Sex Differences in Sudden Cardiac Death During Long-Term Follow-up in Patients With Chronic Heart Failure　― A Report From the CHART-2 Study ―

Abstract

Background: Although sudden cardiac death (SCD) generally occurs more frequently in men than in women, there are limited data on sex differences in SCD in patients with chronic heart failure (HF) across a range of left ventricular ejection fraction (LVEF).

Methods and Results: We examined sex differences in SCD incidence, timing, and risk factors in 4,683 patients with chronic HF (3,186 men, 1,497 women) from a multicenter prospective observational cohort study (CHART-2). Over a median follow-up of 8.8 years after study enrollment, there were 215 SCDs (160 in men, 55 in women). The SCD incidence rates in men and women were 6.1 and 4.6 per 1,000 person-years, respectively (P=0.088). Among women, more than half the SCDs occurred in the first 5 years of follow-up. Beyond 5 years, the SCD incidence rate was significantly lower in women than in men (3.6 vs. 5.9 per 1,000 person-years, respectively; P=0.044). After adjusting for confounders, age, increased B-type natriuretic peptide, and LVEF <50% were common prognostic factors. After 5 years of follow-up, left ventricular (LV) enlargement was a risk factor for SCD in both sexes.

Conclusions: These results indicate that there are sex differences in SCD, especially beyond 5 years of follow-up, with a lower prevalence in women. LV enlargement is a common long-term prognostic factor in both sexes, suggesting the importance of preventing LV remodeling in HF management.

Sudden cardiac death (SCD) is an unexpected death from a cardiac cause within a short period, generally ≤1 h, from the onset of symptoms. Patients with heart failure (HF) are classified according to left ventricular ejection fraction (LVEF) as HF with reduced ejection fraction (HFrEF), HF with midrange ejection fraction, and HF with preserved ejection fraction (HFpEF), but all are at high risk of SCD.^1–5 The annual incidence estimates in the US range from under 200,000 to 500,000, indicating the magnitude of SCD.⁶ Therefore, the clinical management and prevention of SCD are crucial for improving the prognosis of patients with HF. In general, at any age, women have a lower incidence of SCD than men, even after adjusting for risk factors for coronary artery disease (CAD).⁷ An epidemiological study reported that the incidence of SCD is much higher in men than in women, reflecting sex differences in the incidence of CAD.⁸ However, limited data exist on sex differences in the incidence, timing, and risk factors for SCD over long-term follow-up in HF patients.^9–12

The Chronic Heart Failure Analysis and Registry in the Tohoku District-2 (CHART-2) study is a prospective observational multicenter cohort study.¹³ Patients with symptomatic HF, structural cardiac disorder but without HF, or CAD were consecutively enrolled from October 2006 to March 2010. The CHART-2 study has provided real-world evidence and recently evaluated 10-year survival and hospitalization rates across all HF stages.

The aim of the present long-term follow-up study was to examine sex differences in the incidence and timing of SCD in chronic HF patients across a broad spectrum of LVEF using data from the CHART-2 study.¹³ A secondary objective of this study was to examine sex differences in the risk factors for SCD in HF.

Methods

Study Setting

The details of the CHART-2 study have been reported previously,^13–16 and the study is registered with ClinicalTrials.gov (ID: NCT00418041). Briefly, we prospectively enrolled patients aged ≥20 years with either significant CAD or HF Stages B, C, or D as defined by the American College of Cardiology (ACC)/American Heart Association (AHA) guidelines.¹⁷ Study enrollment was started in October 2006 and ended in March 2010. In all, 10,219 patients were enrolled in the CHART-2 study from Tohoku University Hospital and 23 affiliated hospitals. Of these patients, 4,683 with Stage C (3,186 men, 1,497 women) were included in final analysis in the present study (Figure 1). We compared baseline characteristics, clinical outcomes, and prognostic factors according to sex. Because in a previous study we observed sex differences in clinical outcomes for 5 years,¹⁵ we extended the observation period in the present study to 10 years and divided it into 2 periods: ≤5 and >5 years.

Figure 1.

Flowchart of patient selection. CHART-2, Chronic Heart Failure Analysis and Registry in the Tohoku District-2; LVEF, left ventricular ejection fraction.

To adjudicate SCD events, we reviewed medical records, discharge summaries, and autopsy reports or conducted telephone interviews with family members. We also required a consensus among 3 investigators from the CHART-2 study regarding the classification of SCD events. If the 3 investigators could not reach an agreement, the event committee was responsible for adjudicating the events. The 7 categories of mode of death categories were as follows: SCD; HF death; myocardial infarction death; stroke death; other cardiovascular death; non-cardiovascular death; and unknown death.

In this study, SCD was defined as an unexpected death, presumed to be of cardiac origin, occurring in a previously stable patient. It was further classified as either witnessed (if loss of consciousness or a change in symptoms was observed within 1 h of an unexpected death) or unwitnessed (occurring during sleep or after the patient had been last seen, within 24 h, in a stable condition).^4,18

This study was approved by the local ethics committee in each participating hospital and informed consent was obtained from all patients. The investigation conforms with the principles outlined in the Declaration of Helsinki.

Statistical Analysis

Continuous variables are expressed as mean±SD or as the median with interquartile range (IQR), as appropriate, and were compared using Welch’s t-test. Categorical variables are expressed as numbers with percentage and were compared by Fisher’s exact test. SCD was estimated by Kaplan-Meier curves, which were compared using log-rank tests. The incidence rate of SCD per 1,000 person-years was compared between sexes with the exact binominal test. Risk factors for SCD were examined by a multivariable Cox proportional hazard model with variables selected using a stepwise selection procedure. The following variables were included as potential confounders: age, blood chemistry data (serum hemoglobin, creatinine, and B-type natriuretic peptide [BNP] concentrations), LVEF, left ventricular (LV) end-diastolic diameter, the use of drugs at baseline (β-blockers, renin-angiotensin system inhibitors, calcium channel blockers, statins, aldosterone antagonists, and diuretics), and HF etiologies (ischemic heart disease [IHD], dilated cardiomyopathy [DCM], hypertensive heart disease [HHD], valvular heart disease [VHD], and hypertrophic cardiomyopathy [HCM]). We used classification and regression trees (CART) analysis to detect prognostic factors stratified by sex. CART analysis is a statistical technique that can be used for classification or regression predictive modeling problems.¹⁹ Two-sided P<0.05 was considered statistically significant. All statistical analyses were performed using R version 3.6.1 (R Foundation for Statistical Computing, Vienna, Austria).

Results

Clinical Characteristics

Clinical characteristics of the 4,683 chronic HF patients stratified by sex are presented in Table 1. Compared with men, women with HF were older (67.6±12.1 vs. 71.5±12.2 years, respectively) and had preserved LVEF (55.1% vs. 59.9%, respectively). In addition, women had lower hemoglobin concentrations (12.3±1.7 vs. 13.6±2.0 g/dL), better renal function (median creatinine 0.7 [IQR 0.6–0.9] vs. 0.9 [IQR 0.8–1.1] mg/dL), higher BNP concentrations (median 123 [IQR 51.4–264] vs. 96.4 [IQR 27.6–227] pg/mL), and a higher prevalence of a history of HF hospitalization (56.8% vs. 51.7%) than men. In contrast, men had a higher prevalence of diabetes (41.8% vs. 36.5%), hyperuricemia (63.9% vs. 45.2%), and a history of myocardial infarction (40.6% vs. 20.9%) than women. IHD was more common in men than in women (56.4% vs. 35.9%), whereas HHD (16.5% vs. 23.4%) and VHD (6.3% vs. 16.4%) were more common in women. Beta-blockers, renin-angiotensin system inhibitors, and statins were used more frequently in men, whereas aldosterone antagonists and diuretics were used more frequently in women.

Table 1.

Baseline Characteristics by Sex

	Overall (n=4,683)	Men (n=3,186)	Women (n=1,497)	P value
Age (years)	68.8±12.3	67.6±12.1	71.5±12.2	<0.001
BMI (kg/m2)	23.8±3.9	24.0±3.6	23.3±4.4	<0.001
SBP (mmHg)	126.1±19.2	125.9±18.8	126.6±20.0	0.282
LVDd (mm)	52.1±9.2	53.6±9.0	48.9±8.9	<0.001
LVEF (%)	56.6±15.3	55.1±15.1	60.0±15.2	<0.001
Hemoglobin (g/dL)	13.2±2.0	13.6±2.0	12.3±1.7	<0.001
Creatinine (mg/dL)	0.9 [0.7–1.1]	0.9 [0.8–1.1]	0.7 [0.6–0.9]	<0.001
eGFR (mL/min/1.73 m2)	60.8±21.3	61.8±20.8	58.7±22.1	<0.001
BNP (pg/mL)	104 [41.3–237]	96.4 [37.6–227]	123 [51.4–264]	<0.001
Clinical history
Hypertension	4,232 (90.4)	2,886 (90.6)	1,346 (89.9)	0.49
Diabetes	1,878 (40.1)	1,332 (41.8)	546 (36.5)	<0.001
Dyslipidemia	3,846 (82.1)	2,639 (82.8)	1,207 (80.6)	0.072
Hyperuricemia	2,713 (57.9)	2,036 (63.9)	677 (45.2)	<0.001
Chronic AF	1,319 (28.2)	871 (27.3)	448 (29.9)	0.099
Paroxysmal AF	634 (13.5)	424 (13.3)	210 (14.0)
Myocardial infarction	1,607 (34.3)	1,294 (40.6)	313 (20.9)	<0.001
HF hospitalization	2,497 (53.3)	1,646 (51.7)	851 (56.8)	<0.001
Cancer	647 (13.8)	473 (14.8)	174 (11.6)	0.003
NYHA functional class
I	1,096 (23.5)	842 (26.5)	254 (17.0)	<0.001
II	3,057 (65.6)	2,048 (64.6)	1,009 (67.7)
III	477 (10.2)	262 (8.3)	215 (14.4)
IV	33 (0.7)	20 (0.6)	13 (0.9)
HF etiology
IHD	2,336 (49.9)	1,798 (56.4)	538 (35.9)	<0.001
Hypertensive cardiomyopathy	876 (18.7)	525 (16.5)	351 (23.4)	<0.001
Valvular disease	448 (9.6)	202 (6.3)	246 (16.4)	<0.001
DCM	623 (13.3)	452 (14.2)	171 (11.4)	0.01
HCM	115 (2.5)	69 (2.2)	46 (3.1)	0.068
Previous treatment
PCI	1,464 (31.3)	1,175 (36.9)	289 (19.3)	<0.001
CABG	427 (9.1)	340 (10.7)	87 (5.8)	<0.001
Medication
β-blockers	2,336 (49.9)	1,670 (52.4)	666 (44.5)	<0.001
ACEi	2,102 (44.9)	1,523 (47.8)	579 (38.7)	<0.001
ARBs	1,788 (38.2)	1,207 (37.9)	581 (38.8)	0.562
AAs	1,163 (24.8)	728 (22.8)	435 (29.1)	<0.001
Statins	1,781 (38.0)	1,247 (39.1)	534 (38.3)	0.024
Calcium channel blockers	1,784 (38.1)	1,210 (38.0)	574 (38.3)	0.821
Diuretics	2,718 (58.0)	1,740 (54.6)	978 (65.3)	<0.001

Unless indicated otherwise, data are given as the mean±SD, median [interquartile range], or n (%). AAs, aldosterone antagonists; ACEi, angiotensin-converting enzyme inhibitors; AF, atrial fibrillation; ARB, angiotensin II receptor blocker; BMI, body mass index; BNP, B-type natriuretic peptide; CABG, coronary artery bypass surgery; DCM, dilated cardiomyopathy; HCM, hypertrophic cardiomyopathy; HF, heart failure; IHD, ischemic heart disease; LVDd, left ventricular end-diastolic diameter; LVEF, left ventricular ejection fraction; NYHA, New York Heart Association; PCI, percutaneous coronary intervention; SBP, systolic blood pressure.

Incidence and Timing of SCD

During the median follow-up of 8.8 years (from October 2006 to March 2020), there were 215 SCD events (160 in men, 55 in women; Figure 2). Fifty-five men and 21 women survived fatal arrhythmias, such as ventricular tachycardia and ventricular fibrillation, likely due in part to the appropriate use of implantable cardioverter defibrillator (ICD)/cardiac resynchronization therapy with a defibrillator (CRT-D) therapy. The incidence rate of SCD in men and women was 6.1 and 4.6 per 1000 person-years, respectively, which was not significantly different (P=0.088). Detailed data on the modes of death are presented in the Supplementary Table.

Figure 2.

Cumulative incidence of sudden cardiac death (SCD) in men and women. CI, confidence interval; HR, hazard ratio.

Importantly, among women, more than half the SCDs occurred in the first 5 years of follow-up (Figure 3). In the first 5 years of follow-up, the incidence rate of SCD in men and women was 3.4 and 3.1 per 1000 person-years, respectively, which was not significantly different (P=0.648). However, after 5 years, the incidence rate of SCD was significantly lower in women than in men (3.6 vs. 5.9 per 1000 person-years, respectively; P=0.044; Figure 3).

Figure 3.

Cumulative incidence of sudden cardiac death according to observation period: (A) from 0–5 years; (B) after 5 years.

Sex Differences in Risk Factors for SCD

The prognostic factors for SCD over the 10-year follow-up are presented in Table 2. After adjustment, we found that body mass index, hemoglobin, creatinine, increased BNP concentrations, LVEF, LV end-diastolic diameter, hypertension, diabetes, dyslipidemia, a history of HF hospitalization, IHD, HHD, VHD, DCM, HCM, β-blockers, renin–angiotensin system inhibitors, statins, diuretics, atrial fibrillation, New York Heart Association functional class, age, and LVEF <50% were common prognostic factors in men and women. In men, renal dysfunction (creatinine ≥1.0 mg/dL; hazard ratio [HR] 1.48; 95% confidence interval [CI] 1.07–2.06; P=0.019) and LV enlargement (LV end-diastolic diameter ≥65 mm; HR 1.89; 95% CI 1.23–2.88; P=0.003) were associated with SCD after adjustment for potential confounders. In women, IHD etiology (HR 2.38; 95% CI 1.35–4.21; P=0.003) and not taking statins (HR 2.39; 95% CI 1.27–4.49; P=0.007) heightened the risk of SCD.

Table 2.

Risk Factors for Sudden Cardiac Death Over 10-Year Follow-up

	Men			Women
	HR	95% CI	P value	HR	95% CI	P value
Age ≥70 years	1.9	1.36–2.66	<0.001	2.51	1.28–4.95	0.008
BMI ≥20 kg/m2	0.67	0.43–1.06	0.085
Creatinine ≥1.0 mg/dL	1.48	1.07–2.06	0.019
40 pg/mL<BNP≤170 pg/mL	2.07	1.28–3.33	0.003	0.95	0.41–2.19	0.898
BNP >170 pg/mL	2.8	1.71–4.59	<0.001	2.36	1.11–5.05	0.026
LVEF <50%	1.59	1.11–2.27	0.011	1.81	1.04–3.15	0.034
LVDd ≥65 mm	1.89	1.23–2.88	0.003
IHD				2.38	1.35–4.21	0.003
No statin use				2.39	1.27–4.49	0.007

The model was adjusted for age, BMI, hemoglobin, creatinine, BNP, LVEF, LVDd, hypertension, diabetes, dyslipidemia, a history of HF hospitalization, IHD, hypertensive heart disease, valvular heart disease, dilated cardiomyopathy, hypertrophic cardiomyopathy, the use of β-blockers, renin-angiotensin system inhibitors, statins, and/or diuretics, AF, and NYHA functional class. CI, confidence interval; HR, hazard ratio. Other abbreviations as in Table 1.

Table 3 presents results of the landmark analysis showing risk factors according to observation periods. Men and women shared almost the same 5-year risk factors for SCD, except for body mass index <20 kg/m² in women (HR 2.35; 95% CI 1.18–4.67; P=0.015). Importantly, when assessing the risk factors beyond the first 5 years of follow-up, LV enlargement was a prognostic factor in both sexes.

Table 3.

Landmark Analysis for Risk Factors of Sudden Cardiac Death Stratified by Observation Period (Years 1–5 vs. Years ≥5 of Follow-up)

	Years 1–5 of follow-up						Years ≥5 of follow-up
	Men			Women			Men			Women
	HR	95% CI	P value	HR	95% CI	P value	HR	95% CI	P value	HR	95% CI	P value
Age ≥70 years	1.67	1.06–2.64	0.026	2.4	0.98–5.92	0.056	1.6	0.88–2.89	0.123	3.4	1.08–10.7	0.037
BMI ≥20 kg/m2				2.35	1.18–4.67	0.015
Creatinine ≥1.0 mg/dL	2.04	1.27–3.25	0.003
40 pg/mL<BNP≤ 170 pg/mL	2.67	1.26–5.62	0.01	1.17	0.29–4.67	0.828	2.04	0.92–4.49	0.078
BNP >170 pg/mL	4.06	1.94–8.51	<0.001	5.14	1.54–17.2	0.008	3.7	1.63–8.53	0.002
LVEF <50%	2.03	1.30–3.16	0.002				1.88	0.95–3.71	0.068
LVDd ≥65 mm				2.53	0.87–7.34	0.087	3.18	1.57–6.44	0.001	7.53	2.12–26.8	0.002
IHD				4.02	1.98–8.14	<0.001

The model was adjusted for age, BMI, hemoglobin, creatinine, BNP, LVEF, LVDd, hypertension, diabetes, dyslipidemia, a history of HF hospitalization, IHD, hypertensive heart disease, valvular heart disease, dilated cardiomyopathy, hypertrophic cardiomyopathy, the use of β-blockers, renin-angiotensin system inhibitors, statins, and/or diuretics, AF, and NYHA functional class. Abbreviations as in Tables 1,2.

Discussion

To our knowledge, the present CHART-2 study is one of the largest cohort studies to examine sex differences in the incidence and predictors of SCD in patients with congestive HF (CHF). There are 2 novel findings of this study. First, during the first 5 years of observation, the rates of SCD were comparable between the sexes. However, beyond this point, the incidence of SCD notably escalated in men compared with women. Second, age, elevated BNP concentrations, and LVEF <50% emerged as consistent prognostic factors for SCD in both sexes, with LV enlargement identified as a common long-term prognostic factor.

Sex Differences in SCD Rate

The clinical trajectory of HF is marked by variability, involving a range of cardiovascular disease (CVD) and non-CVD events leading to mortality. Approximately half of these initial events involve fatal and non-fatal cardiac incidents. Although Pons et al. proposed that SCD primarily occurs within the early years of follow-up,²⁰ our study demonstrated a consistent incidence of SCD throughout the observation period within the first 5 years of follow-up. Significantly, we observed an increase in SCD rates, especially among men, beyond 5 years of observation (Figure 3).

Previous studies have shown that CVD mortality is higher in men than in women.²¹ However, limited data exists when assessing sex differences among CHF patients regarding the mode of death, particularly in the case of SCD. By extending the follow-up period of the CHART-2 study, our findings build upon existing SCD data, demonstrating that the incidence of cardiovascular death, particularly that attributable to HF, was significantly higher in women with HF. In addition, there was no sex difference in SCD rates over a median 3.8-year follow-up.¹⁵ In this study we further elucidated the prognostic relevance of sex differences in the frequency of SCD, revealing a significantly lower incidence in women than in men over the extended 10-year follow-up period.

In the Second Australian National Blood Pressure Study (ANBP2), Sahle et al. reported that the 5- and 10-year survival rates following HF diagnosis during the trial period were 37% and 15%, respectively, in men, compared with 60% and 33%, respectively, in women.²²

From the 5 trials or registries that met the ACC/AHA/Heart Rhythm Society guideline criteria for implantation of a primary prevention ICD, Rho et al. found that the proportion of sudden death was 30% lower for women than men, whereas the proportion of pump failure death was 54% higher for women.²³

The ICD has been established as therapy for both primary and secondary prevention of sudden death. Some studies suggest that prophylactic ICD implantation may offer less benefit to female patients. In a cohort study of ICD patients,^24,25 the time to appropriate device therapy was shorter in men than women (HR 1.71; 95% CI 1.36–2.14; P<0.001). Although the frequency of appropriate device therapy decreased after 3 years of follow-up in both sexes, the disparity between men and women widened.²⁴

Sex-specific switches in adrenergic signaling under stress conditions may represent an endogenous protective mechanism in women. When stressed, women tend to develop smaller hearts with thicker walls compared with men, and increases in LV stiffness with aging are more pronounced in women.^26,27 Conversely, men tend to develop more fibrosis under stress, such as pressure overload.^28,29 Clinicopathologic correlation studies suggest that myocardial fibrosis could serve as a substrate for malignant ventricular arrhythmia and SCD.³⁰ Indeed, estrogen suppresses collagen production in cardiac fibroblasts of female origin but stimulates it in those of male origin.²⁶

Although the subjects of the present study were of an aged population, it is of note that sex hormones may also influence arrhythmia. In women, under the influence of estrogen, arachidonic acid is metabolized to epoxyeicosatrienoic acid (EET), whereas in men, it is metabolized to hydroxyeicosatetraenoic acid (HETE) under the influence of androgens.³¹ EET exhibits antiarrhythmic and cardioprotective properties; in contrast, HETE is proarrhythmic.³² In addition, EET inhibits the onset of ventricular fibrillation after electrical stimulation of the heart.³³

Predictors of SCD

In the present study, SCD accounted for a substantial portion of cardiovascular deaths not only in HFrEF but also in HFpEF. Previous studies demonstrated that SCD accounted for 21–39% of cardiovascular deaths in HFrEF and for 18–43% of cardiovascular deaths in HFpEF.^2–5 In the present study, SCD accounted for 21.2% of cardiovascular deaths, consistent with previous studies.^2–5 Several observational studies have been conducted to identify risk factors for SCD, with severely decreased LV systolic function the only established predictor.^33,34 Other factors listed as potential risk factors for SCD in HFpEF include age, sex, diabetes, and IHD.^18,35,36 However, limited data exist regarding sex differences in these risk factors for SCD. Our findings underscore the prognostic relevance of sex differences in risk factors for SCD. In both women and men, age, increased BNP concentrations, and LVEF were commonly identified as predictors of SCD.

Mortality rates following HF diagnosis were found to increase with advancing age (HR 1.09; 95% CI 1.04–1.33; P<0.001).³⁷ In 3 large HFpEF trials, it was noted that sudden death emerged as the primary cause of death among younger patients, whereas elderly patients had higher rates of composite cardiovascular event, including sudden death, over a span of 5 years compared with their younger counterparts.³⁸ In our previous study, we reported that the incidence of HF death became proportionally more prevalent among elderly patients, whereas that of SCD exhibited the opposite trend.³⁹ BNP concentrations have been used as a prognostic marker for patients with CHF. Berger et al. reported that BNP was a robust, independent predictor of SCD in patients with CHF.⁴⁰

In men, renal dysfunction and LV enlargement (LV end-diastolic diameter ≥65 mm) were also associated with SCD. Patients with chronic kidney disease (CKD) face an elevated risk of SCD compared with the general population.⁴¹ However, data from observational studies have been conflicting, because patients with moderate or severe CKD were often excluded from pivotal randomized controlled trials.^42,43 Nonetheless, there are studies indicating an independent association between kidney dysfunction and SCD, as evidenced by subgroup analyses of clinical trials assessing the efficacy of ICDs. For example, in the Multicenter Automatic Defibrillator Implantation Trial II (MADIT-II trial), researchers examined the risk of SCD among patients with CKD and found that the risk of SCD increased by 17% for every 10-mL/min/1.73 m² decrement in estimated glomerular filtration rate among patients receiving optimal medical therapy.⁴⁴ CKD has also been identified as a risk factor for SCD in the Comparison of Medical Therapy, Pacing, and Defibrillation in Heart Failure (COMPANION trials), which reported that renal dysfunction was associated with a 67% greater risk of SCD during the 16-month follow-up period.⁴⁵

Our analysis revealed that IHD and a lack of statin use heightened the risk of SCD in women. IHD stands as a major etiological factor in patients with HF,²⁰ and its prevalence increases with age, showing no significant sex difference in HFrEF.⁴⁶ Following menopause, women experience increases in total cholesterol, low-density lipoprotein cholesterol, and triglyceride levels.^47,48 However, despite these changes, women were less likely to receive evidence-based drug therapy than men as recommended in the guidelines.⁴⁹ This discrepancy could reflect a perception of lower risk of recurrent cardiovascular events in women than in men.

When examining predictors separately for different observation periods, we found that LV enlargement was associated with SCD in both sexes during the longer-term follow-up. In our previous study, we revealed that patients who experienced SCD had a higher mean LV end-diastolic diameter.⁵⁰ Combining BNP levels with LV dimensions could prove valuable for assessing the risk of SCD.⁵¹ In addition, we reported that chronic atrial fibrillation and LV end-diastolic diameter ≥65 mm were independent predictors of fatal arrhythmic events in CHF patients, which meets the prophylactic ICD implantation criteria in the Japanese Circulation Society guidelines.⁵²

Aleong et al. demonstrated in their GRADE study that severe LV end-diastolic diameter not only led to worse ICD shock-free survival but also resulted in worse freedom from death, transplant, or ventricular assist compared with normal and mild LV end-diastolic diameter.⁵³ LV end-diastolic diameter was associated with appropriate ICD shocks (HR 1.22; P=0.020) and time to death, transplant, or ventricular assist device (HR 1.29; P=0.0009).⁵²

Narayanan et al. revealed that LV enlargement posed a similar risk to LVEF reduction and was linked to the risk of SCD in conjunction with LVEF reduction, as evidenced by the Oregon Sudden Unexpected Death Study.⁵⁴ Narayanan et al. categorized LV size by sex, indicating that moderate dilation (men, 64–68 mm; women, 58–61 mm) or severe LV dilatation (men, ≥69 mm; women, ≥62 mm) were associated with significantly higher odds ratios compared with normal LV size (men, 42–59 mm; women, 39–53 mm).⁵⁴ Assessing LV dilatation is straightforward during transthoracic echocardiography at the time of LVEF measurement. It is essential to consider LV enlargement as an additional risk factor in HF patients.

Study Limitations

This study has several limitations that should be mentioned. First, because the CHART-2 study is an observational study conducted in Japan, caution should be paid when extrapolating the findings to other patient populations. Second, our study included patients with ICD or CRT-P/D, devices that could potentially reduce the prevalence of SCD by preventing fatal arrhythmias or HF progression. At enrollment, 62 men and 20 women had ICDs, and 24 men and 10 women had CRT-Ds. The small sample size of patients with ICDs or CRT-Ds limited the study’s power to evaluate the clinical significance of these devices in relation to SCD events. Third, our analysis was conducted using baseline medication data and did not account for the prognostic significance of changes in medications for SCD. Fourth, censoring subjects at the time of non-SCD-related death could have led to an overestimation of the incidence of SCD.

Conclusions

The long-term observations of the CHART-2 study demonstrate sex differences in the frequency of SCD, with women showing a relatively lower risk. LV enlargement emerged as a common long-term prognostic factor in both sexes, underscoring the significance of preventing LV remodeling in HF management.

Acknowledgments

The authors thank all the members of the Tohoku Heart Failure Association, the CHART-2 Investigators, and the staff of the Departments of Cardiovascular Medicine and Evidence-based Cardiovascular Medicine, Tohoku University Graduate School of Medicine for their kind contributions.

Sources of Funding

This study was supported, in part, by Grants-in-Aid from the Ministry of Health, Labour, and Welfare, and the Ministry of Education, Culture, Sports, Science, and Technology, Japan.

Disclosures

S.Y. and H.S. are members of the Circulation Journal’s Editorial Team. The remaining authors have no conflicts of interest to declare.

IRB Information

The study was approved by the Ethics Committee of Tohoku University Graduate School of Medicine (Reference no. 2021-1-634).

Data Availability

The deidentified participant data will not be shared.

Supplementary Files

Please find supplementary file(s);

https://doi.org/10.1253/circj.CJ-24-0484

References

• 1.   Tribouilloy C, Buiciuc O, Rusinaru D, Malaquin D, Lévy F, Peltier M. Long-term outcome after a first episode of heart failure: A prospective 7-year study. Int J Cardiol 2010; 140: 309–314.
• 2.   Chan MMY, Lam CSP. How do patients with heart failure with preserved ejection fraction die? Eur J Heart Fail 2013; 15: 604–613.
• 3.   Packer DL, Prutkin JM, Hellkamp AS, Mitchell LB, Bernstein RC, Wood F, et al. Impact of implantable cardioverter-defibrillator, amiodarone, and placebo on the mode of death in stable patients with heart failure: Analysis from the sudden cardiac death in heart failure trial. Circulation 2009; 120: 2170–2176.
• 4.   Desai AS, Macurray JJV, Packer M, Swedberg K, Rouleau JL, Chen F, et al. Effect of the angiotensin-receptor-neprilysin inhibitor LCZ696 compared with enalapril on mode of death in heart failure patients. Eur Heart J 2015; 36: 1990–1997.
• 5.   Zheng ZJ, Croft JB, Giles WH, Mensah GA. Sudden cardiac death in the United States, 1989 to 1998. Circulation 2001; 104: 2158–2163.
• 6.   Kitai T, Miyakoshi C, Morimoto T, Yaku H, Murai R, Kaji S, et al. Mode of death among Japanese adults with heart failure with preserved, midrange, and reduced ejection fraction. JAMA Network Open 2020; 3: e204296.
• 7.   Kannel WB, Schatzkin A. Sudden death: Lessons from subsets in population studies. J Am Coll Cardiol 1985; 5: 141B–149B.
• 8.   Neuspiel DR, Kuller LH. Sudden and unexpected natural death in childhood and adolescence. JAMA 1985; 254: 1321–1325.
• 9.   Adams KF Jr, Sueta CA, Gheorghiade M, O’Connor CM, Schwartz TA, Koch GG, et al. Gender differences in survival in advanced heart failure. Insights from the FIRST study. Circulation 1999; 99: 1816–1821.
• 10.   Simon T, Mary-Krause M, Funck-Brentano C, Jaillon P. Sex differences in the prognosis of congestive heart failure: Results from the Cardiac Insufficiency Bisoprolol Study (CIBIS II). Circulation 2001; 103: 375–380.
• 11.   Beale AL, Meyer P, Marwick TH, Lam CSP, Kaye DM. Sex differences in cardiovascular pathophysiology: Why women are overrepresented in heart failure with preserved ejection fraction. Circulation 2018; 138: 198–205.
• 12.   Ghali JK, Krause-Steinrauf HJ, Adams KF, Khan SS, Rosenberg YD, Yancy CW, et al. Gender differences in advanced heart failure: Insights from the BEST study. J Am Coll Cardiol 2003; 42: 2128–2134.
• 13.   Shiba N, Nochioka K, Miura M, Kohno H, Shimokawa H; CHART-2 Investigators. Trend of westernization of etiology and clinical characteristics of heart failure patients in Japan: First report from the CHART-2 study. Circ J 2011; 75: 823–833.
• 14.   Nochioka K, Sakata Y, Takahashi J, Miyata S, Miura M, Takada T, et al. Prognostic impact of nutritional status in asymptomatic patients with cardiac diseases: A report from the CHART-2 study. Circ J 2013; 77: 2318–2326.
• 15.   Sakata Y, Miyata S, Nochioka K, Miura M, Takada T, Tadaki S, et al. Gender differences in clinical characteristics, treatment and long-term outcome in patients with Stage C/D heart failure in Japan: Report from the CHART-2 study. Circ J 2014; 78: 428–435.
• 16.   Miura M, Sakata Y, Miyata S, Nochioka K, Takada T, Tadaki S, et al. Usefulness of combined risk stratification with heart rate and systolic blood pressure in the management of chronic heart failure: A report from the CHART-2 study. Circ J 2013; 77: 2954–2962.
• 17.   Yancy CW, Jessup M, Bozkurt B, Butler J, Casey DE Jr, Drazner MH, et al. 2013 ACCF/AHA guideline for the management of heart failure: Executive summary: A report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Circulation 2013; 128: 1810–1852.
• 18.   Vaduganathan M, Claggett BL, Chatterjee NA, Anand IS, Sweitzer NK, Fang JC, et al. Sudden death in heart failure with preserved ejection fraction: A competing risks analysis from the TOPCAT trial. JACC Heart Fail 2018; 6: 653–661.
• 19.   Breiman L, Friedman JH, Olshen RA, Stone CJ. Classification and regression trees. Chapman and Hall/CRC, 1984.
• 20.   Pons F, Lupón J, Urrutia A, González B, Crespo E, Díez C, et al. Mortality and cause of death in patients with heart failure: Findings at a specialist multidisciplinary heart failure unit. Rev Esp Cardiol 2010; 63: 303–314.
• 21.   Bots SH, Peters SAE, Woodward M. Sex differences in coronary heart disease and stroke mortality: A global assessment of the effect of ageing between 1980 and 2010. BMJ Glob Health 2017; 2: e000298.
• 22.   Sahle BW, Owen AJ, Krum H, Reid CM; Second Australian National Blood Pressure Study Management Committee. Incidence of heart failure in 6083 elderly hypertensive patients: The Second Australian National Blood Pressure Study (ANBP2). Eur J Heart Fail 2016; 18: 38–45.
• 23.   Rho RW, Patton KK, Poole JE, Cleland JG, Shadman R, Anand I, et al. Important differences in mode of death between men and women with heart failure who would qualify for a primary prevention implantable cardioverter-defibrillator. Circulation 2012; 126: 2402–2407.
• 24.   van der Lingen ALC, Theuns DAMJ, Rijnierse MT, Becker MAJ, van de Ven PM, van Rossum AC, et al. Sex-specific differences in outcome and risk stratification of ventricular arrhythmias in implantable cardioverter defibrillator patients. ESC Heart Fail 2021; 8: 3726–3736.
• 25.   Providência R, Marijon E, Lambiase P, Bouzeman A, Defaye P, Klug D, et al. Primary prevention implantable cardioverter defibrillator (ICD) therapy in women: Data from a multicenter French registry. J Am Heart Assoc 2016; 5: e002756.
• 26.   Regitz-Zagrosek V, Kararigas G. Mechanistic pathways of sex differences in cardiovascular disease. Physiol Rev 2017; 97: 1–37.
• 27.   Dworatzek E, Mahmoodzadeh S, Schriever C, Kusumoto K, Kramer L, Santos G, et al. Sex-specific regulation of collagen I and III expression by 17β-estradiol in cardiac fibroblasts: Role of estrogen receptors. Cardiovasc Res 2019; 115: 315–327.
• 28.   Petrov G, Dworatzek E, Schulze TM, Dandel M, Kararigas G, Mahmoodzadeh S, et al. Maladaptive remodeling is associated with impaired survival in women but not in men after aortic valve replacement. JACC Cardiovasc Imaging 2014; 7: 1073–1080.
• 29.   Petrov G, Regitz-Zagrosek V, Lehmkuhl E, Krabatsch T, Dunkel A, Dandel M, et al. Regression of myocardial hypertrophy after aortic valve replacement: Faster in women? Circulation 2010; 122(Suppl): S23–S28.
• 30.   Pogwizd SM, Mckenzie, Cain ME. Mechanisms underlying spontaneous and induced ventricular arrhythmias in patients with idiopathic dilated cardiomyopathy. Circulation 1998; 98: 2404–2414.
• 31.   Muller DN, Schmidt C, Barbosa-Sicard E, Wellner M, Gross V, Hercule H, et al. Mouse Cyp4a isoforms: Enzymatic properties, gender- and strain-specific expression, and role in renal 20-hydroxyeicosatetraenoic acid formation. Biochem J 2007; 403: 109–118.
• 32.   Pascale JV, Lucchesi PA, Garcia V. Unraveling the role of 12- and 20-HETE in cardiac pathophysiology: G-protein-coupled receptors, pharmacological inhibitors, and transgenic approaches. J Cardiovasc Pharmacol 2021; 77: 707–717.
• 33.   Westphal C, Spallek B, Konkel A, Marko L, Qadri F, DeGraff LM, et al. CYP2J2 overexpression protects against arrhythmia susceptibility in cardiac hypertrophy. PLoS One 2013; 30: e73490.
• 34.   Stecker EC, Vickers C, Waltz J, Socoteanu C, John BT, Mariani R, et al. Population-based analysis of sudden cardiac death with and without left ventricular systolic dysfunction: Two-year findings from the Oregon Sudden Unexpected Death Study. J Am Coll Cardiol 2006; 47: 1161–1166.
• 35.   Adabag S, Smith LG, Anand IS, Berger AK, Luepker RV. Sudden cardiac death in heart failure patients with preserved ejection fraction. J Card Fail 2012; 18: 749–754.
• 36.   Adabag S, Rector TS, Anand IS, McMurray JJ, Zile M, Komajda M, et al. A prediction model for sudden cardiac death in patients with heart failure and preserved ejection fraction. Eur J Heart Fail 2014; 16: 1175–1182.
• 37.   Sahle BW, Owen AJ, Wing LMH, Beilin LJ, Krum H, Reid CM; Second Australian National Blood Pressure Study Management Committee. Long-term survival following the development of heart failure in an elderly hypertensive population. Cardiovasc Ther 2017, doi:10.1111/1755-5922.12303.
• 38.   Tromp J, Shen L, Jhund PS, Anand IS, Carson PE, Desai AS, et al. Age-related characteristics and outcomes of patients with heart failure with preserved ejection fraction. J Am Coll Cardiol 2019; 74: 601–612.
• 39.   Yamanaka S, Nochioka K, Hayashi H, Shiroto T, Takahashi J, Miyata S, et al. Age-stratified profiles and outcomes of patients with heart failure with preserved ejection fraction. ESC Heart Fail 2024; 11: 2223–2233.
• 40.   Berger R, Huelsman M, Strecker K, Bojic A, Moser P, Stanek B, et al. B-Type natriuretic peptide predicts sudden death in patients with chronic heart failure. Circulation 2002; 105: 2392–2397.
• 41.   Chonchol M, Goldenberg I, Moss AJ, McNitt S, Cheung AK. Risk factors for sudden cardiac death in patients with chronic renal insufficiency and left ventricular dysfunction. Am J Nephrol 2007; 27: 7–14.
• 42.   Pfeffer MA, Claggett B, Assmann SF, Boineau R, Anand IS, Clausell N, et al. Regional variation in patients and outcomes in the Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist (TOPCAT) trial. Circulation 2015; 131: 34–42.
• 43.   Massie BM, Carson PE, McMurray JJ, Komajda M, McKelvie R, Zile MR, et al.; I-PRESERVE Investigators. Irbesartan in patients with heart failure and preserved ejection fraction. N Engl J Med 2008; 359: 2456–2467.
• 44.   Goldenberg I, Moss AJ, McNitt S, Zareba W, Andrews ML, Hall WJ, et al. Relations among renal function, risk of sudden cardiac death, and benefit of the implanted cardiac defibrillator in patients with ischemic left ventricular dysfunction. Am J Cardiol 2006; 98: 485–490.
• 45.   Saxon LA, Bristow MR, Boehmer J, Krueger S, Kass DA, De Marco T, et al. Predictors of Sudden Cardiac Death and Appropriate Shock in the Comparison of Medical Therapy, Pacing, and Defibrillation in Heart Failure (COMPANION) Trial. Circulation 2006; 114: 2766–2772.
• 46.   Dunlay SM, Roger VL. Gender differences in the pathophysiology, clinical presentation, and outcomes of ischemic heart failure. Curr Heart Fail Rep 2012; 9: 267–276.
• 47.   Akahoshi M, Soda M, Nakashima E, Shimaoka K, Seto S, Yano K. Effects of menopause on trends of serum cholesterol, blood pressure, and body mass index. Circulation 1996; 94: 61–66.
• 48.   Cífková R, Krajčoviechová A. Dyslipidemia and cardiovascular disease in women. Curr Cardiol Rep 2015; 17: 609.
• 49.   Sumarsono A, Xie L, Keshvani N, Zhang C, Patel L, Alonso WW, et al. Sex disparities in longitudinal use and intensification of guideline-directed medical therapy among patients with newly diagnosed heart failure with reduced ejection fraction. Circulation 2024; 149: 510–520.
• 50.   Watanabe J, Shinozaki T, Shiba N, Fukahori K, Koseki Y, Karibe A, et al. Accumulation of risk markers predicts the incidence of sudden death in patients with chronic heart failure. Eur J Heart Fail 2006; 8: 237–242.
• 51.   Watanabe J, Shiba N, Shinozaki T, Koseki Y, Karibe A, Komaru T, et al. Prognostic value of plasma brain natriuretic peptide combined with left ventricular dimensions in predicting sudden death of patients with chronic heart failure. J Card Fail 2005; 11: 50–55.
• 52.   Satake H, Fukuda K, Sakata Y, Miyata S, Nakano M, Kondo M, et al. Current status of primary prevention of sudden cardiac death with implantable cardioverter defibrillator in patients with chronic heart failure. Circ J 2015; 79: 381–390.
• 53.   Aleong RG, Mulvahill MJ, Halder I, Carlson NE, Singh M, Bloom HL, et al. Left ventricular dilatation increases the risk of ventricular arrhythmias in patients with reduced systolic function. J Am Heart Assoc 2015; 4: e001566.
• 54.   Narayanan K, Reinier K, Teodorescu C, Uy-Evanado A, Aleong R, Chugh H, et al. Left ventricular diameter and risk stratification for sudden cardiac death. J Am Heart Assoc 2014; 3: e00119.