - HOCM Genetic disorder HCM + Obstruction ASH SAM Feedback Symptoms LVH

Alcohol Septal Ablation in HOCM Results at Follow-up 3.01.3 Years Stress-induced LVOT (mm Hg) Resting LVOT (mm Hg) Peak Oxygen Consumption (ml/kg/min) LVEF % Shamim et al. N Engl J Med 2002;347:1326

Alcohol Septal Ablation in HOCM Reduction in Septal Thickness (N=63) 2.5 2 1.5 1 0.5 2.1 1.6 1.3 1.2 1.2 1.1 1 Baseline 3 mo 1 year 2 years 3 years 4 years 5 years Spencer, Clin Cardiol 2005;28:124

When to Consider ASA for HOCM Factors Favoring ASA Advanced age Significant comorbidities that would elevate surgical risk (i.e., severe lung disease) Previously implanted pacemaker or ICD Previous open-heart surgery (including prior failed myectomy) Prior stroke Ideal anatomy for alcohol septal ablation: small, focal septal bulge and appropriate sized and placed septal perforator to the target myocardium Baseline RBBB Large institutional experience with excellent ASA outcomes

Alcohol Septal Ablation in HOCM Method One or more septal perforators 1-5cc absolute (desiccated) alcohol Temporary pacemaker via RIJ Co-axial guide catheter to avoid trauma to LMCA Small short balloons (Maverick 1.5-2.5/9mm) Runthrough or BMW or any hydrophilic floppy wires Contrast echocardiography Liberal use of Versed and Morphine 1cc/min slow continuous alcohol infusion, guided by echo Measure gradient – catheter and echo In CCU for 2 days with TPM and then d/c once CKMB <60U

ASA: Safety and Complications In-hospital Mortality 0.7% in North American Registry (n=874) 0.7% in European Multi-center Registry (n=421) 0.3% in Scandinavian Registry (n=313) Data are similar to Surgical Myectomy mortality as shown in Mayo Clinic, Cleveland Clinic and Toronto General Hospital (i.e. <1%)

Complete Heart Block after ASA Multivariate Predictors of PPM Placement after ASA 261 consecutive pts 37 had PPM/AICD before ASA 14% (31/224) developed CHB and required PPM post-ASA 30 pts developed CHB in-hospital, 1 pt came back with CHB in 1 week Clinical and Echocardiographic Outcome of Pts Who Require vs Who did Not Require PPM Chang et al., J Am Coll Cardiol 2003;42:296

Alcohol Septal Ablation Vs. Myectomy in HOCM Average Pressure Gradients at Follow-up Alcohol Septal Ablation (n = 25) Myectomy (n = 26) P=NS Resting PG (mmHg) P<0.001 P<0.01 Before Immediately after Follow-up at 3 month Qin et al., JACC 2001;38:1994

Alcohol Septal Ablation Vs. Surgery in HOCM One-Year Results Alcohol septal ablation (n=41) Surgery P LVOT gradient (mmHg) 8  15 4  7 <0.01 NYHA class (%): I 88 78 NS II 12 20 III - 2 CCS angina class I (%) 100 93 Presyncope (%) 5 17 Permanent pacemaker (%) 44 41 Due to heart block (%) 9 1 <0.05 Cardiac medications (%) Beta-blockers 59 Ca antagonists Disopyramide 7 Amiodarone none Sotalol 4 CV death, other events were not different Nagueh et al., JACC 2001;38:1701

Alcohol Septal Ablation vs Myectomy

Sudden Death After Invasive Therapy

Alcohol Septal Ablation vs Myectomy

Survival After Alcohol Septal Ablation Sorajja et al., Circulation 2012;126:2374

Alcohol Septal Ablation vs Myectomy or MT for HCM

Mortality and SCD in 1,047 Patients with HCM Med Treatment (n=124) ASA (n=321) Myectomy (n=253) Control (Non-onbstructive HCM (n=349) %

Alcohol Septal Ablation Recommendations Class I Recommendations: Septal reduction therapy should only be performed by experienced operators* in the context of a comprehensive HCM clinical program and only for the treatment of eligible patients with severe drug-refractory symptoms and LVOT obstruction. *Experienced = 20 procedures, then, 5-10 per year afterwards

Alcohol Septal Ablation Recommendations Class IIa Recommendations (select): Consultation with centers experienced with performing both surgical septal myectomy and alcohol septal ablation is reasonable Surgical septal myectomy, when performed in experienced centers, can be beneficial and is the first consideration for the majority…

Alcohol Septal Ablation Recommendations Class IIa Recommendation (select): When surgery is contraindicated or the risk is considered unacceptable because of serious comorbidities or advanced age, alcohol septal ablation, when performed in experienced centers, can be beneficial…

Alcohol Septal Ablation Recommendations Class IIb Recommendations: Alcohol septal ablation, when performed in experienced centers, may be considered … when, after a balanced and thorough discussion, the patient expresses a preference for septal ablation. The effectiveness of alcohol septal ablation is uncertain in patients with HCM with marked (i.e. >30 mm) septal hypertrophy, and therefore the procedure is generally discouraged in such patients.

Alcohol Septal Ablation Recommendations Class III Recommendations (select): Alcohol septal ablation should not be done in patients with HCM with concomitant disease that independently warrants surgical correction. Alcohol septal ablation should not be done in patients with HCM who are less than 21 years of age and is discourage in adults less than 40.

Alcohol Septal Ablation Vs. Myectomy in HOCM Procedural Data and Choice Alcohol Septal Ablation (ASA) Surgical Myectomy (SM) Length of stay (days) 4  2 8  3 PPM Higher (20%) Lower (<5%) Procedure mortality <1% Available F/U (yrs) >5 >30 Septal thickness (mm) 15-25 >25 mm Treatment of choice Elderly with co-morbidities and no significant MR Young with no comorbidities and other valve disease/CAD

Alcohol Septal Ablation in HOCM Mount Sinai Hospital Experience (9/2001-12/2014) N = 168 Mean age (years) 53  12 Female gender (%) 70 Baseline resting gradient mean (mm Hg) 46  18 Baseline post-PVC gradient (mm Hg) 110  32 Post ASA resting gradient (mm Hg) 12  6 Post ASA post-PVC gradient (mm Hg) 32  20 Alcohol dose (cc) 2.5 (1-5) Peak CPK/ peak MB (U/L) 1800  550 /212 32 Need for permanent pacemaker 12 In-hospital death 1 pt (ref VT) Average LOS (days) 3  2

Evolving Modalities of Treatment for HOCM Nonalcoholic Percutaneous Transluminal Septal Ablation Using JOMED Stent Graft Pre Post LAD stenting Vanderheyden et al. AJC 2002;89:361

Take Home Message: Alcohol Septal Ablation vs. Myectomy for HOCM Septal reduction therapy of surgical myectomy &/or ASA are viable options in symptomatic HOCM pts and should be tried only in drug refractory or drug intolerant pts Alcohol septal ablation is a reasonable treatment option in older HOCM pts (>40yrs) especially with comorbidities which makes them high surgical risk. Need for PPM is >10-20% and may play important role in decision making for alcohol septal ablation

Question # 1 Following statements are true regarding surgical myectomy vs. alcohol septal ablation (ASA) for HOCM except: Improved survival with myectomy vs ASA on long-term Improved survival after ASA vs myectomy on long-term Higher residual gradient after ASA vs myectomy Similar need for PPM with ASA and myectomy

Question # 2 Based on the available data, ASA for HOCM will be preferred in the following subset of HOCM pt: 70 year old male with 50mm LVOT gradient and 60% LAD lesion 40 year old male with 50mm LVOT gradient and 80% LM lesion 70 year old male with 50mm LVOT gradient and 4+MR 40 year old male with 50mm LVOT gradient and LBBB

Question # 3 Following technique of alcohol injection during ASA for HOCM is associated with higher incidence of need for PPM: A. Slow injection of 2cc of alcohol B. Rapid bolus of 2cc of alcohol C. Intermittent infusion of 4cc of alcohol D. Alcohol infusion technique has not shown to correlate with PPM need

Correct answer: C Answer to Question # 1 Following statements are false regarding surgical myectomy vs. alcohol septal ablation (ASA) for HOCM except: Improved survival with myectomy vs ASA on long-term Improved survival after ASA vs myectomy on long-term Higher residual gradient after ASA vs myectomy Similar need for PPM with ASA and myectomy Correct answer: C

Correct answer: A Answer to Question # 2 Based on the available data, ASA for HOCM will be preferred in the following subset of HOCM pt: 70 year old male with 50mm LVOT gradient and 60% LAD lesion 40 year old male with 50mm LVOT gradient and 80% LM lesion 70 year old male with 50mm LVOT gradient and 4+MR 40 year old male with 50mm LVOT gradient and LBBB Correct answer: A

Correct answer: B Answer to Question # 3 Following technique of alcohol injection during ASA for HOCM is associated with higher incidence of need for PPM: A. Slow injection of 2cc of alcohol B. Rapid bolus of 2cc of alcohol C. Intermittent infusion of 4cc of alcohol D. Alcohol infusion technique has not shown to correlate with PPM need Correct answer: B