Gersh, Bernard J.

Background: Mutations in sarcomeric/myofilament proteins are commonly implicated in hypertrophic cardiomyopathy (HCM). However, the mechanisms underlying disease pathogenesis are not completely understood. Utilizing flash-frozen surgically resected left ventricular (LV) tissue from patients with obstructive HCM, we investigated the effect of sarcomeric HCM on tissue expression of various myofilament proteins. Methods: Frozen surgical specimens from 47 patients with HCM who underwent septal myectomy at the Mayo Clinic between 1999 and 2003 were examined. Using PCR, DHPLC, and direct DNA sequencing, all were genotyped for mutations involving the 8 myofilament-encoding genes that currently comprise the clinically available genetic test for sarcomeric HCM. Whole protein lysate was extracted from the frozen myectomy tissues and levels of myosin binding protein C, myosin heavy chain, alpha actin and alpha actinin were analyzed by Western Blot; GAPDH was used as a loading control. Frozen LV tissue derived from normal hearts of accidental death victims served as a reference group. Results: Overall, 25/47 (53%) patients had sarcomeric HCM including 13 patients with myosin binding protein C (MYBPC3) mutations and 10 with mutations in the beta myosin heavy chain (MYH7). Compared to normal heart tissue, the expression of myosin heavy chain was up-regulated significantly regardless of the underlying disease-causing genotype (genotype positive = genotype negative). However, there was gene-specific upregulation of myosin binding protein C with marked increases detected in patients with MYH7-HCM. In contrast, normal levels of myosin binding protein C were seen in patients with either MYBPC3-HCM or genotype-negative HCM. Conclusions: This is the first study to examine the expression pattern of sarcomeric proteins in a large collection of flash frozen human HCM myectomy tissue. Up-regulated, genotype-specific cardiac tissue expression of myosin binding protein C among patients with MYH7 (beta myosin heavy chain)-HCM suggests a novel compensatory pathway underlying the development of cardiac hypertrophy for one of most common genetic subtypes of HCM.

Thienopyridine administration has a class Ia recommendation in patients with non-ST elevation acute coronary syndromes (ACS). Despite this many physicians withhold this treatment until after angiography because of concerns over the minority of patients who may require coronary artery bypass surgery (CABG). We sought to evaluate the one year composite ischemic outcomes (death, myocardial infarction, revascularization) in ACS patients requiring CABG based on thienopyridine exposure and timing of CABG. Methods: In the ACUITY trial, thienopyridine administration and timing was left to investigators’ discretion. In the subset of patients requiring CABG, the one year composite ischemic outcome was compared in those not exposed to thienopyridines (group A), those who received thienopyridine and went to CABG ≤120 hours from the last dose (group B) and those who received thienopyridine and went to CABG >120 hours after the last dose (group C). Major bleeding was defined based on ACUITY definitions. Results: CABG was performed in 1539 (11.1%) patients. There were no significant differences in baseline characteristics among the three groups. Mean time from angiography to CABG, major bleeding, and 1-year composite ischemia are presented in the table below. Conclusions: Based on our analysis of ACS patients undergoing CABG in the ACUITY trial, those who received thienopyridine preoperatively and went to CABG >120 hours from the last dose had improved one year composite ischemic outcomes compared to those not exposed or those who received thienopyridine and went to CABG ≤120 hours after the last dose.

Background Recently, genetic testing for sarcomeric hypertrophic cardiomyopathy (HCM) became a commercially available diagnostic test involving analysis of 8 HCM-associated myofilament genes, four of which encode thin filament proteins - TNNT2- encoded cardiac troponin T, TPM1 -encoded alpha tropomyosin, TNNI3- encoded cardiac troponin I, and ACTC- encoded cardiac actin. Compared to the two most common subtypes of sarcomeric HCM, much less is known about the prevalence and spectrum of thin filament HCM. Methods Comprehensive open reading frame/splice site mutational analysis of these 4 thin filament-encoding genes was performed, using polymerase chain reaction, denaturing high performance liquid chromatography, and direct DNA sequencing, on the largest assembled cohort of unrelated patients (N = 1025, 61% male, 49 ± 18 years at diagnosis, maximal left ventricular wall thickness, LVWT, 22.3 ± 7 mm) with clinically diagnosed HCM that were seen at the Mayo Clinic. Results Nineteen distinct missense mutations, involving conserved residues and absent in 600 reference alleles, were identified in 36 of 1025 patients (3.5%) including TNNT2 (16 patients), TNNI3 (12), TPM1 (7) and ACTC (1). Among these 36 patients with thin filament-HCM, their average age at diagnosis was 33.2 ± 16 years and the average LVWT was 21 ± 8 mm. Eighteen patients (50%) had evidence for familial HCM and 13% had a positive history for sudden cardiac death. Only 13 patients (36%) had a reverse septal curvature by echocardiography. Instead, 12 patients (34%) had either sigmoidal or neutral septal contours and 9 patients (25%) had apical variant-HCM. Conclusion Here, we present the largest cohort analysis of thin filament HCM to date and detail the prevalence and spectrum of HCM-associated mutations in these 4 genes. Compared to the strong association between reverse septal curvature and thick filament HCM, the septal morphology associated with thin filament HCM was quite varied. Contrary to published estimates of the frequency of troponin T-HCM (5 – 10%) and the other subtypes of thin filament HCM, the prevalence of thin filament HCM was very low in this cohort. If confirmed in other cohorts, a revised cascade for HCM genetic testing should be considered.

Background: In the ACUITY Trial, patients (pts) with chronic renal insufficiency (CRI) had significantly higher rates of ischemic events and major bleeding compared to pts without CRI at 30 days. Bivalirudin (Biv) monotherapy provided similar protection from ischemic events but with significantly less bleeding compared to heparin + a GPIIb/IIIa inhibitor (Hep+GPI). The impact of a Biv alone strategy on one year mortality is unknown. Methods: Pts with moderate and high risk acute coronary syndromes (ACS) were randomized to Hep + GPI, Biv + GPI, or Biv monotherapy. CRI was defined as baseline creatinine clearance (CrCl) <60 mL/min. We evaluated the impact of CRI and antithrombotic strategy on composite ischemia (death, MI, or revascularization) and mortality at one year. Results: Of the pts enrolled, 12,933 had baseline CrCl data: 2468 (19.1%) pts had CrCl ≥60 mL/min and 10,465 (80.9%) pts had CrCl <60 mL/min. Rates of major bleeding at 30 days in pts with CRI were significantly lower with Biv alone vs Hep+GPI (6.2% vs 9.8%, p<0.01). Pts with CRI had higher mortality at one year compared to those without CRI (8.7% vs 3.0%, p<0.001). There was no difference in composite ischemia for pts who received Biv monotherapy vs Hep + GPI (23.0% vs 21.4%, p=0.10). One year mortality by antithrombin strategy is shown in the Figure . Conclusions: CRI in pts with ACS is associated with higher rates of one year mortality. In these high risk pts, Biv monotherapy improved early clinical outcomes compared to Hep + GPI by reducing major bleeding, and resulted in similar rates of one year mortality. Cumulative Mortality at One Year, Patients with CRI

Background : Lipid lowering therapy reduces mortality in patients with both ischemic and nonischemic cardiomyopathies and recently has been shown to decrease ICD shocks. Radiofrequency ablation (RFA) of recurrent VT in patients with an ICD also reduces shocks following intervention. It is unclear if statin therapy after VT RFA will further impact ICD shock rates. Methods : All patients from 1993–2005 who underwent a RFA procedure for recurrent VT at the Mayo Clinic with an ICD were included. Patient records were extracted for medical and procedural details and all ICD interrogations were reviewed for VT recurrence and therapies. Results: 63 patients (age 62±15 years) were followed over 3.9±3.6 years. Comorbid diseases included: coronary artery disease 37(58%, 34 prior myocardial infarction), ARVD/C 6(10%), nonischemic dilated cardiomyopathy 7(11%), moderate-severe valve disease 14(22%), hypertension 34(54%), and hyperlipidemia 35(56%). Ejection fraction was <0.35 in 34(56%). VT was induced in all patients (LV 55 (LVOT 1), RV 8 (RVOT 3) with multiple inducible VTs in 21(33%). VT was noninducible after RFA in 39(62%) patients. Dismissal medications included: statins 19(30%), beta blockers 40(66%), ACE/ARB 37(61%), diuretics 34(55%), and digoxin 23(37%). 5-year overall survival was 63%(95% CI 55–71). Age, diabetes, and renal insufficiency were associated with increased post ablation mortality, with no medication improving survival. 5-year survival free of ICD shocks was 31%(95% CI 24–38). Only statin therapy at discharge was associated with a decreased risk of ICD shocks [5(26%) versus 26(59%), p=0.020]. 7 additional patients received statins during follow-up, but not at discharge, of these 5(71%) had shocks. Conclusion : Statin use at discharge in patients with an ICD undergoing RFA for refractory VT significantly reduced recurrent ventricular arrhythmias and ICD shocks. Although the mechanism underlying the effects of statins on arrhythmic recurrence early after RFA requires further study, these data support aggressive therapy of the underlying substrate responsible for the VT.

Background: Myocardial late gadolinium enhancement (LGE) on Contrast-Enhanced Magnetic Resonance Imaging (CE-MRI) of patients (pts) with hypertrophic cardiomyopathy (HCM) may indicate intra-myocardial fibrosis. We explored whether the presence and extent of LGE on CE-MRI among pts with HCM predicted ventricular arrhythmogenicity, and decreased survival. Methods: 424 HCM pts [age = 55 ± 16 years (range 2 – 90), 41% females], without prior history of septal ablation/myectomy, underwent CE-MRI (GE 1.5T) during a 6-year period. We compared the presence and amount of LGE with degree of ventricular ectopy on Holter ECG (available in 220 pts) recorded during the same time period of the CE-MRI. All cause death and appropriate, VF-terminating ICD therapies were then recorded during a mean follow-up of 34 ± 14 months (range 7 – 85). Results: 239 pts (56%) had LGE ranging from 0.4 – 65% of the myocardium. LGE -positive pts were more likely to have non-sustained ventricular tachycardia on Holter ECG [34/126 (27%) vs 8/94 (8.5%), p < 0.001], and had more total ventricular extrasystoles/24 hours (700 ± 2080 vs 103 ± 460, p < 0.001). During follow-up, 7 pts died and 4 received appropriate ICD discharges (9.7% of 41 pts with ICD). All 11 pts were LGE-positive. Event free survival was excellent (100%) in pts without LGE, and lower (95.4%) in pts with LGE (log rank, p < 0.002). Multivariate analysis (adjusting for age, gender, morphologic and functional data, and comorbidities) identified LGE involving ≥ 5% of LV mass (p=0.03, present in 7/11 pts with events), septal thickness≥30mm (p=0.03), and atrial fibrillation (p=0.02) as independent predictors of death or appropriate ICD discharges. Conclusions : In pts with HCM, LGE by CE-MRI was strongly associated with surrogates of arrhythmia and was independently associated with subsequent death and/or ICD discharge. If replicated, LGE may be considered a major risk for sudden death in HCM.

Background: Contrast enhanced magnetic resonance imaging (CE-MRI) is a useful tool to define cardiac morphology, systolic function, and the presence of late gadolinium enhancement (LGE). In patients (pts) with hypertrophic cardiomyopathy (HCM), LGE may represent intra-myocardial fibrosis. We explored the association between left ventricular (LV) morphology and function to the presence and amount of LGE in pts with HCM. Methods: 424 HCM pts (age = 55 ± 16 years, 41% females), without prior history of septal ablation/myectomy, underwent CE-MRI (GE 1.5T) during a 6-year period. LV volumes, diameter, ejection fraction (EF), septal shape and thickness, and the presence of obstructive physiology were assessed from standard steady state free precession pulse sequences. The presence and amount of LGE were traced from a dynamic post contrast inversion recovery pulse sequence. Morphologic and functional findings were then compared with presence and amount of LGE. Results: Over half of the pts [239/424 (56%)] had LGE, most commonly localizing to RV insertion points [174/239 pts, (73%)]. The extent of LGE ranged from 0.4–65% of LV mass. Univariate (morphologic) predictors of LGE were: reverse curve septal shape [OR = 7.8, (95% CI, 3.9–15.6)], septal thickness ≥ 16 mm (OR = 4.5, 2.4–8.2), LV mass ≥ 150 grams (OR = 2.6, 1.7–3.8)], LVEF<50% (OR = 4.6, 1.3–16), and presence of obstructive physiology (OR = 1.8, 1.02–3). The percentage of LV mass involved with LGE increased with higher LV mass, increased septal wall thickness, and decreasing LVEF (Spearman rank = 0.2– 0.4, p<0.0001 for all). Multivariate analysis (adjusting for all morphologic and functional parameters) showed that septal thickness ≥ 16mm (p = 0.0001), LV mass ≥ 150 grams (p = 0.01) and LVEF < 50% (p = 0.02) were independent predictors of LGE on CE-MRI. Conclusions: LGE, as determined by CE-MRI, was seen in over half of the patients with HCM. Decreased LVEF, increased septal thickness, and increased LV mass were associated with the presence of LGE. The clinical and prognostic impact of these morphological features warrants further investigation.

Periprocedural bleeding is one of the most frequent complications of percutaneours coronary interventions. We assessed the relation between blood transfusion and all-cause mortality or incident cardiovascular events (death, MI, stroke) among 6103 patients of the Evaluation of Oral Xemilofiban in Controlling Thrombotic Events (EXCITE)-trial. Subjects were followed for 7 months after enrollment for the occurrence of events. Multivariate Cox-regression analysis evaluated the independent association of blood transfusion with each outcome adjusted for age, gender, race, diabetes mellitus, hypertension, hypercholesterolemia, history of MI, PCI, CABG, heart failure, LVEF<30%, use of beta-blockers, statins, ACE-inhibitors, platelet inhibitors and allocation to treatment with xemolifiban. In addition, propensity score analyses were performed (ROC 0.80). Mean age was 59.2 years, 21.7% were female, and 18.9% had diabetes mellitus. Of the169 patients who received blood transfusion, 14 (8.3%) died and 42 (24.9%) experienced a CVD event. Of the 5934 patients without transfusion, 65 (1.1%) died (p-value: <0.001) and 555 (9,4%) experienced a CVD event (p-value: <0.001) In multivariate analysis, blood transfusion was associated with a 5.3 fold increased risk of mortality (HR 5.3; 95% CI 2.8 –10.2), and a 2.5 fold increased risk of incident CVD (HR 2.5; 95% CI 1.7–3.4.) Noteworthy, patients who were US citizens had a higher transfusion rate then non-US citizens (OR 1.45, 95%CI 1.02–2.06) The need of blood transfusion is a strong and independent predictor of all-cause mortality and incident CVD events among patients undergoing PCI.

Introduction: Left atrial appendage (LAA) flow depends largely on left ventricular compliance and may play a role in mediating the regulation of left atrial volume-pressure relationships. Hypothesis: We hypothesize that LAA emptying flow velocity (LAAEV) is a predictive factor of long-term outcomes (e.g. recurrent AF, stroke, and survival) after cardioversion for non-valvular AF. Method: We identified 3,251 consecutive patients with non-valvular AF who underwent successful TEE-guided electrical cardioversion (ECV) at our institution between May 2000 and March 2012. Successful ECV was defined as sinus rhythm at time of discharge from the cardioversion unit. Patients were monitored following their ECV procedure for first documentation of recurrent AF, stroke or death. Multivariate Cox proportional hazards models were used to identify independent predictors of long-term outcomes. Patients with >= moderate valvular regurgitation or stenosis were excluded. Results: Among the 3,251 patients who were successfully cardioverted to sinus rhythm, the mean (±SD) LAAEV was 38.43±23 cm/s and the median was 33 cm/s, (interquartile range [IQR], 20-50). Patients with LAAEV <=33 cm/s had higher CHA 2 DS 2 -VASc score (2.6±1.2 vs. 1.9±1.3, P =.009), larger LAVI (52.0±20.9 cc/m 2 vs. 43.3±13.6 cc/m 2 , P <.001) than those with LAAEV >33 cm/s. Pre or post-procedure antiarrhythmic drug use was similar between the two groups. During 1-year follow-up, patients with LAAEV <=33 cm/s had significantly higher rate of AF recurrence than those with LAAEV >33 cm/s (55% vs 45%, P <.001). Likewise, during a mean follow-up of 4.9±3.6 years, similar patterns in 5-year rates were observed for first recurrence of AF (81% vs 73%, P <.001), stroke (7% vs 4%, P =.003) and mortality (31% vs 23%, P <.001) for LAAEV <=33 vs > 33cm/s, respectively. Stepwise multivariate Cox regression analysis revealed that LAAEV <=33 cm/s, age, CHA 2 DS 2 -VASc score were independent predictors of AF recurrence, stroke and mortality. Conclusions: LAA emptying flow velocity is an effective and convenient method for risk stratification of patients undergoing cardioversion for AF. Our data showed that patients with reduced LAAEV have an increased risk for AF recurrence, stroke and death following electrical cardioversion.

Background: Patients with sinus node dysfunction (SND) are at increased risk of atrial tachyarrhythmias, including atrial fibrillation (AF). Whether the presence of SND is also associated with worse outcomes among those with AF has not been well described. Methods: The ORBIT-AF registry enrolled patients with AF from a range of clinical practices across the US. SND was defined clinically, based on the presence of sinus bradycardia, severe sinus bradycardia, sinus arrest, sinoatrial exit block, or features of tachycardia-bradycardia syndrome. Descriptive statistics and multivariable logistic regression analysis were used to describe treatment patterns and outcomes for patients with and without SND and AF. Results: Overall, 1,710 (17.7%) patients had SND at enrollment. Patients with SND had lower left-ventricular ejection fractions, higher CHA 2 DS 2 -VASc risk scores, and more prior cerebrovascular events. Patients with SND had more severe symptoms (EHRA class IV: 17.5% vs. 13.9%; p=0.007) and poorer quality of life (median AFEQT 77.5 vs. 81.1; p=0.008) as compared to those without. SND patients were more frequently treated with oral anticoagulants (79.2% vs. 75.9%, p=0.004) and had more often received interventional therapy for AF (16.1% vs. 10.5%, p<0.0001). There were no differences in the current AF management strategy between patients with SND and those without [rate control (69.7% vs. 67.7%), rhythm control (30.0% vs. 32.0%); P=0.11]. After adjustment, significantly more patients with SND had progressed from paroxysmal AF at baseline to persistent or permanent AF at any follow-up or persistent AF at baseline to permanent AF at any follow-up than those without (OR 1.23, 95% CI 1.01-1.49, p=0.035). Conclusion: Sinus node dysfunction is associated worse symptoms, lower quality of life, and higher risk of progression to permanent AF. However, SND is not associated with increased risk of all-cause hospitalization, incident stroke, or all-cause death.