Take-Home Messages

• Sudden cardiac death (SCD) is common in the United States and there is a need to develop better means of predicting SCD.
• In recent years, investigators have identified important modulating or triggering factors that act on the vulnerable myocardium precipitating sudden death, with the specific chain of events varying based on the specific heart disease or combination of diseases.
• One particular study, known as MUSIC, has been a rich source of information on the mechanisms of SCD.

Sudden death is one of the most challenging issues in modern cardiology, occurring in about 400,000 people each year in the United States. Antonio Bayes de Luna, MD, has dedicated his career to teaching and research in electrocardiology, as well as the clinical and noninvasive aspects of arrhythmias and sudden death. As he explains in his recent textbook, Clinical Arrhythmology, sudden death is the final stage of a chain of events that ends in cardiac arrest.¹

Nearly 25 years ago, he was first author of a paper analyzing seven published series of ambulatory patients who died while wearing Holter devices.² The data revealed important information on the electrical triggering mechanisms leading to the terminal event. From this evaluation of studies (all with 10 or more cases), he and his colleagues noted that the most frequent causes of sudden cardiac death (SCD) were ventricular tachyarrhythmias (VT; 84% of cases) and bradyarrhythmias (16%). Ventricular fibrillation (VF) was the most frequent arrhythmia, usually secondary to VT. The rest were due to torsades de pointes in patients often without heart disease but who were taking antiarrhythmic drugs. The VT leading to VF was often preceded by sinus tachycardia or new atrial tachyarrhythmia. Only a small percentage of patients presented ischemic ST changes.

In all cases of SCD, Dr. Bayes de Luna and others have demonstrated modulating or triggering factors that act on the vulnerable myocardium precipitating sudden death. The chain of events varies based on the specific heart disease or combination of diseases. For example, VF can appear without previous VT, unleashed by a premature ventricular contraction in the presence of other factors, such as environmental and genetic variables, and/or sympathetic overdrive secondary to physical or mental stress. Under normal circumstances, all of these factors may be of little consequence but, in the presence of acute ischemia, they may trigger sudden death.

Advances in Understanding SCD
Dr. Bayes de Luna's team has been involved in a number of studies that have advanced understanding of sudden death, including MUSIC (MUerte Subita en Insuficiencia Cardiaca), a prospective, multicenter, longitudinal study designed to assess risk predictors of cardiac mortality in nearly 1,000 patients with mild-to-moderate heart failure (HF).

Highlights of his recent work:

• Beat-to-beat fluctuations in the morphology of the ECG waveform, known as T-wave alternans (TWA), are a well-documented noninvasive method for identifying patients at risk for SCD. Absence of TWA (TWA-) indicates minimal risk of SCD. In this study, investigators evaluated whether the long-term average TWA activity on Holter monitoring provides prognostic information in patients with chronic HF. Analysis was performed on 24-hour Holter ECGs from 650 ambulatory patients with mild-to-moderate HF.³ After a median follow-up of 48 months, survival was significantly higher in the TWA- group for cardiac death and SCD (p = 0.017 and p = 0.001, respectively). So, average TWA activity measured automatically from Holter ECGs did predict SCD in these HF patients.
• Among individuals with HF, body mass index (BMI) is inversely associated with mortality, giving rise to the so-called obesity paradox. Dr. Bayes de Luna and colleagues examined 979 patients with mild-to- moderate HF.⁴ After a median follow-up of 44 months, higher BMI emerged as an independent predictor of all-cause mortality (hazard ratio [HR] = 0.94; p = 0.0003) and pump failure death (HR = 0.93; p = 0.004). However, there was no significant relationship between BMI and sudden death (HR = 0.97; p = 0.28). The only independent predictors of SCD were prior history of MI (HR = 1.89; p = 0.004), hypertension (HR = 1.66; p = 0.03), left ventricular ejection fraction (LVEF; HR = 0.88; p = 0.006), and N-terminal pro–B-type natriuretic peptide (NT-proBNP; HR = 1.01; p = 0.048).
• The MUSIC study also was used to develop better prognostic models for HF patients.⁵ Several such models have been developed, but all of them have some limitations for their use in current clinical practice: they relied on either peak oxygen consumption or invasive measures of cardiac function; were validated during a hospitalization for HF; included only patients with systolic dysfunction; and/or included a substantial proportion of patients not taking contemporary evidence-based treatments.

Multivariable Cox models were developed to predict all-cause mortality (n = 267), cardiac mortality (primary endpoint, n = 213), pump-failure death (n = 123), and sudden death (n = 90). The four final models included several combinations of the same 10 independent predictors:

– prior atherosclerotic vascular event
– left atrial size >26 mm/m²
– LVEF
– atrial fibrillation
– left bundle-branch block or intraventricular conduction delay
– nonsustained VT and frequent ventricular premature beats
– estimated glomerular filtration rate <60 ml/min/1.73="">²
– hyponatremia <138>
– NT-proBNP >1.000 ng/L
– troponin-positive

On the basis of Cox models, the MUSIC risk scores were calculated and a cardiac mortality score >20 points identified a high-risk subgroup with a four-fold cardiac mortality risk. The authors concluded that use of this model in clinical practice identifies a subgroup of high-risk patients who should be closely managed.

Finally, Dr. de Luna and colleagues used a large registry of patients with heart failure to determine if the soluble form of ST2 (sST2), an interleukin-1 receptor family member, predicts the risk of SCD.⁶ A nested case-control study was performed on 36 cases of SCD and 63 controls (matched for age, sex, and LVEF) enrolled in a registry of ambulatory HF patients. Concentrations of sST2 were higher among those who died. Combining sST2 and NT-proBNP improved the accuracy: only 4% of patients with low sST2 and low NT-proBNP experienced SCD. The rate was 34% when either marker was elevated and 71% when both markers were elevated. Thus, sST2 may be useful for predicting the risk of SCD, especially when combined with NT-proBNP.

References
1. Bayes de Luna A. Clinical Arrhythmiology. Wiley-Blackwell. 2011.
2. Bayes de Luna A, Coumel P, Leclercq JF. Am Heart J. 1989;117:151-9.
3. Monasterio V, Laguna P, Cygankiewicz I, et al. Heart Rhythm. 2012;9:383-9.
4. Gastelurrutia P, Pascual-Figal D, Vazquez R, et al. Am Heart J. 2011;161:158-64.
5. Vazquez R, Bayes-Genis A, Cygankiewicz I, et al. Eur Heart J. 2009;30:1088-96.
6. Pascual-Figal DA, Ordoñez-Llanos J, Tornel PL, et al. J Am Coll Cardiol. 2009;54:2174-9. http://content.onlinejacc.org/article.aspx?articleid=1140237

To listen to an interview with Antonio Bayes De Luna, MD, about predicting sudden cardiac death, visit youtube.cswnews.org. The interview was conducted by Alfred A. Bove, MD.

Keywords: Registries, Follow-Up Studies, Body Mass Index, Heart Failure, Receptors, Interleukin-1, Myocardium, Hypertension, Death, Sudden, Cardiac, Natriuretic Peptide, Brain

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