Arq Bras Cardiol Arquivos Brasileiros de Cardiologia Arq. Bras. Cardiol. 0066-782X 1678-4170 Sociedade Brasileira de Cardiologia SJZdzJY8Fk6dhFCLDrtHrMd S0066-782X2014002200011 00011 10.5935/abc.20140125 Review Article Stratification of the Risk of Sudden Death in Nonischemic Heart Failure Pimentel Maurício 1 2 Zimerman Leandro Ioschpe 1 2 Rohde Luis Eduardo 1 2 Universidade Federal do Rio Grande do Sul Curso de Pós-graduação em Ciências Cardiovasculares Porto Alegre RS Brazil Curso de Pós-graduação em Ciências Cardiovasculares - Universidade Federal do Rio Grande do Sul, Porto Alegre, RS - Brazil Hospital de Clínicas de Porto Alegre Serviço de Cardiologia Porto Alegre RS Brazil Serviço de Cardiologia do Hospital de Clínicas de Porto Alegre, Porto Alegre, RS - Brazil Mailing Address: Maurício Pimentel, Av. Luiz Manoel Gonzaga, 23 ap. 1002, Petrópolis. Postal Code 90470280, Porto Alegre, RS - Brazil. E-mail: mauriciopimentel@cardiol.br; mpimentelrs@gmail.com

Potential Conflict of Interest

No potential conflict of interest relevant to this article was reported.

 29 08 2014 10 2014 103 4 348 357 31 01 2014 31 03 2014 03 04 2014 This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Despite significant therapeutic advancements, heart failure remains a highly prevalent clinical condition associated with significant morbidity and mortality. In 30%-40% patients, the etiology of heart failure is nonischemic. The implantable cardioverter-defibrillator (ICD) is capable of preventing sudden death and decreasing total mortality in patients with nonischemic heart failure. However, a significant number of patients receiving ICD do not receive any kind of therapy during follow-up. Moreover, considering the situation in Brazil and several other countries, ICD cannot be implanted in all patients with nonischemic heart failure. Therefore, there is an urgent need to identify patients at an increased risk of sudden death because these would benefit more than patients at a lower risk, despite the presence of heart failure in both risk groups. In this study, the authors review the primary available methods for the stratification of the risk of sudden death in patients with nonischemic heart failure.

 Heart Failure / mortality Death, Sudden, Cardiac Defibrillators, Implantable Introduction

The prevalence and incidence of heart failure (HF) indicate that it is an important public health problem. Data from the city of São Paulo indicate high rates of hospitalization in the elderly population, in addition to high treatment costs and a mortality rate approaching 15%1. In 30%-40% patients with heart failure accompanied by a decreased ejection fraction (EF), the etiology of ventricular dysfunction is nonischemic2,3. Data from the I Brazilian Registry of Heart Failure (BREATHE registry) indicate that HF is nonischemic in 70% hospitalized patients (Graph 1)4. Nonischemic HF (NIHF) is characterized by the absence of major lesions on coronary angiography or by negative findings on imaging studies performed to assess ischemia. Among patients with NIHF, the cause of ventricular dysfunction-designated as idiopathic dilated cardiomyopathy-may be unknown; alternatively, it can be attributed to several causes, including hypertension, exposure to potentially toxic agents (chemotherapeutic drugs and alcohol), Chagas disease, myocarditis, infiltrative disease, peripartum cardiomyopathy, valvular heart disease, and genetic and autoimmune diseases.

Etiology of HF: BREATHE registry data. HF: heart failure; BREATHE: I Brazilian Registry of Heart Failure.

Sudden cardiac death (SD) is an unexpected natural death from cardiac causes, and it usually occurs within an hour of symptom onset5. Considering that advancements in the treatment of NIHF have brought about a significant decrease in mortality in recent decades, SD remains a significant problem, accounting for approximately 30% deaths6,7. The primary prevention of SD in patients with NIHF involves pharmacological treatment and the use of implantable cardioverter-defibrillators (ICD)8. Randomized clinical trials have demonstrated that the use of beta-blockers and spironolactone significantly decreased SD in this group of patients. The Sudden Cardiac Death in Heart Failure Trial (SCD-HeFT), which included patients with both ischemic and nonischemic HF of New York Heart Association (NYHA) functional class II-III, indicated that ICD decreased SD and total mortality in patients with NIHF9. Moreover, an analysis of all patients with implanted ICD revealed that 33.2% received some level of shock by the defibrillator, 22.4% received appropriate defibrillator shocks, and 10.7% received only inappropriate shocks10. Undoubtedly, the costs and potential complications related ICD implantation demand a better selection of patients who are at an increased risk of SD and would benefit the most from ICD implantation. For ischemic HF, in addition to EF, electrophysiological studies identified groups of patients at an increased risk of SD11, as opposed to NIHF, which still requires a better selection of patients12. Therefore, this study aimed to review the primary available options for the stratification of SD risk in patients with NIHF (Table 1).

Predictors of SD Risk In Patients with NIHF
Method Marker/Risk Comment
Clinical Evaluation
NYHA functional class NYHA class II → 64% deaths from SD Associated with different risks of SD
Class III → 59% deaths from SD
Syncope With syncope → 45% SD in 1 year In patients with advanced HF (NYHA class III and IV)
Without syncope → 12% SD in 1 year
Laboratory tests BNP, uric acid, and hemoglobin Included in risk prediction scores
LVEF → RR for major arrhythmic events was 2.28 for every 10% decrease in EF Major risk factor for SD
Validated in ICD cohorts and trials
ECG Duration of the QRS interval and late potentials QRS was not associated with risk of SD in NIHF.
Late potentials with conflicting results
Holter ECG
NSVT NSVT → RR of 3.2 for sudden death Independent marker in a meta-analysis with meta-regression
NSVT + LVEF < 30% → RR of 8.2 for events
HRV SDNN Studies with controversial results
TWA Altered TWA → RR of 2.99 for death or arrhythmia Independent marker in meta-analysis.
Studies with conflicting results
Cardiopulmonary exercise test Occurrence of periodic breathing → chi-square of 44.7 Independent marker in a study with ischemic and NIHF patients
123I-MIBG Altered result → HR of 4.79 for SD In a study of ischemic and NIHF patients
EPS Positive EPS → HR of 4.19 for ICD therapy In a study of patients with NIHF
Genetic Evaluation Genotype Arg389Gly of the β1-adrenergic receptor Mutations and polymorphisms associated with increased risk of SD
Cardiac MRI Fibrosis → HR of 3.2-5.4 for arrhythmic events Fibrosis increases risk of SD in patients with NIHF

SD: sudden death; HF: heart failure; NIHF: nonischemic heart failure; NYHA: New York Heart Association; ICD: cardioverter-defibrillator; LVEF: left ventricular ejection fraction; NSVT: nonsustained ventricular tachycardia; MIBG: metaiodobenzylguanidine; MRI: magnetic resonance imaging; TWA: T-wave alternans; ECG: electrocardiogram; HRV: heart rate variability; SD: sudden death; RR: relative risk; SDNN: standard deviation of normal-to-normal R-R intervals; EPS: electrophysiological study; BNP: basal natriuretric peptide; HR: hazard ratio.

 Clinical and laboratory evaluation

Routine clinical and laboratory evaluations provide information that can be used for the risk stratification of patients with NIHF. The functional class of patients with HF is related to distinct SD risks. Among patients with NYHA functional class II HF, SD is responsible for 64% deaths, whereas HF progression is responsible for 12% deaths. Among patients with NYHA functional class III HF, SD accounts for 59% deaths and HF progression accounts for 26% (Table 2). Among patients with NYHA functional class IV HF, HF progression accounts for 56% deaths and SD accounts for 33%13. Chagas disease, NYHA functional class III-IV HF, cardiomegaly on chest radiography, ventricular dysfunction on echocardiography, low voltage of the QRS complex on electrocardiography, nonsustained ventricular tachycardia on Holter electrocardiography, and male sex are risk factors for total mortality. However, a specific analysis of SD has not been performed14. Both Brazilian and international guidelines include functional classes among the criteria for ICD implantation for the primary prevention of NIHF12,15.

Functional class and type of death in patients with HF<xref ref-type="table-fn" rid="tfn01t02">(*)</xref>
NYHA Functional Class Sudden Death (%) Death from HF progression (%) Death from other causes (%)
II 64 12 24
III 59 26 15
IV 33 56 11

HF: heart failure; NYHA: New York Heart Association.

Adapted from reference 13

Syncope is considered to be an important risk factor for SD in patients with NIHF. In a cohort study involving 491 patients with severe HF, 51% of whom experienced NIHF, Middlekauff et al. demonstrated that the incidence of SD was 45% among patients with syncope compared with 12% for patients without a history of syncope16. A cohort study of patients with NIHF who received ICD indicated that the administration of appropriate therapies was similar for patients with syncope and those who experienced resuscitated SD17. Phang et al. followed 108 patients with NIHF and syncope and 71 patients with NIHF and sustained ventricular arrhythmia18 and observed that the incidence of ventricular arrhythmia, SD, and total mortality was similar in both groups. The occurrence of syncope is contemplated in the guidelines as an indication for ICD in patients with NIHF12,15. In addition to NYHA functional class and syncope, other clinical factors associated with an increased risk of arrhythmic events include the lack of use of beta-blockers and systolic blood pressure19,20.

Several studies have evaluated the prognostic value of routine screening procedures for the risk stratification of patients with NIHF. Blood tests, including those for hemoglobin, uric acid, and atrial natriuretic peptide (ANP), were identified in isolated studies as predictors of mortality and arrhythmic events20,21. However, considering that these results are still inconsistent, these tests cannot be considered in isolation for risk assessment. Using risk prediction models derived from the Seattle score on the basis of routine clinical and laboratory variables, Levy et al. classified the patients in the SCD-HeFT into 5 risk groups22. In group I patients, ICD significantly decreased the relative risk of SD by 88%, whereas in group V, the decrease was 24%. However, these differences were not significant. With regard to total mortality, the absolute decrease in risk after ICD implantation, in risk quintiles I to V, was 6.6%, 8.8%, 10.6%, 14%, and -4.9%, respectively. However, an analysis including only patients with NIHF was not performed.

 Left ventricular ejection fraction

Left ventricular EF (LVEF) can be evaluated using several available methods, the primary one being echocardiography. The decrease in EF is considered to be a major risk factor for SD and total mortality in patients with HF6,23. However, few studies till date have evaluated EF as a risk factor for SD specifically in patients with NIHF. The Marburg Cardiomyopathy Study (MACAS), a prospective cohort study involving 343 patients with NIHF, revealed that in patients with sinus rhythm, the relative risk for major arrhythmic events was 2.28 for every 10% decrease in EF19. In patients with atrial fibrillation, the relative risk was 4.5.

EF ≤ 35% was an inclusion criterion for the SCD-HeFT, a trial that serves as the basis for ICD indications in patients with NIHF9. Both Brazilian and international guidelines consider EF ≤ 35% as a criterion for ICD implantation as the primary preventive measure in patients with NIHF12,15. However, we should note that, although EF is considered a major risk factor for SD, several other events occur in patients with EF > 35%23. In addition, the relative risk of SD is significantly higher in patients with EF ≤ 35% than in those with EF > 35%. However, the absolute number of SD cases is higher among patients with more preserved EF, considering that these patients represent a much larger subgroup. Data from the Maastricht study indicate that, among patients for whom EF was measured before an SD episode, 52% had EF > 30% and 32% had EF > 40%24.

 Electrocardiography

The electrocardiogram (ECG) is a simple, readily available tool that provides useful information for the risk stratification of patients with NIHF. The rate of prolongation of the QRS interval in patients with HF ranges from 20% to 50%6. In specific cohort studies involving patients with NIHF, no correlation was found between the presence of bundle branch block and the increased risk of SD19,25. In the Defibrillators in Nonischemic Cardiomyopathy Treatment Evaluation (DEFINITE), a clinical trial involving patients with NIHF, ICD decreased the arrhythmic causes of SD without causing a significant decrease in total mortality, and no correlation was found between the QRS duration and total mortality26. In the SCD-HeFT, an increased benefit from ICD implantation was observed in patients with QRS > 120 ms. However, a specific analysis was not performed for the group with NIHF9. Another study indicated that fragmentation of the QRS complex (default RSR' and a duration of < 120 ms in two contiguous leads) was associated with a higher incidence of arrhythmic events in patients with NIHF27. However, this finding warrants further investigation. In addition, observational studies indicate conflicting results for the association between the measured QT interval and mortality from HF, and a specific analysis was not performed in patients with NIHF23. Furthermore, the dispersion in the QT interval (maximum difference between the QT intervals on a surface ECG) was evaluated in patients with NIHF. Although previous studies have indicated a positive correlation, recent studies have found no association between QT interval dispersion and an increase in major arrhythmic events28.

The high-resolution ECG (HRECG) is a useful tool for the amplification and processing of ECG signals. It evaluates the presence of late potentials at the end of the QRS complex and the duration of the QRS interval. Previous studies on the role of HRECG in the risk stratification of patients with NIHF have revealed conflicting results. The presence of late potentials using HRECG was identified in 27% patients with NIHF and was associated with an increased cardiovascular mortality and arrhythmic events29. However, in other studies, this method could not stratify the risk of arrhythmic events in patients with NIHF, despite similar variations in HRECG19,30.

 Holter electrocardiogram (ambulatory electrocardiographic monitoring)

Holter ECG is a widely available diagnostic tool used for risk assessment of patients with NIHF, taking into consideration the presence of nonsustained ventricular tachycardia (NSVT) and the analysis of measures of autonomic activity, including heart rate (HR) variability (HRV) and HR turbulence (HRT).

The incidence of NSVT (Figure 1) in patients with NIHF ranges from 30%-79%; therefore, its use in the risk stratification of arrhythmic events is considered controversial31. In a prospective study involving 179 patients, Iacovielo et al. revealed that the presence of NSVT was associated with a relative risk of 2.96 [95% confidence interval (CI), 1.17-7.49; p = 0.022] for the occurrence of major arrhythmic events32. In the MACAS, the presence of NSVT alone was not significantly correlated with an increased risk of arrhythmic events19. However, a combination of NSVT with EF < 30% was associated with an 8.2-fold increase in the risk of arrhythmic events (95% CI, 3.1-22.6; p = 0.0001). In this same cohort, a subsequent analysis was performed after taking into consideration the duration of and HR in NSVT. The incidence of arrhythmic events was 2% per year in patients without NSVT, 5% per year in patients with NSVT lasting from 5 to 9 beats, and 10% per year in patients with NSVT lasting > 10 beats (Table 3)33. With regard to HR in NSVT, there was no significant difference between groups with and without arrhythmic events. Meta-analysis data indicated that the presence of NSVT was associated with a 3.2-fold increase in the risk of SD (95% CI, 2.12-4.89; p < 0.05)34. In patients with NIHF who were implanted with ICD, the presence of NSVT was associated with a 7.8-times increase in the risk of appropriate therapy for ICD (95%CI, 1.8-33.7; p = 0.006)35. The presence of NSVT or ≥ 10 ventricular extrasystoles per hour on Holter ECG was an inclusion criterion in the DEFINITE26. A combined analysis of these results demonstrates that the detection of NSVT can indicate an increased risk of major ventricular arrhythmias. However, these results do not allow us to justify the clinical decision on ICD implantation on the basis of NSVT detection.

Example of nonsustained ventricular tachycardia (NSVT) on a Holter electrocardiogram. Incidence of major arrhythmic events and NSVT on 24-h Holter ECG<xref ref-type="table-fn" rid="tfn01t03">(*)</xref>
NSVT Major arrhythmic events (% per year)(†)
Absence of NSVT 2
NSVT of 5-9 beats 5
NSVT of ≥ 10 beats 10

NSVT: nonsustained ventricular tachycardia

ECG: electrocardiogram. Adapted from reference33 .

p < 0.05.

HRV is a measure of autonomic activity that takes into consideration the beat-to-beat variation in the R-R interval. HRV analysis can be performed as a function of time or frequency. In clinical practice, the most commonly used measure is the standard deviation of normal-to-normal R-R intervals (SDNN), which represents the standard deviation in R-R intervals. A decreased HRV is associated with an increased risk of death from HF progression, but not an increased risk of SD36,37. In the MACAS, no association was found between a decreased HRV and an increased risk of arrhythmic events19. Moreover, an analysis of the DEFINITE reveals that patients with preserved HRV exhibit a good prognosis and may not benefit from ICD implantation38.

HRT is a measure of autonomic activity that takes into account variations in R-R intervals that manifest after the occurrence of ventricular extrasystoles. During follow-up of patients from the MACAS, there was no significant correlation between HRT and arrhythmic events, similar to the finding observed in the study by Klingenheben, who evaluated a series of markers of autonomic activity19,39.

 T-wave alternans

T-wave alternans (TWA) can be defined as the beat-to-beat alternation in morphology, amplitude, and/or polarity of T-waves. Considering that these changes are measured in microvolts, specific processing programs are available for the detection of specific TWA. The T-Wave Alternans in Patients with Heart Failure (ALPHA) study prospectively monitored 476 patients with NYHA functional class II and III NIHF40. Of these, 44.8% had positive TWA, 34.6% had negative TWA, and 20.6% were undetermined. The primary outcome (cardiac death in addition to serious arrhythmias) occurred in 6.5% patients with altered TWA (positive or indeterminate) and 1.6% patients with normal TWA. According to multivariate analysis, the relative risk was 3.2 (95% CI, 1.12-9.20; p = 0.013). The negative predictive value for this outcome after 18 months was 97.3% (95% CI, 93.3-99.3). However, the positive predictive value was only 9% (95% CI, 5.9-13.0).

In contrast, in the MACAS study, TWA was not able to stratify patients with an increased risk of arrhythmic events19. The event rate was 13% in patients with positive TWA, 10% in those with negative TWA, and 24% in those with indeterminate TWA, without significant differences between groups. In a meta-analysis that evaluated major arrhythmic events combined with death from any cause, the relative risk for altered TWA (abnormal or indeterminate) was 2.99 (95% CI, 1.88- 4.75), with a negative predictive value of 96.2%41. In the assessment of TWA in the SCD-HeFT, no significant differences were observed in major arrhythmic events among patients with normal, altered, or undetermined TWA42. Therefore, these studies with conflicting results and the absence of clinical trials that addressed TWA as an inclusion criteria preclude TWA from being included in the guidelines as a criterion for the selection of patients eligible for ICD implantation.

 Cardiopulmonary exercise test

The cardiopulmonary exercise test is recommended for the evaluation and follow-up of patients with HF8. Meta-analysis data indicate that variables derived from cardiopulmonary exercise testing and oxygen consumption (VO2), slope of the ventilatory equivalent for CO2 (VE/VCO2 slope), and the occurrence of periodic breathing, in isolation, indicate an increased risk of combined events, including total mortality, cardiac death, heart transplantation, hospitalization, and the need for ventricular assistive devices43. A national database of patients using beta-blockers indicated that peak VO2 ≤ 10 ml/kg-1/min-1 indicates an increased risk of cardiovascular events, peak VO2 between 10 and 16 ml/kg-1/min-1 represents a moderate risk, and peak VO2 > 16 ml/kg-1/min-1 indicate a lower risk. In addition, a VE/VCO2 slope of > 34 was associated with an increased risk44. Patients with NIHF accounted for 68% of the sample. However, a stratified analysis on the etiology of HF was not performed.

Guazzi et al45 assessed the performance of the cardiopulmonary exercise test variables in relation to the risk of SD. Patients without complications exhibited a peak VO2 of 16.8 ± 4.5 ml/kg-1/min-1, a VE/VCO2 slope of 32.8 ± 6.4, and a 20.3% prevalence of periodic breathing. Patients who developed SD exhibited a peak VO2 of 13.58 ± 3.2 mL/kg/min, a VE/VCO2 slope of 41.5 ± 11.4, and a 100% prevalence of periodic breathing. According to multivariate analysis, the only variable associated with an increased risk of SD was the development of periodic breathing. In this study, patients with NIHF represented 37% of the sample (n = 156). However, a stratified analysis according to the etiology of HF was not performed. These findings warrant further investigations involving a larger number of patients that can analyze the etiology of HF.

 Myocardial scintigraphy with iodine-123-metaiodobenzylguanidine

Myocardial scintigraphy with iodine-123-metaiodobenzylguanidine (123I-MIBG) can evaluate the function of the sympathetic nervous system in patients with HF. Recent data indicate that a low late heart-to-mediastinum ratio and an increased washout rate of 123I-MIBG were associated with an increased incidence of cardiovascular events46. In a cohort study with 106 patients, 44% of whom had NIHF, patients with abnormal 123I-MIBG scintigraphy results exhibited a significantly higher risk of SD (hazard ratio, 4.79; 95% CI, 1.55-14.76; p = 0.006)47. In another study that monitored 116 patients with ICD, those with alterations in 123I-MIBG exhibited a higher rate of ICD therapy (52% versus 5%, p < 0.01)48. In both studies, no specific analysis was performed in patients with NIHF. Considering these promising findings, it is estimated that other prospective studies will be conducted with a larger number of patients, with the view to performing a stratified analysis of the etiology of HF, and will enable the inclusion of 123I- MIBG in the guidelines for the risk stratification of patients with NIHF.

 Electrophysiological study

In a group of patients with ischemic HF, an electrophysiological study (EPS) with programmed ventricular stimulation was able to identify patients at a higher risk of major arrhythmic events11. However, the results are controversial for patients with NIHF. Poll et al49 conducted EPS involving 20 patients with NIHF and observed the induction of ventricular tachyarrhythmia in 30% patients. Of these, 50% had ventricular tachyarrhythmia during follow-up. Among those with negative EPS, 36% experienced arrhythmias. In the 1990s, Brembilla-Perrot et al50 conducted EPS involving 92 patients and observed the induction of ventricular tachyarrhythmia in only 8%. The incidence of ventricular arrhythmias in this group was 50%; however, it was only 4% in the group with negative EPS findings. In another study involving 34 patients, Grimm et al51 induced ventricular tachyarrhythmia in 38%. The incidence of ventricular arrhythmias in this group was 30% compared with 24% in the group with negative EPS findings. Nonetheless, these studies involved a small number of patients, adopted heterogeneous methodologies, and were conducted before the widespread use of beta-blockers for HF treatment.

Recent studies have re-evaluated EPS conducted in these conditions. In a subanalysis of the DEFINITE EPS findings were positive in 14% patients, and 34% of these patients presented with ventricular arrhythmias52. Among patients with negative EPS findings, the incidence of ventricular arrhythmias was 12%. The positive and negative predictive values of EPS for determining the requirement of ICD therapy were 34% and 88%, respectively. Gatzoulis et al53 prospectively monitored 158 patients with NIHF undergoing EPS for the primary prevention of SD. EPS findings were positive (induction of ventricular tachycardia or ventricular fibrillation) in 44 patients (28%) and negative in 114 (72%). ICD implantation was performed in 41 patients from the positive EPS group and 28 patients from the negative EPS group. However, the total mortality during a follow-up of 46.9 months was not significantly different between patients with positive or negative EPS. In patients implanted with ICD, the rate of administration of therapies for ICD (e.g., shock or anti-tachycardia stimulation) was 73.2% for those with positive EPS and 17.9% for those with negative EPS (p = 0.001). Positive EPS was the only prognostic factor for the administration of ICD therapy (hazard ratio, 4.19; 95% CI, 1.467-11.994; p = 0.007). Considering the overall results of these studies, the guidelines do not recommend the routine performance of EPS for the risk stratification of patients with NIHF12,15. Therefore, future studies using a larger number of patients, optimal pharmacological therapies, and more uniform protocols for ventricular stimulation can better assess the role of EPS in this group of patients.

 Genetic evaluation

Several studies have evaluated the association between genetic mutations and the pathophysiology and prognosis of patients with NIHF, particularly those with familial diseases54. Among the best investigated conditions are mutations in the lamin A/C (LMNA) gene. Pasotti et al55 demonstrated that patients with NIHF carrying LMNA mutations have a high incidence of major arrhythmic events (40%-67%), and the risk factors included NYHA functional class, type of mutation, and practice of competitive physical activity. In the study by van Rijsingen et al56, the incidence of major arrhythmic events was 18%, and the risk factors included NSVT, EF, male sex, and type of mutation. Furthermore, mutations in the SCN5A sodium channel gene have been associated with an increased risk of arrhythmic events57. Mutations in the RBM20 gene, which is responsible for regulation of the splicing process in cardiac tissue, were identified in 2.8% patients from a cohort with NIHF and ICD and were not associated with an increased risk of ventricular arrhythmias58. Considering the prevalence and the important prognostic implications, the investigation of mutations in the LMNA gene may be considered in all patients with idiopathic NIHF, particularly when there is significant impairment in the conduction system59. In Brazil, this genetic evaluation is not yet available for routine clinical use.

Moreover, analysis of the presence of genetic polymorphisms has been evaluated as a tool for the risk stratification of patients with NIHF. In a cohort study, the presence of the Gly389 allele in the polymorphism of the β1-adrenergic receptor Arg389Gly was associated with a lower incidence of ventricular arrhythmias60. In addition, a national cohort study including patients with ICD identified a protective effect of the presence of the Gly389 allele61. However, a stratified analysis of patients with NIHF - which corresponded to 41% of the study group - was not performed. The AT1R-1166CC genotype of the polymorphism associated with the renin-angiotensin-aldosterone system was correlated with a two-fold increase in the requirement of ICD therapies in patients with CI62. In this same study, circulating levels of the microRNA miR-155 were associated with an increased risk of ICD therapies. In addition, 23% patients who received ICD therapy presented with NIHF. Therefore, the analysis of genetic polymorphisms is very promising, and future studies may lead to the identification of patients with genetic patterns associated with greater risk and patients who may benefit the most from ICD implantation.

 Cardiac magnetic resonance imaging

The presence of myocardial fibrosis is an important arrhythmogenic substrate in patients with NIHF6,63. The detection of myocardial fibrosis using serum markers of collagen metabolism or imaging methods could identify high-risk patients. Kanoupakis et al. demonstrated that patients with NIHF and changes in serum markers of collagen metabolism exhibited a higher rate of appropriate ICD therapies64. Cardiac magnetic resonance imaging (MRI) using the delayed enhancement technique is the primary imaging method used to detect and quantify the extent of myocardial fibrosis. Approximately 30% patients with NIHF exhibited myocardial fibrosis on MRI65 (Figure 2).

MRI of a patient with cardiac NIHF, 35% EF, and a mesocardiac area of fibrosis in the interventricular septum. MRI: magnetic resonance imaging; EF: ejection fraction.

Several studies have evaluated the relationship between the presence of fibrosis on MRI and the occurrence of major arrhythmic events in patients with NIHF. In a pioneering study, Nazarian et al66 evaluated 26 patients with NIHF subjected to EPS and MRI. The presence of fibrosis covering 26%-75% of the wall thickness was associated with a nine-fold increase in the risk of ventricular arrhythmia according to EPS. In a cohort study with 101 patients, Assomull et al67 revealed that fibrosis was an independent predictor of SD associated with ventricular tachycardia (hazard ratio, 5.2; 95% CI, 1.10-32.2; p = 0.04). In a study by Lehrke et al68 involving 184 patients, the presence of fibrosis was considered to be an independent predictor of the combined events of cardiac death, appropriate ICD therapy, and hospitalization (hazard ratio, 3.4; 95% CI, 1.26-9.00; p = 0.015). In this cohort, a fibrosis rate of > 4.4% of the left ventricular (LV) mass was associated with a worse prognosis, and the prognostic value of the presence of fibrosis was restricted to patients with EF < 30%. However, these findings were not confirmed in the study of Hombach et al69, who monitored 151 patients and found no association between the presence of fibrosis and the combined events of cardiac death and SD. MRI variables associated with the event were cardiac index, index of the end-diastolic volume of the right ventricle, and the presence of QRS > 110 ms and diabetes.

Gulati et al. recently published the results for the largest cohort of patients with NIHF examined on MRI.70 In this study, 472 patients were monitored, with a median follow up of 5.3 years. The primary outcome of total mortality occurred in 26.8% patients, and myocardial fibrosis occurred in 10.6% patients without fibrosis. After multivariate analysis with adjustment for EF and other prognostic factors, the presence of fibrosis represented a hazard ratio of 2.43 (95% CI, 1.50-3.92; p < 0.001), and the extent of fibrosis represented a hazard ratio of 1.11 (95% CI, 1.06-1.16; p < 0.001). Combined events of SD and aborted SD were observed in 29.6% patients with myocardial fibrosis and 7.0% patients without fibrosis. For this event, the presence of fibrosis represented a hazard ratio of 4.61 (95% CI, 2.75-7.74; p < 0.001), and the extent of fibrosis represented a hazard ratio of 1.10 (95% CI, 1.05-1.16; p < 0.001). These results, together with those from previous studies, indicate that MRI can be a useful technique for the risk stratification of patients with NIHF. The usefulness of MRI needs further confirmation through prospective multicenter studies designed specifically for this purpose.

 Conclusions

The risk stratification of SD among patients with NIHF remains an important clinical challenge. To make a decision regarding ICD implantation, the most important factors that should be considered are EF, NYHA functional class, and presence of syncope (Figure 3). Several noninvasive tests and invasive EPS have yielded controversial results. In addition, cardiac MRI has shown promising results and should be considered for the risk stratification of patients with NIHF. Prospective multicenter studies evaluating the association between different noninvasive and invasive methods may generate risk scores capable of identifying high-risk patients with SD and those who would benefit the most from ICD implantation with a greater accuracy.

Risk stratification of sudden death in patients with nonischemic heart failure EF: ejection fraction; EPS: electrophysiological study; MRI: magnetic resonance imaging; HRV: heart rate variability; TWA: T-wave alternans.

Author contributions

Conception and design of the research: Pimentel M, Rohde LE; Acquisition of data: Pimentel M; Writing of the manuscript and Critical revision of the manuscript for intellectual content: Pimentel M, Zimerman LI, Rohde LE.

Sources of Funding

There were no external funding sources for this study.

Study Association

This article is part of the thesis of Doctoral submitted by Maurício Pimentel, from Universidade Federal do Rio Grande do Sul.

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Differentiation of heart failure related to dilated cardiomyopathy and coronary artery disease using gadolinium-enhanced cardiovascular magnetic resonance. Circulation. 2003;108(1):54-9. McCrohon JA Moon JC Prasad SK McKenna WJ Lorenz CH Coats AJ et al Differentiation of heart failure related to dilated cardiomyopathy and coronary artery disease using gadolinium-enhanced cardiovascular magnetic resonance Circulation 2003 108 1 54 59 66. Nazarian S, Bluemke DA, Lardo AC, Zviman MM, Watkins SP, Dickfeld TL, et al. Magnetic resonance assessment of the substrate for inducible ventricular tachycardia in nonischemic cardiomyopathy. Circulation. 2005;112(18):2821-5. Nazarian S Bluemke DA Lardo AC Zviman MM Watkins SP Dickfeld TL et al Magnetic resonance assessment of the substrate for inducible ventricular tachycardia in nonischemic cardiomyopathy Circulation 2005 112 18 2821 2825 67. Assomull RG, Prasad SK, Lyne J, Smith G, Burman ED, Khan M, et al. Cardiovascular magnetic resonance, fibrosis, and prognosis in dilated cardiomyopathy. J Am Coll Cardiol. 2006;48(10):1977-85. Assomull RG Prasad SK Lyne J Smith G Burman ED Khan M et al Cardiovascular magnetic resonance, fibrosis, and prognosis in dilated cardiomyopathy J Am Coll Cardiol 2006 48 10 1977 1985 68. Lehrke S, Lossnitzer D, Schöb M, Steen H, Merten C, Kemmling H, et al. Use of cardiovascular magnetic resonance for risk stratification in chronic heart failure: prognostic value of late gadolinium enhancement in patients with non-ischaemic dilated cardiomyopathy. Heart. 2011;97(9):727-32. Lehrke S Lossnitzer D Schöb M Steen H Merten C Kemmling H et al Use of cardiovascular magnetic resonance for risk stratification in chronic heart failure: prognostic value of late gadolinium enhancement in patients with non-ischaemic dilated cardiomyopathy Heart 2011 97 9 727 732 69. Hombach V, Merkle N, Torzewski J, Kraus JM, Kunze M, Zimmermann O, et al. Electrocardiographic and cardiac magnetic resonance imaging parameters as predictors of a worse outcome in patients with idiopathic dilated cardiomyopathy. Eur Heart J. 2009;30(16):2011-8. Hombach V Merkle N Torzewski J Kraus JM Kunze M Zimmermann O et al Electrocardiographic and cardiac magnetic resonance imaging parameters as predictors of a worse outcome in patients with idiopathic dilated cardiomyopathy Eur Heart J 2009 30 16 2011 2018 70. Gulati A, Jabbour A, Ismail TF, Guha K, Khwaja J, Raza S, et al. Association of fibrosis with mortality and sudden cardiac death in patients with nonischemic dilated cardiomyopathy. JAMA. 2013;309(9):896-908. Erratum in JAMA. 2013;310(1):99. Gulati A Jabbour A Ismail TF Guha K Khwaja J Raza S et al Association of fibrosis with mortality and sudden cardiac death in patients with nonischemic dilated cardiomyopathy JAMA 2013 309 9 896 908 Erratum in JAMA. 2013;310(1):99 Estratificação do Risco de Morte Súbita na Insuficiência Cardíaca de Etiologia Não Isquêmica Pimentel Maurício 1 2 Zimerman Leandro Ioschpe 1 2 Rohde Luis Eduardo 1 2 Universidade Federal do Rio Grande do Sul Curso de Pós-graduação em Ciências Cardiovasculares Porto Alegre RS Brasil Curso de Pós-graduação em Ciências Cardiovasculares - Universidade Federal do Rio Grande do Sul, Porto Alegre, RS - Brasil Hospital de Clínicas de Porto Alegre Serviço de Cardiologia Porto Alegre RS Brasil Serviço de Cardiologia do Hospital de Clínicas de Porto Alegre, Porto Alegre, RS - Brasil Correspondência: Maurício Pimentel, Av. Luiz Manoel Gonzaga, 23 ap. 1002, Petrópolis. CEP 90470280, Porto Alegre, RS - Brasil. E-mail: mauriciopimentel@cardiol.br; mpimentelrs@gmail.com

Potencial conflito de interesse

Declaro não haver conflito de interesses pertinentes.

A insuficiência cardíaca é uma condição clínica de elevada prevalência, associada a morbidade e mortalidade significativas, apesar de importantes avanços em sua terapêutica. Em 30-40% dos casos, a etiologia da insuficiência cardíaca é definida como não isquêmica. O implante de cardioversor-desfibrilador (CDI) mostrou-se capaz de reduzir a morte súbita e a mortalidade total entre os pacientes com insuficiência cardíaca não isquêmica. Observa-se, porém, que número significativo de pacientes que recebem o CDI não apresenta nenhuma terapia ao longo de seu acompanhamento. Por outro lado, dentro da realidade brasileira e de vários outros países, o CDI não pode ser implantado em todos os pacientes com insuficiência cardíaca não isquêmica que teriam indicação pelas diretrizes. Não há dúvida sobre a necessidade de se identificar melhor quais pacientes têm maior risco de morte súbita e, assim, maior benefício com implante de CDI em relação àqueles de menor risco, apesar do diagnóstico de insuficiência cardíaca. Neste trabalho, os autores apresentam uma revisão sobre os principais métodos disponíveis para a estratificação do risco de morte súbita nos pacientes com insuficiência cardíaca de etiologia não isquêmica.

 Insuficiência Cardíaca / mortalidade Morte Súbita Cardíaca Desfibriladores Implantáveis Introdução

A prevalência e a incidência da insuficiência cardíaca (IC) indicam tratar-se de importante problema de saúde pública. Dados do município de São Paulo sugerem elevado número de internações, particularmente na população idosa, altos custos de tratamento e taxas de mortalidade que se aproximam de 15%1. Em 30-40% dos casos de insuficiência cardíaca com fração de ejeção (FE) reduzida, a etiologia da disfunção ventricular é definida como não isquêmica2,3. Dados do Registro BREATHE (I Registro Brasileiro de Insuficiência Cardíaca) indicam que, em 70% dos pacientes que são internados com IC, a etiologia é não isquêmica (Gráfico 1)4. A IC é considerada de etiologia não isquêmica (ICNI) na ausência de lesões significativas na angiografia coronariana ou com resultado negativo em método de imagem para investigação de isquemia. Entre os pacientes com ICNI, a causa da disfunção ventricular pode ser desconhecida, sendo chamada miocardiopatia dilatada idiopática, ou pode ser atribuída a uma séria de motivos, como hipertensão arterial, exposição a agentes potencialmente tóxicos (quimioterápicos, álcool), doença de Chagas, miocardites, doenças infiltrativas, miocardiopatia periparto, valvulopatias, doenças genéticas e autoimunes.

Etiologia da IC – dados do Registro BREATHE. BREATHE: I Registro Brasileiro de Insuficiência Cardíaca; IC: insuficiência cardíaca.

Morte súbita cardíaca (MS) é a morte natural inesperada por causas cardíacas, que ocorre geralmente em até uma hora do início dos sintomas5. Mesmo que avanços na terapêutica da ICNI tenham trazido redução significativa da mortalidade nas últimas décadas, a MS permanece como problema importante, sendo responsável por aproximadamente 30% dos óbitos6,7. A prevenção primária da MS nos pacientes com ICNI inclui tratamento farmacológico e o uso de cardioversor-desfibrilador implantável (CDI)8. Ensaios clínicos randomizados demonstraram que o emprego de betabloqueadores e espironolactona reduziu significativamente a MS nesse grupo de pacientes. O estudo SCD-HeFT (Sudden Cardiac Death in Heart Failure Trial), que incluiu pacientes com IC, tanto de etiologia isquêmica como não isquêmica, classe funcional II-III da NYHA (New York Heart Association), demonstrou que o CDI foi capaz de reduzir a MS e a mortalidade total nos pacientes com ICNI9. No seguimento desse estudo, analisando-se todos os pacientes que implantaram CDI, 33,2% receberam algum choque pelo dispositivo, 22,4% receberam choque apropriado e 10,7% receberam apenas choques inapropriados10. Considerando-se os custos e as potenciais complicações relacionadas ao implante do CDI, não há dúvida de que uma seleção mais adequada dos pacientes com maior risco de MS e que possam apresentar maior benefício com o implante do CDI ainda se faz necessária. Enquanto na IC de etiologia isquêmica, além da FE, o estudo eletrofisiológico é capaz de identificar o grupo de pacientes com maior risco de MS11, na ICNI ainda se busca melhor seleção dos pacientes12. O objetivo deste artigo é revisar as principais opções para estratificação do risco de MS em pacientes com ICNI (Tabela 1).

Preditores de risco de MS na ICNI
Método Marcador/risco Comentário
Avaliação clínica
Classe funcional NYHA Classe II da NYHA → 64% dos óbitos por MS Associada a diferentes riscos de MS
Classe III da NYHA → 59% dos óbitos por MS
Síncope Com síncope → 45% de MS em 1 ano Em pacientes com IC avançada (classes III e IV da NYHA)
Sem síncope → 12% de MS em 1 ano
Exames laboratoriais BNP, ácido úrico e hemoglobina Incluídos em escores de predição de risco
FEVE Redução de 10% → RR de 2,28 de eventos arrítmicos Principal fator de risco para MS
Validado em coortes e ensaios de CDI
Eletrocardiograma Duração do QRS e potenciais tardios QRS não foi associado a risco de MS na ICNI
Potenciais tardios com resultados conflitantes
Holter
TVNS TVNS → RR de 3,2 de morte súbita TVNS + FEVE <30% → RR de 8,2 de eventos Marcador independente em metanálise com metarregressão
Variabilidade da FC SDNN Estudos com resultados controversos
Microalternância onda T (MOT) MOT alterada → RR 2,99 de morte ou arrítmia Marcador independente em metanálise
Estudos com resultados conflitantes
Teste ergoespirométrico Presença de ventilação periódica → qui-quadrado de 44,7 Marcador independente em estudo de pacientes isquêmicos e com ICNI
Cintilografia com 123I-MIBG Resultado alterado → HR 4,79 para MS Em estudo de pacientes isquêmicos e com ICNI
EEF EEF positivo → HR 4,19 para terapia do CDI Em estudo de pacientes com ICNI
Avaliação genética Genótipo Arg389Gly do receptor β1-adrenérgico Algumas mutações e polimorfismos associados a maior risco de MS
RNM cardíaca Fibrose → HR 3,2-5,4 para eventos arrítmicos Fibrose aumenta risco de MS na ICNI

CDI: cardioversor-desfibrilador; IC: insuficiência cardíaca; ICNI: insuficiência cardíaca não isquêmica; MIBG: metaiodobenzilguanidina; MS: morte súbita; NYHA: New York Heart Association; RNM: ressonância nuclear magnética; TVNS: taquicardia ventricular não sustentada; FEVE: Fração de ejeção do ventrículo esquerdo; EEF: Estudo eletrofisiológico; BNP: peptídeo natriurético atrial; RR: risco relativo; SDNN: desvio-padrão da média dos intervalos R-R

 Avaliação clínica e laboratorial

A avaliação clínica e laboratorial de rotina já traz informações que podem ser utilizadas na estratificação de risco dos pacientes com ICNI. A classe funcional dos pacientes com IC está relacionada a diferentes riscos de MS. Entre os pacientes em classe funcional II da NYHA, a MS é responsável por 64% dos óbitos, e a progressão da IC, por 12%. Na classe funcional III, a MS determina 59% dos óbitos, e a progressão da IC, 26% (Tabela 2). Já na classe IV, a progressão da IC leva a 56% dos óbitos, e a MS, a 33%13. Na cardiopatia chagásica, classe funcional III-IV, cardiomegalia no RX de tórax, disfunção ventricular no ecocardiograma, complexos QRS de baixa voltagem no eletrocardiograma, taquicardia ventricular não sustentada no Holter e sexo masculino compõem o escore de risco para mortalidade total. Não foi realizada análise específica para MS14. Tanto a diretriz brasileira como as diretrizes internacionais incluem a classe funcional entre os critérios para indicação do CDI na prevenção primária de pacientes com ICNI12,15.

Classe funcional e tipo de morte em pacientes com IC<xref ref-type="table-fn" rid="tfn01t05">*</xref>
Classe funcional NYHA Morte súbita (%) Morte por progressão da IC (%) Morte por outras causas (%)
II 64 12 24
III 59 26 15
IV 33 56 11

IC: insuficiência cardíaca; NYHA: New York Heart Association.

Adaptada da referência 13.

A ocorrência de síncope é considerada importante fator de risco para a ocorrência de MS nos pacientes com ICNI. Em estudo de coorte com 491 pacientes com IC grave, sendo 51% ICNI, Middlekauff e cols. demonstraram que, entre os pacientes com síncope, a incidência de MS foi de 45%, comparada a 12% naqueles sem história de síncope16. Estudo de coorte de pacientes com ICNI, portadores de CDI, indicou que a ocorrência de terapias apropriadas nos pacientes com síncope é semelhante à daqueles com MS reanimada17. Phang e cols.18 acompanharam 108 pacientes com ICNI e síncope, e 71 pacientes com ICNI e arritmia ventricular sustentada. A incidência de arritmias ventriculares, MS e mortalidade total foi semelhante nos dois grupos. A presença de síncope é considerada nas diretrizes como indicação de CDI nos pacientes com ICNI12,15. Além da classe funcional e da síncope, outras variáveis clínicas associadas a maior risco de eventos arrítmicos são a ausência de uso de betabloqueador e a pressão sistólica19,20.

Vários estudos têm avaliado o valor prognóstico de exames de rotina da prática clínica para estratificação de risco de pacientes com ICNI. Exames como hemoglobina, ácido úrico e peptídeo natriurético atrial aparecem em estudos isolados como preditores de mortalidade e eventos arrítmicos20,21. Porém, como os resultados ainda não são consistentes, não há como considerar isoladamente esses exames na avaliação de risco. Empregando modelo de predição de risco derivado do escore de Seattle, baseado em variáveis clínicas e laboratoriais rotineiras, Levy e cols.22 dividiram os pacientes do estudo SCD-HeFT em cinco grupos de risco. Enquanto, no grupo I, o CDI reduziu significativamente o risco relativo de MS em 88%, no grupo V a redução foi de 24%, não significativa. Em relação à mortalidade total, as reduções absolutas do risco com CDI foram de 6,6%, 8,8%, 10,6%, 14% e -4,9%, respectivamente, nos quintis de risco I a V. Não foi apresentada análise incluindo exclusivamente os pacientes com ICNI.

 Fração de ejeção do ventrículo esquerdo

A FE do ventrículo esquerdo pode ser mensurada por uma série de métodos largamente disponíveis, sendo o principal deles o ecocardiograma. A redução da FE é considerada o principal fator de risco para MS e mortalidade total em pacientes com IC6,23. Poucos trabalhos, porém, avaliaram a FE como fator de risco para MS especificamente nos pacientes com ICNI. O estudo MACAS (Marburg Cardiomyopathy Study), coorte prospectiva com 343 pacientes com ICNI, demonstrou que, em pacientes com ritmo sinusal, para cada 10% de redução da FE houve risco relativo de 2,28 para eventos arrítmicos maiores19. Em pacientes com fibrilação atrial, o risco relativo foi de 4,5.

FE ≤ 35% foi critério de inclusão no SCD-HeFT, ensaio clínico que fundamenta a indicação do CDI na ICNI9. A diretriz brasileira e as diretrizes internacionais colocam FE ≤ 35% como critério para indicação de CDI como prevenção primária em pacientes com ICNI12,15. É importante ressaltar que, apesar de a FE ser considerada o principal fator de risco para MS, número significativo de eventos ocorre em pacientes com FE > 35%23. Embora o risco relativo de MS seja significativamente maior em pacientes com FE ≤ 35%, o número absoluto de casos de MS é maior em pacientes com FE mais preservada, já que estes constituem um subgrupo muito maior. Dados do estudo de Maastricht mostram que, em pacientes que tinham FE aferida antes de episódio de MS, 52% tinham FE > 30% e 32% FE > 40%24.

 Eletrocardiograma

O eletrocardiograma (ECG) é um método simples, facilmente disponível, com informações que podem ser utilizadas na estratificação de risco de pacientes com ICNI. A prevalência de prolongamento do intervalo QRS nos pacientes com IC varia de 20-50% 6. Nos estudos de coorte específicos de pacientes com ICNI, não foi demonstrada relação entre presença de bloqueio de ramo e aumento do risco de MS19,25. No estudo DEFINITE (Defibrillators in Nonischemic Cardiomyopathy Treatment Evaluation), ensaio clínico de pacientes com ICNI em que o CDI reduziu a MS de causa arrítmica sem redução significativa da mortalidade total, não houve relação entre duração do QRS e mortalidade total26. No SCD-HeFT houve maior benefício com implante do CDI em pacientes com QRS ≥ 120 ms, mas não foi realizada análise específica para o grupo com ICNI9. A presença de fragmentação do complexo QRS (padrão RSR', duração < 120 ms em duas derivações contíguas) foi associada a maior ocorrência de eventos arrítmicos em pacientes com ICNI em um trabalho27. Esse achado ainda necessita de confirmação em estudos posteriores. Estudos observacionais mostram resultados controversos sobre a associação entre medida do intervalo QT e mortalidade de pacientes com IC, e não há análise específica para pacientes com ICNI23. A dispersão do intervalo QT (diferença máxima entre os intervalos QT no ECG de superfície) foi avaliada nos pacientes com ICNI. Embora estudos iniciais tivessem mostrado associação positiva, trabalhos recentes não encontraram associação entre a dispersão do intervalo QT e o aumento de eventos arrítmicos graves28.

O eletrocardiograma de alta resolução (ECGAR) é um método de amplificação e processamento dos sinais eletrocardiográficos que permite análise da presença de potenciais tardios ao final do complexo QRS e da duração do intervalo QRS. Os trabalhos que avaliaram o papel do ECGAR na estratificação de risco de pacientes com ICNI apresentam resultados conflitantes. Presença de potenciais tardios no ECGAR foi identificada em 27% dos pacientes com ICNI, estando associada a aumento da mortalidade cardiovascular e de eventos arrítmicos29. Em outros trabalhos, porém, apesar da semelhante prevalência de alteração no ECGAR, esse método não se mostrou capaz de estratificar o risco de eventos arrítmicos nos pacientes com ICNI19,30.

 Holter (monitoração eletrocardiográfica ambulatorial)

O Holter é um método diagnóstico facilmente disponível, e pode ser considerado na avaliação de risco de pacientes com ICNI levando em consideração a presença de taquicardia ventricular não sustentada (TVNS) e a análise de medidas da atividade autonômica, como a variabilidade da frequência cardíaca (VFC) e a turbulência da frequência cardíaca (TFC).

A incidência de TVNS (Figura 1) em pacientes com ICNI varia de 30-79%, e sua utilização na estratificação de risco de eventos arrítmicos é considerada controversa31. Iacovielo e cols.32, em estudo prospectivo de 179 pacientes, demonstraram que a presença de TVNS foi associada a risco relativo de 2,96 (IC95%: 1,17-7,49; p = 0,022) para ocorrência de eventos arrítmicos graves. No estudo MACAS, a presença de TVNS isoladamente não foi associada de modo significativo a maior risco de eventos arrítmicos19. Já a combinação da presença de TVNS com FE < 30% foi associada a aumento de 8,2 vezes no risco de eventos arrítmicos (IC 95%: 3,1-22,6; p = 0,0001). Nessa mesma coorte foi realizada análise subsequente levando-se em consideração a duração e a FC da TVNS. A incidência de eventos arrítmicos foi de 2% ao ano nos pacientes sem TVNS, 5% ao ano nos pacientes com TVNS com duração de 5-9 batimentos e 10% ao ano nos pacientes com TVNS com duração ≥ 10 batimentos (Tabela 3)33. Com relação à FC da TVNS, não houve diferença significativa entre os grupos com e sem eventos arrítmicos. Dados de metanálise indicam que a presença de TVNS foi associada a aumento de 3,2 vezes no risco de MS (IC 95%: 2,12-4,89; p < 0,05)34. Em pacientes com ICNI portadores de CDI, presença de TVNS foi associada a aumento de 7,8 vezes no risco de terapias apropriadas pelo CDI (IC 95%: 1,8-33,7; p = 0,006)35. Presença de TVNS ou 10 ou mais extrassístoles ventriculares por hora no Holter foi critério de inclusão no estudo DEFINITE, já descrito26. A análise conjunta dos resultados dos estudos indica que a presença de TVNS pode indicar maior risco de arritmias ventriculares graves. No entanto, os resultados dos estudos ainda não permitem que se possa atribuir à presença de TVNS no Holter valor suficiente para a tomada de decisão clínica em relação ao implante ou não de CDI.

Exemplo de taquicardia ventricular não sustentada em Holter. Incidência de eventos arrítmicos maiores e TVNS em Holter de 24 h<xref ref-type="table-fn" rid="tfn01t06">*</xref>
TVNS Eventos arrítmicos maiores (%/ano)**
Ausência de TVNS 2
TVNS de 5-9 batimentos 5
TVNS ≥ 10 batimentos 10

TVNS: taquicardia ventricular não sustentada.

Adaptada da referência 33.

p < 0,05.

A VFC é uma medida da atividade autonômica que leva em consideração a variação, batimento a batimento, do intervalo R-R. A análise da VFC pode ser realizada no domínio do tempo ou da frequência, sendo que a medida mais comumente utilizada na prática clínica é o SDNN, que representa o desvio-padrão da média dos intervalos R-R. A redução da VFC foi associada a maior risco de morte por progressão da IC, mas não a maior risco de MS36,37. No estudo MACAS, não houve associação entre redução da VFC e aumento do risco de eventos arrítmicos19. Por outro lado, análise do estudo DEFINITE aponta que pacientes com VFC preservada apresentam bom prognóstico e poderiam não se beneficiar do implante de CDI38.

A TFC é uma medida da atividade autonômica que leva em consideração variações no intervalo R-R que ocorrem após a presença de extrassístole ventricular. No seguimento de pacientes do estudo MACAS, não houve associação significativa entre TFC e eventos arrítmicos, assim como no estudo de Klingenheben, que avaliou uma série de marcadores de atividade autonômica19,39.

 Microalternância de onda T

A microalternância de onda T (MOT) pode ser definida como alterações batimento a batimento na morfologia, amplitude e/ou polaridade da onda T. Como essas alterações ocorrem em microvolts, existem programas de processamento específicos para detecção de MOT. O estudo ALPHA (T-Wave Alternans in Patients with Heart Failure) acompanhou prospectivamente 476 pacientes com ICNI classe funcional II-III40. Destes, 44,8% apresentaram MOT positiva, 34,6% negativa e 20,6% indeterminada. O desfecho primário (morte cardíaca + arritmias graves) ocorreu em 6,5% dos pacientes com MOT alterada (positiva ou indeterminada) e em 1,6% daqueles com MOT normal. Na análise multivariada, o risco relativo foi de 3,2 (IC95%: 1,12-9,2; p = 0,013). O valor preditivo negativo para esse desfecho em 18 meses foi de 97,3% (IC95%: 93,3-99,3), porém o valor preditivo positivo foi de 9% (IC95%: 5,9-13).

No estudo MACAS, por outro lado, a MOT não foi capaz de estratificar os pacientes com maior risco de eventos arrítmicos19. A taxa de eventos foi de 13% nos pacientes com MOT positiva, 10% com MOT negativa e 24% com MOT indeterminada, sem diferença estatisticamente significativa. Em metanálise que considerou o desfecho combinado evento arrítmico grave ou morte por qualquer causa, o risco relativo para MOT alterada (anormal ou indeterminada) foi de 2,99 (IC95%: 1,88-4,75), com valor preditivo negativo de 96,2%41. No estudo de MOT dentro do ensaio clínico SCD-HeFT, não houve diferença significativa de eventos arrítmicos graves entre pacientes com MOT normal, alterada ou indeterminada42. Assim, estudos com resultados conflitantes e a ausência de ensaio clínico que tenha considerado a MOT como critério de inclusão fazem com que a MOT não seja considerada nas diretrizes como critério para seleção de pacientes candidatos a implante de CDI.

 Teste ergoespirométrico

O teste ergoespirométrico (teste cardiopulmonar) é recomendado para avaliação e seguimento de pacientes com IC8. Dados de metanálise indicam que variáveis derivadas do teste ergoespirométrico, como consumo de oxigênio (VO2), inclinação do equivalente ventilatório de CO2 (VE/VCO2 slope) e presença de ventilação periódica, indicam de modo independente aumento do risco de eventos combinados, incluindo mortalidade total, mortalidade cardíaca, transplante cardíaco, hospitalização e necessidade de dispositivo de assistência ventricular43. Dados nacionais de pacientes em uso de betabloqueador mostraram que VO2 de pico ≤ 10 ml/kg-1/min-1 indica alto risco de eventos cardiovasculares, VO2 entre 10-16 ml/kg-1/min-1 indica risco moderado, e VO2 >16 ml/kg-1/min-1 indica menor risco. Inclinação VE/VCO2 > 34 também foi associada a maior risco44. Pacientes com ICNI correspondiam a 68% da amostra. Não foi realizada análise estratificada quanto à etiologia da IC.

Guazzi e cols.45 avaliaram o desempenho das variáveis do teste ergoespirométrico com relação ao risco de MS. Os pacientes que evoluíram sem eventos apresentavam VO2 de pico de 16,8 ± 4,5 ml/kg-1/min-1, inclinação VE/VCO2 de 32,8 ± 6,4 e prevalência de ventilação periódica de 20,3%. Os pacientes que evoluíram com MS apresentavam VO2 de pico de 13,58 ± 3,2 ml/kg-1/min-1, inclinação VE/VCO2 de 41,5 ± 11,4 e prevalência de ventilação periódica de 100%. Em análise multivariada, a única variável associada a maior risco de MSC foi a presença de ventilação periódica. Nesse trabalho, pacientes com ICNI constituíram 37% da amostra (n = 156), não tendo sido realizada análise estratificada quanto à etiologia da IC. Esses achados necessitam de confirmação em estudos prospectivos envolvendo maior número de pacientes, preferencialmente possibilitando análise com relação à etiologia da IC.

 Cintilografia miocárdica com 123I-MIBG

A cintilografia miocárdica com iodo-123-metaiodobenzilguanidina (123I-MIBG) pode avaliar a função do sistema nervoso simpático em pacientes com IC. Dados recentes indicam que baixa relação 123I-MIBG coração/mediastino tardia e taxa de washout aumentada foram associadas a maior incidência de eventos cardiovasculares46. Em estudo de coorte com 106 pacientes, sendo 44% com ICNI, pacientes com cintilografia com 123I-MIBG anormal tiveram risco de MS significativamente maior (hazard ratio 4,79, IC95% 1,55-14,76; p = 0,006)47. Em outro trabalho, que acompanhou 116 pacientes portadores de CDI, aqueles com alterações na cintilografia com 123I-MIBG apresentaram maior taxa de terapias do CDI (52% versus 5%, p < 0,01)48. Em ambos os trabalhos, não foi realizada análise específica para pacientes com ICNI. Considerando-se os achados promissores desses e de outros trabalhos, estima-se que venham a ser realizados estudos prospectivos com maior número de pacientes, com possibilidade de análise estratificada quanto à etiologia da IC, que possibilitem a inclusão da cintilografia com 123I-MIBG nas diretrizes para estratificação de risco dos pacientes com ICNI.

 Estudo eletrofisiológico

No grupo de pacientes com IC de etiologia isquêmica, o estudo eletrofisiológico (EEF) com estimulação ventricular programada é capaz de identificar pacientes com maior risco de eventos arrítmicos graves11. Porém, entre pacientes com ICNI, os resultados dos trabalhos são controversos. Poll e cols.49 realizaram EEF em 20 pacientes com ICNI, com indução de taquiarritmia ventricular em 30% dos casos. Destes, 50% apresentaram taquiarritmia ventricular durante o seguimento. Entre aqueles com EEF negativo, 36% apresentaram arritmia. Na década de 1990, Brembilla-Perrot e cols.50 realizaram EEF em 92 pacientes, com indução de taquiarritmia ventricular em 8%. A incidência de arritmia ventricular nesse grupo foi de 50%, enquanto no grupo com EEF negativo foi de 4%. Grimm e cols.51, em estudo com 34 pacientes, induziram taquiarritmia ventricular em 38% dos casos. A incidência de arritmia ventricular nesse grupo foi de 30% comparada a 24% no grupo com EEF negativo. Esses estudos envolveram número pequeno de pacientes, apresentaram metodologia heterogênea e foram realizados antes do largo emprego dos betabloqueadores no tratamento da IC.

Estudos recentes têm novamente avaliado o desempenho do EEF nesse cenário. Em subanálise do estudo DEFINITE, o EEF foi positivo em 14% dos pacientes e, destes, 34% apresentaram arritmia ventricular52. Entre aqueles com EEF negativo, a incidência de arritmia ventricular foi de 12%. O valor preditivo positivo do EEF foi de 34%, e o valor preditivo negativo foi de 88% para a ocorrência de terapias do CDI. Gatzoulis e cols.53 acompanharam prospectivamente 158 pacientes com ICNI submetidos à realização de EEF tendo em vista a prevenção primária de MS. O EEF foi considerado positivo (indução de taquicardia ventricular ou fibrilação ventricular) em 44 pacientes (28%) e negativo em 114 (72%). Implante de CDI foi realizado em 41 pacientes do grupo EEF positivo e em 28 do grupo EEF negativo. A mortalidade total ao longo de 46,9 meses de acompanhamento não foi estatisticamente diferente entre os pacientes com EEF positivo ou negativo. Entre os pacientes que receberam CDI, a taxa de ocorrência de terapias pelo CDI (choque ou estimulação antitaquicardia) foi de 73,2% no grupo com EEF positivo e de 17,9% no grupo com EEF negativo (p = 0,001). EEF positivo foi o único fator prognóstico para ocorrência de terapia pelo CDI (hazard ratio 4,19, IC95% 1,467-11,994; p = 0,007). Considerando-se o conjunto dos resultados dos estudos, as diretrizes não recomendam a realização de EEF como rotina para estratificação de risco dos pacientes com ICNI12,15. Estudos futuros com maior número de pacientes sob terapia farmacológica ótima e com protocolos de estimulação ventricular uniformes poderão definir melhor o papel do EEF nesse grupo de pacientes.

 Avaliação genética

Há vários estudos avaliando a associação entre mutações genéticas com a fisiopatologia e o prognóstico de pacientes com ICNI, particularmente naqueles com doença familiar54. Entre as condições mais bem investigadas estão as mutações do gene da lamina A/C (LMNA). Pasotti e cols.55 demonstraram que pacientes com ICNI portadores de mutações LMNA apresentam alta incidência de eventos arrítmicos graves (40-67%), tendo como fatores de risco classe funcional da NYHA, tipo de mutação e prática de atividade física competitiva. Em estudo de van Rijsingen e cols.56, a incidência de eventos arrítmicos graves foi de 18%, tendo como fatores de risco TVNS, FE, sexo masculino e o tipo de mutação. Mutações no gene dos canais de sódio SCN5A foram igualmente associadas a maior risco de eventos arrítmicos57. Mutações no gene RBM20, responsável por regulação de processo de splicing em tecido cardíaco, foram identificadas em 2,8% dos pacientes de uma coorte com ICNI e CDI, não estando associadas a maior risco de arritmias ventriculares58. Considerando-se a prevalência e a importante implicação prognóstica, a pesquisa de mutações LMNA pode ser considerada em todos os pacientes com ICNI idiopática, especialmente quando houver comprometimento significativo do sistema de condução59. No Brasil, não há disponibilidade dessa avaliação genética para uso clínico rotineiro.

A análise da presença de polimorfismos genéticos também vem sendo avaliada como ferramenta para estratificação de risco de pacientes com ICNI. Em estudo de coorte, a presença do alelo Gly389 no polimorfismo do receptor β1-adrenérgico Arg389Gly foi associada a menor ocorrência de arritmias ventriculares60. Estudo de coorte nacional, incluindo pacientes com CDI, também identificou efeito protetor da presença do alelo Gly38961. Não foi realizada análise estratificada para pacientes com ICNI, que correspondiam a 41% do grupo. O genótipo AT1R-1166CC do polimorfismo associado ao sistema renina-angiotensina-aldosterona foi associado a risco duas vezes maior de terapias do CDI em pacientes com IC62. Nesse mesmo trabalho, níveis circulantes de micro-RNA miR-155 também foram associados a maior risco de terapias do CDI. Pacientes com ICNI corresponderam a 23% dos pacientes que receberam terapia do CDI. A análise de polimorfismos genéticos é uma área promissora. Estudos futuros poderão levar à identificação de pacientes com padrão genético de maior risco e que possam apresentar maior benefício com o implante de CDI.

 Ressonância nuclear magnética cardíaca

A presença de fibrose miocárdica constitui importante substrato arritmogênico nos pacientes com ICNI6,63. A detecção da presença de fibrose miocárdica através de marcadores séricos do metabolismo do colágeno ou métodos de imagem poderia identificar pacientes de maior risco. Kanoupakis e cols.64 demonstraram que pacientes com ICNI e alteração em marcadores séricos do metabolismo do colágeno apresentaram maior taxa de terapias apropriadas do CDI. A ressonância nuclear magnética cardíaca (RNM), pela técnica do realce tardio, é o principal método de imagem utilizado para detectar a presença e quantificar a extensão da fibrose miocárdica. Aproximadamente 30% dos pacientes com ICNI apresentam fibrose miocárdica na RNM65 (Figura 2).

RNM cardíaca de paciente com ICNI, FE 35%, mostrando área de fibrose mesocárdica no septo interventricular.

Vários estudos avaliaram a relação entre a presença de fibrose na RNM e a ocorrência de eventos arrítmicos graves em pacientes com ICNI. Em estudo pioneiro, Nazarian e cols.66 avaliaram 26 pacientes com ICNI submetidos à realização de EEF e RNM. A presença de fibrose envolvendo 26-75% da espessura parietal foi associada a aumento de nove vezes no risco de indução de arritmia ventricular no EEF. Em estudo de coorte com 101 pacientes, Assomull e cols.67 evidenciaram que a presença de fibrose foi preditor independente para a ocorrência do desfecho combinado MS ou taquicardia ventricular (hazard ratio 5,2 IC95% 1,1-32,2; p = 0,04). No estudo de Lehrke e cols.68, que acompanhou 184 pacientes, a presença de fibrose foi considerada preditor independente para o desfecho combinado morte cardíaca, terapia apropriada do CDI e hospitalização (hazard ratio 3,4 IC95% 1,26-9; p = 0,015). Nessa coorte, extensão da fibrose >4,4% da massa do VE foi associada a pior prognóstico, e o valor prognóstico da presença de fibrose foi restrito aos pacientes com FE < 30%. Esses achados não foram confirmados no trabalho de Hombach e cols.69, que não evidenciaram associação entre a presença de fibrose e o desfecho combinado morte cardíaca ou MS, no acompanhamento de 151 pacientes. As variáveis derivadas da RNM associadas ao desfecho foram índice cardíaco e índice do volume diastólico final do ventrículo direito, além da presença de QRS >110 ms e diabetes.

Gulati e cols.70 publicaram recentemente os resultados da maior coorte de pacientes com ICNI submetidos a RNM. Foram acompanhados 472 pacientes com mediana de seguimento de 5,3 anos. O desfecho primário mortalidade total ocorreu em 26,8% dos pacientes com fibrose miocárdica e em 10,6% dos pacientes sem fibrose. Após análise multivariada com ajuste para FE e outros fatores prognósticos, a presença de fibrose apresentou hazard ratio de 2,43 (IC95% 1,50-3,92; p < 0,001), e a extensão da fibrose, hazard ratio de 1,11 (IC95% 1,06-1,16; p < 0,001). O desfecho combinado MS e MS abortada ocorreu em 29,6% dos pacientes com fibrose miocárdica e em 7,0% dos pacientes sem fibrose. Para esse desfecho, a presença de fibrose apresentou hazard ratio de 4,61 (IC95% 2,75-7,74; p < 0,001), e a extensão da fibrose hazard ratio foi de 1,10 (IC95% 1,05-1,16; p < 0,001). Esses resultados, assim como os dos estudos anteriores, indicam que a RNM pode ser um método útil na estratificação de risco de pacientes com ICNI. A utilidade da RNM necessita de confirmação em estudos prospectivos multicêntricos, delineados especificamente para essa questão.

 Conclusão

A estratificação do risco de MS entre os pacientes com ICNI permanece como importante desafio clínico. Tendo em vista a tomada de decisão sobre implante ou não de CDI, os aspectos mais bem estabelecidos no momento e que devem ser considerados são fração de ejeção, classe funcional e presença de síncope (Figura 3). Vários testes não invasivos e o estudo eletrofisiológico invasivo apresentam resultados ainda controversos. A RNM cardíaca vem apresentando resultados promissores e poderá vir a ser considerada na estratificação de risco da ICNI. Estudos prospectivos multicêntricos, avaliando a associação de diferentes métodos não invasivos e invasivos, poderão gerar escores de risco capazes de identificar mais adequadamente os pacientes de maior risco MS e, assim, com maior possibilidade de benefício com implante de CDI.

Estratificação de risco de morte súbita na insuficiência cardíaca não isquêmica. EEF: estudo eletrofisiológico; FE: fração de ejeção do ventrículo esquerdo; MOT: microalternância de onda T; RNM: ressonância nuclear magnética; VFC: variabilidade da frequência cardíaca.

Contribuição dos autores

Concepção e desenho da pesquisa: Pimentel M, Rohde LE; Obtenção de dados: Pimentel M; Redação do manuscrito e Revisão crítica do manuscrito quanto ao conteúdo intelectual importante: Pimentel M, Zimerman LI, Rohde LE.

Fontes de financiamento

O presente estudo não teve fontes de financiamento externas.

Vinculação acadêmica

Este artigo é parte de tese de Doutorado de Maurício Pimentel pela Universidade Federal do Rio Grande do Sul.