Jacqueline L. Buros

Occurrence and Frequency of Arrhythmias in Hypertrophic Cardiomyopathy in Relation to Delayed Enhancement on Cardiovascular Magnetic Resonance

OBJECTIVES Our aim was to determine whether myocardial fibrosis, detected by cardiovascular magnetic resonance (CMR), represents an arrhythmogenic substrate in hypertrophic cardiomyopathy (HCM). BACKGROUND Myocardial fibrosis is identified frequently in HCM; however, the clinical significance of this finding is uncertain. METHODS We studied prevalence and frequency of tachyarrhythmias on 24-h ambulatory Holter electrocardiogram (ECG) with regard to delayed enhancement (DE) on contrast-enhanced CMR in 177 HCM patients (age 41 +/- 16 yrs; 95% asymptomatic or mildly symptomatic). RESULTS Premature ventricular contractions (PVCs), couplets, and nonsustained ventricular tachycardia (NSVT) were more common in patients with DE than those without DE (PVCs: 89% vs. 72%; couplets: 40% vs. 17%; NSVT: 28% vs. 4%; p < 0.0001 to 0.007). Patients with DE also had greater numbers of PVCs (202 +/- 655 vs. 116 +/- 435), couplets (1.9 +/- 5 vs. 1.2 +/- 10), and NSVT runs (0.4 +/- 0.8 vs. 0.06 +/- 0.4) than non-DE patients (all p < 0.0001); DE was an independent predictor of NSVT (relative risk 7.3, 95% confidence interval 2.6 to 20.4; p < 0.0001). However, extent (%) of DE was similar in patients with and without PVCs (8.2% vs. 9.1%; p = 0.93), couplets (8.5% vs. 8.4%; p = 0.99), or NSVT (8.3% vs. 8.5%; p = 0.35). CONCLUSIONS In this large HCM cohort with no or only mild symptoms, myocardial fibrosis detected by CMR was associated with greater likelihood and increased frequency of ventricular tachyarrhythmias (including NSVT) on ambulatory Holter ECG. Therefore, contrast-enhanced CMR identifies HCM patients with increased susceptibility to ventricular tachyarrhythmias.

Efficacy of Ranolazine in Patients With Chronic Angina: Observations From the Randomized, Double-Blind, Placebo-Controlled MERLIN–TIMI (Metabolic Efficiency With Ranolazine for Less Ischemia in Non–ST-Segment Elevation Acute Coronary Syndromes) 36 Trial

OBJECTIVES We aimed to evaluate the efficacy and safety of ranolazine in a larger and more diverse group of patients with angina than previously studied. BACKGROUND Ranolazine is an antianginal shown to reduce angina and improve exercise performance in selected patients with early-positive exercise testing and those with frequent angina. METHODS We investigated the antianginal effects of ranolazine in the subgroup of patients with prior chronic angina (n = 3,565, 54%) enrolled in the randomized, double-blind, placebo-controlled MERLIN-TIMI (Metabolic Efficiency With Ranolazine for Less Ischemia in Non-ST Elevation Acute Coronary Syndromes) 36 trial of patients with acute coronary syndrome. Follow-up was a median of 350 days. RESULTS Patients with prior angina received evidence-based therapy (95% aspirin, 78% statins, 89% beta-blockers, average 2.9 antianginal agents). The primary end point (cardiovascular death, myocardial infarction, recurrent ischemia) was less frequent with ranolazine (hazard ratio [HR]: 0.86; 95% confidence interval [CI]: 0.75 to 0.97; p = 0.017), due entirely to a significant reduction in recurrent ischemia (HR: 0.78; 95% CI: 0.67 to 0.91; p = 0.002). Ranolazine also reduced worsening angina (HR: 0.77; 95% CI: 0.59 to 1.00; p = 0.048) and intensification of antianginal therapy (HR: 0.77; 95% CI: 0.64 to 0.92, p = 0.005). Exercise duration at 8 months was greater with ranolazine (514 s vs. 482 s, p = 0.002). Cardiovascular death or myocardial infarction did not differ between treatment groups (HR: 0.97; 95% CI: 0.80 to 1.16; p = 0.71). Symptomatic documented arrhythmias (2.9% vs. 2.9%, p = 0.92) and total mortality (6.2% vs. 6.4%, p = 0.96) were similar with ranolazine or placebo. CONCLUSIONS In this largest study of ranolazine in patients with established coronary artery disease, ranolazine was effective in reducing angina with favorable safety in a substantially broader group of patients with angina than previously studied. (Metabolic Efficiency With Ranolazine for Less Ischemia in Non-ST Elevation Acute Coronary Syndromes; NCT00099788).

Prognostic Utility of Heart-Type Fatty Acid Binding Protein in Patients With Acute Coronary Syndromes

Background— Heart-type fatty acid binding protein (H-FABP) is a cytosolic protein that is released rapidly from the cardiomyocyte in response to myocardial injury. Although it has been investigated as an early marker of acute myocardial infarction, its prognostic utility in acute coronary syndromes has not been established. Methods and Results— We measured H-FABP in 2287 patients with acute coronary syndromes from the OPUS-TIMI 16 trial. H-FABP was elevated (>8 ng/mL) in 332 patients (14.5%). Patients with an elevated H-FABP were more likely to suffer death (hazard ratio [HR], 4.1; 95% CI, 2.6 to 6.5), recurrent myocardial infarction (HR, 1.6; 95% CI, 1.0 to 2.5), congestive heart failure (HR, 4.5; 95% CI, 2.6 to 7.8), or the composite of these end points (HR, 2.6; 95% CI, 1.9 to 3.5) through the 10-month follow-up period. H-FABP predicted the risk of the composite end point both in patients who were troponin I negative (HR, 2.1; 95% CI, 1.3 to 3.4) and in those who were troponin I positive (HR, 3.3; 95% CI, 2.0 to 5.3). In a Cox proportional-hazards model that adjusted for baseline variables, including demographics, clinical characteristics, creatinine clearance, ST deviation, index diagnosis, and troponin I, elevated H-FABP remained a significant predictor of the composite end point (HR, 1.9; 95% CI, 1.3 to 2.7), as well as the individual end points of death (HR, 2.7; 95% CI, 1.5 to 4.9) and CHF (HR, 2.4; 95% CI, 1.2 to 5.0). In a multimarker approach, H-FABP, troponin I, and B-type natriuretic peptide provided complementary information. Conclusions— Elevation of H-FABP is associated with an increased risk of death and major cardiac events in patients presenting across the spectrum of acute coronary syndromes and is independent of other established clinical risk predictors and biomarkers.

Significance of papillary muscle abnormalities identified by cardiovascular magnetic resonance in hypertrophic cardiomyopathy.

Increased thickness of the left ventricular (LV) wall is the predominant feature of the hypertrophic cardiomyopathy (HC) phenotype. The structural characteristics of the LV papillary muscles (PMs) have received little attention. In this study, cardiovascular magnetic resonance (CMR) was used to characterize PM morphology in a large HC population. Cine and delayed enhancement (DE) CMR images were obtained in 201 patients with HC and 43 control subjects. PM number and mass index were greater in patients with HC compared with controls (2.5 vs 2.1, p <0.001, and 6 +/- 2 vs 3 +/- 2 g/m(2), p <0.001, respectively), including 109 (54%) with PM mass > or =7 g/m(2) (> or =2 SDs above the mean for controls). Greater LV wall mass index was associated with more substantial PM mass (r = 0.09, p <0.001). Furthermore, 12 patients with HC (19%) had normal LV mass with localized wall thickness but increased PM mass. In patients with HC with LV outflow obstruction at rest, PMs were positioned closer to the ventricular septum (displaced anteriorly: 58% vs 42% for subjects without obstruction, p = 0.02), with more marked hypertrophy (9 +/- 5 vs 6 +/- 4 g/m(2), p <0.001). Preoperative CMR identified 3 patients with accessory, anteriorly displaced PMs judged to contribute to outflow obstruction, which were resected during septal myectomy. DE of the PMs was identified in 13 patients with HC (6%), including 3 with DE confined to PMs. In conclusion, CMR demonstrates LV PMs to be part of the cardiomyopathic process in HC, with increases in number and mass, and not uncommonly associated with remodeling with DE. The identification of accessory PMs may be useful in planning preoperative strategy.

Use of the TIMI frame count in the assessment of coronary artery blood flow and microvascular function over the past 15 years

Since its introduction, the TIMI frame count method has contributed to the understanding of the pathophysiology of coronary artery disease. In this article, the evolution of the TFC method and its applicability in the assessment of various therapeutic modalities are described.

Effect of prasugrel versus clopidogrel on outcomes among patients with acute coronary syndrome undergoing percutaneous coronary intervention without stent implantation: A TRial to assess Improvement in Therapeutic Outcomes by optimizing platelet inhibitioN with prasugrel (TRITON)–Thrombolysis in Myocardial Infarction (TIMI) 38 Substudy

BACKGROUND Prasugrel led to a significant reduction in ischemic cardiovascular events among patients with acute coronary syndrome (ACS) undergoing percutaneous coronary intervention (PCI) with stent implantation compared to clopidogrel. Whether this benefit extends to patients undergoing PCI without stent implantation is unknown. METHODS In TRial to assess Improvement in Therapeutic Outcomes by optimizing platelet inhibitioN with prasugrel (TRITON)-Thrombolysis in Myocardial Infarction (TIMI) 38, patients (n = 13 608) undergoing PCI for ACS were randomized to aspirin plus clopidogrel or prasugrel. This postrandomization analysis of a prespecified subgroup was restricted to patients who underwent PCI without stent implantation (n = 569). RESULTS Patients who underwent PCI without stent implantation were older and had a higher incidence of hypertension, diabetes, prior myocardial infarction (MI), prior coronary artery bypass (CABG) surgery, and renal dysfunction than patients who underwent stent implantation. In the group that did not undergo stent implantation, baseline characteristics were similar between patients receiving clopidogrel and prasugrel. The composite of cardiovascular death, nonfatal MI, and nonfatal stroke occurred in 14.2% of patients receiving prasugrel and 17.1% of patients receiving clopidogrel (HR 0.82, P = .27). There were significant reductions favoring prasugrel in the rates of urgent target vessel revascularization (TVR; HR 0.46, P = .040) and any TVR (HR 0.40, P = .009) and a trend toward a reduction in the incidence of nonfatal MI (HR 0.65, P = .11). CABG-related TIMI major bleeding was more frequent among patients receiving prasugrel. There were no significant interactions between treatment and PCI type. CONCLUSION Among ACS patients who underwent PCI without stent implantation, prasugrel therapy tended to reduce clinical ischemic events and to increase bleeding events to a similar magnitude as among patients who received stents.

Association of Impaired Thrombolysis In Myocardial Infarction Myocardial Perfusion Grade With Ventricular Tachycardia and Ventricular Fibrillation Following Fibrinolytic Therapy for ST-Segment Elevation Myocardial Infarction

OBJECTIVES The goal of this analysis was to evaluate the association of impaired Thrombolysis In Myocardial Infarction myocardial perfusion grade (TMPG) with sustained ventricular tachycardia (VT) or ventricular fibrillation (VF). BACKGROUND Impaired TMPG after successful restoration of epicardial flow among patients treated with fibrinolytic therapy for ST-segment elevation myocardial infarction (STEMI) has been associated with adverse clinical outcomes, but its relationship to VT/VF has not been evaluated. METHODS In the CLARITY-TIMI 28 (Clopidogrel as Adjunctive Reperfusion Therapy-Thrombolysis In Myocardial Infarction 28) study, 3,491 patients underwent angiography a median of 3.5 days after fibrinolytic administration for STEMI; TMPG was assessed, and its association with VT/VF was evaluated. RESULTS We observed VT/VF in 4.8% of patients. Impaired myocardial perfusion (TMPG 0/1/2) was associated with an increased incidence of VT/VF (7.1% vs. 2.6% with TMPG 3; log-rank p < 0.001). Among patients with restoration of normal epicardial flow (Thrombolysis In Myocardial Infarction flow grade 3), the incidence of VT/VF was increased among patients with impaired TMPG (4.7% vs. 2.7%; p = 0.02). Among patients with left ventricular ejection fraction >or=30%, impaired TMPG remained associated with an increased incidence of VT/VF (4.7% vs. 2.5%; p = 0.03). We found that VT/VF was associated with increased mortality (25.2% vs. 3.5%; p < 0.0001). Furthermore, among patients with VT/VF, impaired TMPG was associated with increased mortality (17.1% vs. 2.3%; p = 0.02). All but 1 death among patients who had VT/VF were among patients with impaired myocardial perfusion. CONCLUSIONS Despite restoration of normal epicardial flow or a left ventricular ejection fraction >or=30%, impaired myocardial perfusion on angiography 3.5 days after fibrinolytic administration for STEMI is associated with an increased incidence of VT/VF.

Intracoronary pharmacotherapy in the management of coronary microvascular dysfunction

Although percutaneous coronary intervention restores optimal epicardial blood flow in most cases, abnormal myocardial perfusion may still persist. This might be as a result of macro and microembolization, neutrophil plugging, vasoconstriction, myocyte contracture, local intracellular and interstitial edema, intramural haemorrhage, and endothelial blistering. Local delivery of intracoronary pharmacotherapy via the coronary arteries may increase local drug concentration several fold, and may improve drug efficacy. Several pharmacological agents such as adenosine, calcium channel blockers, α blockers, β2 receptor activators, vasodilators, antithrombotics, and antiplatelet agents have been used to treat coronary microvascular dysfunction. This article reviews the results of trials of intracoronary pharmacotherapy to date.

Diagnostic and prognostic value of ambulatory ECG (Holter) monitoring in patients with coronary heart disease: a review

Silent ischemia, the most common expression of atherosclerotic heart disease, affects approximately 30–50% of patients during their activities of daily living. The present review provides a comprehensive and practical summary of current knowledge on perioperative myocardial ischemia through MEDLINE searches up to June 2005, using keywords including “silent ischemia,” “transient ischemia,” and “Holter monitoring.” Holter monitoring (i.e., continuous ambulatory ST-segment monitoring) is an effective tool for assessing the frequency and duration of silent transient myocardial ischemia, particularly in patients who are post-acute myocardial infarction (MI), those with acute coronary syndromes (ACS), and in patients in the acute post-operative period. Holter monitoring allows for further risk stratification of patients who have a positive exercise ECG by collecting long-term ECG data on ischemic and arrhythmic events while patients perform routine activities. Both the presence and increased duration of transient ischemia as detected by continuous ST-segment Holter monitoring are associated with increased rates of coronary events and mortality. Holter monitoring may aid in the identification of patients and subgroups of patients with ACS who may derive the greatest benefit from antiplatelet and antithrombotic therapy. Indeed, many ongoing and upcoming trials of pharmacotherapy include ischemia on Holter monitoring as an endpoint.

Timing and Duration of Myocardial Ischemia on Holter Monitoring Following Percutaneous Coronary Intervention and Their Association With Clinical Outcomes (a PROTECT-TIMI 30 Substudy Analysis)

In patients with unstable angina, evidence of myocardial ischemia on Holter monitoring is associated with an adverse prognosis. However, the association of duration and timing of ischemia on Holter monitoring with outcomes after percutaneous coronary intervention (PCI) in patients with non-ST-segment elevation acute coronary syndromes (NSTEACSs) has not been systematically evaluated. PROTECT-TIMI 30 randomized 857 patients with NSTEACSs undergoing PCI to eptifibatide plus a heparin product or bivalirudin monotherapy. Patients underwent continuous Holter monitoring following PCI, and the association between ischemia and clinical outcomes was evaluated retrospectively. Forty-three patients (5.0%) had ischemia on Holter after PCI. Any ischemia was associated with a significant increase in the incidence of death or myocardial infarction (MI) within 48 hours (32.6% vs 6.1%, odds ratio 7.5, 95% confidence interval 3.70 to 15.10, p <0.001). In patients who developed ischemia, there was a 1.44-fold increase in the odds for death or MI for every 30 minutes of ischemia (95% confidence interval 1.12 to 1.84, p = 0.004). Duration of ischemic events was related to their timing, such that ischemic events that occurred within the first 4 hours after PCI (median duration 141 minutes, interquartile range 36 to 227.5) were significantly longer than events occurring 4 to 24 hours after PCI (median duration 32.8 minutes, interquartile range 17.5 to 118, p = 0.041). In conclusion, early ischemia after PCI for NSTEACS is of longer duration, and longer duration of ischemia recognized by Holter monitoring is associated with an increased incidence of death or MI. Holter monitoring may be a useful surrogate end point in clinical trials.