Left Ventricular Structural Predictors of Sudden Cardiac Death

Official title

Left Ventricular Structural Predictors of Sudden Cardiac Death [Substudy of: Functional Energetics and Imaging for Phenotypic Characterization of Patients at Risk for Sudden Cardiac Death, See Also NCT000181233]

Overview

Sudden cardiac death (SCD) poses a significant health care challenge with high annual incidence and low survival rates. Implantable cardioverter defibrillators (ICDs) prevent SCD in patients with poor heart function. However, the critical survival benefit afforded by the devices is accompanied by short and long-term complications and a high economic burden. Moreover, in using current practice guidelines of reduced heart function, specifically left ventricular ejection fraction (LVEF)≤35%, as the main determining factor for patient selection, only a minority of patients actually benefit from ICD therapy (\<25% in 5 years). There is an essential need for more robust diagnostic approaches to SCD risk stratification. This project examines the hypothesis that structural abnormalities of the heart itself, above and beyond global LV dysfunction, are important predictors of SCD risk since they indicate the presence of the abnormal tissue substrate required for the abnormal electrical circuits and heart rhythms that actually lead to SCD. Information about the heart's structure will be obtained from cardiac magnetic resonance imaging and used in combination with a number of other clinical risk factors to see if certain characteristics can better predict patients at risk for SCD.

Detailed description

Sudden cardiac death (SCD) poses a significant health care challenge with high annual incidence and low survival rates. Implantable cardioverter defibrillators (ICDs) prevent SCD in patients with left ventricular (LV) systolic dysfunction. However, the critical survival benefit afforded by the devices is accompanied by short and long-term complications and a high economic burden. Moreover, in using current practice guidelines of LV ejection fraction (LVEF)≤35% as the main determining factor for patient selection, only a minority of patients actually benefit from ICD therapy (\<25% in 5 years). There is an essential need for more robust diagnostic approaches to SCD risk stratification.

This project examines the hypothesis that LV structural abnormalities above and beyond global LV dysfunction are important predictors of SCD risk since they indicate the presence of abnormal pathophysiologic substrate required for the ventricular arrhythmogenicity leading to SCD. This premise is supported by pre-clinical models and limited patient cohort studies examining the contribution of individual LV structural indices. However, there has been no prospective study of primary prevention ICD candidates in sufficiently large numbers to investigate the incremental value of a comprehensive assessment of LV structure on SCD risk over and above that of LVEF and readily available demographic and clinical variables.

LV structure can be quantified in detail using cardiac magnetic resonance imaging with late gadolinium enhancement (CMR-LGE). Specifically, accurate assessment of global LV function, volumes, mass, geometry, and infarct/scar characteristics are feasible and obtainable clinically in a single examination. We aim to examine whether or not any of these CMR indices or combination of indices are better able to discriminate between patients with high versus low susceptibility to SCD within the broader population of reduced LVEF patients. If the results of these studies demonstrate that LV structure is an important prognostic risk factor, it may be then be possible to more specifically focus ICD therapy to those who are most likely to benefit and avoid unnecessary device implantations.

Primary outcome measures

• Composite SCD outcomes [Time frame: Every 6 months for 5 years]

Secondary outcome measures (1)

• Composite cardiac outcomes [Time frame: Every 6 months for 5 years]

Eligibility criteria

Inclusion criteria

• LVEF≤35%, referred clinically for ICD insertion for primary prevention purposes (i.e. no prior history of sustained ventricular arrhythmias)
• Between the ages of 21 and 80 years old
• Permission of the patient's clinical attending physician

Exclusion criteria

• Patients who refuse or are unable to give consent.
• Individuals with contraindications to MRI (i.e. implanted metallic objects such as pre-existing cardiac pacemakers, cerebral clips or indwelling metallic projectiles)
• Minors.
• Pregnant women.
• NYHA Class IV heart failure.
• Chronic renal insufficiency with creatinine clearance<60 ml/min; acute renal insufficiency of any severity
• Claustrophobia
• Prior adverse reaction to gadolinium-based contrast

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Observational model

Cohort

Study locations

United States · 2 centers

• Christiana Care Health Services — Newark
• Johns Hopkins Medical Institutions — Baltimore

Publications

• Schmidt A, Azevedo CF, Cheng A, Gupta SN, Bluemke DA, Foo TK, Gerstenblith G, Weiss RG, Marban E, Tomaselli GF, Lima JA, Wu KC. Infarct tissue heterogeneity by magnetic resonance imaging identifies enhanced cardiac arrhythmia susceptibility in patients with left ventricular dysfunction. Circulation. 2007 Apr 17;115(15):2006-14. doi: 10.1161/CIRCULATIONAHA.106.653568. Epub 2007 Mar 26. PMID 17389270
• Fernandes VR, Wu KC, Rosen BD, Schmidt A, Lardo AC, Osman N, Halperin HR, Tomaselli G, Berger R, Bluemke DA, Marban E, Lima JA. Enhanced infarct border zone function and altered mechanical activation predict inducibility of monomorphic ventricular tachycardia in patients with ischemic cardiomyopathy. Radiology. 2007 Dec;245(3):712-9. doi: 10.1148/radiol.2452061615. Epub 2007 Oct 2. PMID 17911537
• Wu KC, Weiss RG, Thiemann DR, Kitagawa K, Schmidt A, Dalal D, Lai S, Bluemke DA, Gerstenblith G, Marban E, Tomaselli GF, Lima JA. Late gadolinium enhancement by cardiovascular magnetic resonance heralds an adverse prognosis in nonischemic cardiomyopathy. J Am Coll Cardiol. 2008 Jun 24;51(25):2414-21. doi: 10.1016/j.jacc.2008.03.018. PMID 18565399
• Ouwerkerk R, Bottomley PA, Solaiyappan M, Spooner AE, Tomaselli GF, Wu KC, Weiss RG. Tissue sodium concentration in myocardial infarction in humans: a quantitative 23Na MR imaging study. Radiology. 2008 Jul;248(1):88-96. doi: 10.1148/radiol.2481071027. PMID 18566171
• Ardekani S, Weiss RG, Lardo AC, George RT, Lima JA, Wu KC, Miller MI, Winslow RL, Younes L. Computational method for identifying and quantifying shape features of human left ventricular remodeling. Ann Biomed Eng. 2009 Jun;37(6):1043-54. doi: 10.1007/s10439-009-9677-2. Epub 2009 Mar 26. PMID 19322659
• Bottomley PA, Wu KC, Gerstenblith G, Schulman SP, Steinberg A, Weiss RG. Reduced myocardial creatine kinase flux in human myocardial infarction: an in vivo phosphorus magnetic resonance spectroscopy study. Circulation. 2009 Apr 14;119(14):1918-24. doi: 10.1161/CIRCULATIONAHA.108.823187. Epub 2009 Mar 30. PMID 19332463
• Strauss DG, Selvester RH, Lima JA, Arheden H, Miller JM, Gerstenblith G, Marban E, Weiss RG, Tomaselli GF, Wagner GS, Wu KC. ECG quantification of myocardial scar in cardiomyopathy patients with or without conduction defects: correlation with cardiac magnetic resonance and arrhythmogenesis. Circ Arrhythm Electrophysiol. 2008 Dec;1(5):327-36. doi: 10.1161/CIRCEP.108.798660. Epub 2008 Dec 2. PMID 19808427
• Strauss DG, Wu KC. Imaging myocardial scar and arrhythmic risk prediction--a role for the electrocardiogram? J Electrocardiol. 2009 Mar-Apr;42(2):138.e1-8. doi: 10.1016/j.jelectrocard.2008.12.010. Epub 2009 Jan 30. PMID 19185315

Identifiers

NCT: NCT01076660 · IRB00324567

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗