Denervated Myocardium Is Preferentially Associated With Sudden Cardiac Arrest in Ischemic Cardiomyopathy: A Pilot Competing Risks Analysis of Cause-Specific Mortality

Abstract

Background: Previous studies have identified multiple risk factors that are associated with total cardiac mortality. Nevertheless, identifying specific factors that distinguish patients at risk of arrhythmic death versus heart failure could better target patients likely to benefit from implantable cardiac defibrillators, which have no impact on nonsudden cardiac death.

Methods and results: We performed a pilot competing risks analysis of the National Institutes of Health-sponsored PAREPET trial (Prediction of Arrhythmic Events with Positron Emission Tomography). Death from cardiac causes was ascertained in subjects with ischemic cardiomyopathy (n=204) eligible for an implantable cardiac defibrillator for the primary prevention of sudden cardiac arrest after baseline clinical evaluation and imaging at enrollment (positron emission tomography and 2-dimensional echo). Mean age was 67±11 years with an ejection fraction of 27±9%, and 90% were men. During 4.1 years of follow-up, there were 33 sudden cardiac arrests (arrhythmic death or implantable cardiac defibrillator discharge for ventricular fibrillation or ventricular tachycardia >240 bpm) and 36 nonsudden cardiac deaths. Sudden cardiac arrest was correlated with a greater volume of denervated myocardium (defect of the positron emission tomography norepinephrine analog ¹¹C-hydroxyephedrine), lack of angiotensin inhibition therapy, elevated B-type natriuretic peptide, and larger left ventricular end-diastolic volume index. In contrast, nonsudden cardiac death was associated with a higher resting heart rate, older age, elevated creatinine, larger left atrial volume index, and larger left ventricular end-diastolic volume index.

Conclusions: Distinct clinical, laboratory, and imaging variables are associated with cause-specific cardiac mortality in primary-prevention candidates with ischemic cardiomyopathy. If prospectively validated, these multivariable associations may help target specific therapies to those at the greatest risk of sudden and nonsudden cardiac death.

Clinical trial registration: URL: https://clinicaltrials.gov. Unique identifier: NCT01400334.

Keywords: coronary artery disease; death, sudden, cardiac; defibrillators, implantable; heart failure; positron-emission tomography; risk factors.

Figure 1. Cumulative Distribution Functions for Sudden Cardiac Arrest (SCA), Non-Sudden Cardiac Death (NSCD), and Total Cardiac Mortality

These curves show the cumulative cardiac mortality in the PAREPET trial to 5 years. Adjudicated SCA (red line) included ICD discharge for ventricular tachycardia >240 bpm and ventricular fibrillation. Total cardiac mortality (gray line) included SCA as well as NSCD (blue line).

Figure 2. Cumulative Distribution Functions for Variables Associated with Both Sudden Cardiac Arrest and Non-Sudden Cardiac Death

Left ventricular end-diastolic volume index (LVEDVI), B-type natriuretic peptide (BNP), creatinine, and LV ejection fraction (EF) were all associated with total cardiac mortality (left graphs) as well as its components of sudden cardiac arrest (middle graphs) and non-sudden cardiac death (right graphs). For all variables, the event rates for the high risk (red lines; LVEDVI >99 ml/m², BNP >446 ng/L, creatinine >1.4 mg/dL, EF <24%), intermediate risk (yellow lines) and low risk (green lines; LVEDVI <74 ml/m², BNP <191 ng/L, creatinine <1.1 mg/dL, EF >31%) tertiles are shown. Corresponding p-values for the univariate analyses using continuous variables are in Table 2.

Figure 3. Cumulative Distribution Functions for Variables Preferentially Associated with Sudden Cardiac Arrest

In addition to associations with total cardiac mortality (left graphs), denervated myocardium and angiotensin inhibition therapy were also significantly associated with sudden cardiac arrest (middle graphs). However, neither variable was associated with non-sudden cardiac death (right graphs). The event rates for the high risk (red lines; denervated myocardium >32.8% of LV and no angiotensin inhibition therapy), intermediate risk (yellow lines) and low risk (green lines; denervated myocardium <22.4% of LV and angiotensin inhibition therapy) tertiles are shown. Corresponding p-values for the univariate analyses using continuous variables are in Table 2.

Figure 4. Cumulative Distribution Functions for Variables Preferentially Associated with Non-Sudden Cardiac Death

Resting heart rate, age and LA volume index were significantly associated with non-sudden cardiac death (right graphs). None of the variables were associated with sudden cardiac arrest (middle graphs), and only LA volume index was significantly associated with total cardiac mortality (left graphs). For all variables, the event rates for the high risk (red lines; heart rate >69 bpm, age >74 years, LA volume index >46.3 ml/m²), intermediate risk (yellow lines) and low risk (green lines; heart rate <60 bpm, age <61 years, LA volume index <33.7 ml/m²) tertiles are shown. Corresponding p-values for the univariate analyses using continuous variables are in Table 2.

Figure 5. Estimated Event Rates from the Competing Risks Analysis for Variables Preferentially Associated with Sudden Cardiac Arrest

The upper graph of each pair shows the anticipated effect of each variable on sudden cardiac arrest (SCA, red lines) and non-sudden cardiac death (NSCD, blue lines) within 5 years. Denervated myocardium, B-type natriuretic peptide (BNP), left ventricular end-diastolic volume index (LVEDVI), and angiotensin inhibition were independently associated with SCA. LVEDVI was also weakly correlated with NSCD. The probability of total cardiac mortality is also shown (black lines), although this was not directly derived from the competing risks model. The histogram associated with each variable illustrates the frequency of values in the PAREPET cohort, as well as the frequency of outliers (<5% of the total). For these figures the effect of each variable is assessed individually while controlling for the other variables. The p-values are derived from the competing risks analysis.

Figure 6. Estimated Event Rates from the Competing Risks Analysis for Variables Preferentially Associated with Non-Sudden Cardiac Death

The upper graph of each pair shows the anticipated effect of each variable on sudden cardiac arrest (SCA, red lines) and non-sudden cardiac death (NSCD, blue lines) within 5 years. Resting heart rate, creatinine, left atrial (LA) volume index, and age were associated with NSCD. The probability of total cardiac mortality is also shown (black lines), although this was not directly derived from the competing risks model. The histogram associated with each variable illustrates the frequency of values in the PAREPET study, as well as the frequency of outliers (<5% of the total). For these figures the effect of each variable is assessed individually while controlling for the other variables. The p-values are derived from the competing risks analysis.