Investigation of Myocardial Substrate for Sudden Arrhythmic Death in Coronary Artery Disease Without Acute Coronary Thrombosis or Myocardial Infarction

Figures

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  Figure 1. Schema outlining potential mechanisms underlying sudden coronary death in patients with CAD. Sudden coronary death is defined as sudden unexpected death due to cardiac or unidentifiable cause either within 1 h of symptom onset (event witnessed) or within 24 h of having been observed alive and symptom free (unwitnessed), 1 , 2 , 3 with at least 1 major coronary artery with a luminal thrombus or narrowed ≥75% in cross‐sectional area by plaque with or without plaque rupture. 1 , 4 , 5 Autopsy studies demonstrated ≈50% to 70% of decedents with sudden coronary death had acute plaque rupture or thrombosis and acute myocardial injury, and ≈30% to 50% had stable plaque (Figure 1); both subgroups may have chronic (healed) MI. 1 , 5 , 7 , 8 , 9 , 10 , 11 Some decedents with acute plaque rupture or thrombosis had both acute myocardial injury and chronic MI, 5 whereas some had neither, 5 and some decedents with stable plaque and chronic MI also had acute myocardial injury. 5 , 9 Moreover, several authors described a subgroup of decedents with sudden coronary death and stable plaque without myocardial injury (acute or chronic), representing 15% to 30% of sudden coronary deaths. 4 , 5 , 9 , 11…

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  Figure 2. CONSORTdiagram of the search strategy of the National Coronial Information System to identify decedents with CAD and either sudden noncardiac death or SAD. All decedents had at least 1 coronary artery with ≥75% stenosis; 48 decedents (25 men and 23 women) with sudden death due to a noncardiac cause were matched for sex and age (within 5 y), with 50 decedents (25 men and 25 women) with sudden death presumed to have SAD. None of the decedents had complete occlusion of a coronary artery, acute plaque rupture, thrombosis, MI, or other myocardial abnormality. CAD indicates coronary artery disease; CONSORT, Consolidated Standards of Reporting Trials; MI, myocardial infarction; PCI, percutaneous coronary intervention; and SAD sudden arrhythmic death.

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  Figure 3. Coronary arteries involved and percent area stenosis for decedents with CAD and either sudden noncardiac death or SAD. Shown are the numbers of decedents with coronary stenoses of the left main (A), left anterior descending (B), left circumflex (C), and right coronary arteries (D), and the percent area stenosis for 48 decedents (25 men and 23 women) with CAD and noncardiac death (open columns), and 50 decedents (25 men and 25 women) with CAD and SAD (closed columns). All decedents had ≥1 coronary artery with ≥75% area stenosis. CAD indicates coronary artery disease; and SAD sudden arrhythmic death.

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  Figure 4. Cardiomyocyte width, total myocardial fibrosis, and arteriole perivascular fibrosis in decedents with CAD and either sudden noncardiac death or SAD. Shown are the cardiomyocyte width (A), total myocardial fibrosis (B), and arteriole perivascular fibrosis (C) for inner, middle, and outer regions of left ventricle sections from male and female decedents with either CAD and noncardiac death (open columns) or CAD and SAD (closed columns). Data are shown as mean±SD: n=25 for men and n=23 for women with noncardiac death and n=25 for men and women with SAD. Mean differences (95% CI) between men and women and between decedents with either noncardiac death or SAD were calculated for all regions, and for the inner, middle, and outer regions of each section: *P<0.05; **P<0.01. The lower cardiomyocyte width (P=0.0016) and higher perivascular fibrosis (P=0.018) of decedents with SAD were confirmed in multivariable linear regression analysis with cause of death, sex, and age category as independent predictor or explanatory variables. CAD indicates coronary artery disease; and SAD, sudden arrhythmic death.

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  Figure 5. Arteriole density, minimal arteriole diameter, and arteriole wall area/circumference ratio in decedents with CAD and either sudden noncardiac death or SAD. Shown are arteriole density (A), minimal arteriole diameter (B), and arteriole wall area/circumference ratio (C) for inner, middle, and outer regions of left ventricle sections from male and female decedents with either CAD and noncardiac death (open columns) or CAD and SAD (closed columns). Data are shown as mean±SD: n=25 for men and n=23 for women with noncardiac death, and n=25 for men and women with SAD. Mean differences (95% CI) between men and women and between decedents with either noncardiac death or SAD were calculated for all regions and for the inner, middle, and outer regions of each section: *P<0.05; **P<0.01. Neither arteriole density nor minimal arteriole diameter was different between decedents with either noncardiac death or SAD in multivariable linear regression analysis with cause of death, sex, and age category as independent predictor or explanatory variables. CAD indicates coronary artery disease; and SAD, sudden arrhythmic death.

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  Figure 6. Capillary length density, diffusion radius, and diffusion radius/cardiomyocyte width ratio in decedents with CAD and either sudden noncardiac death or SAD. Shown are capillary length density (A), diffusion radius (B), and diffusion radius/cardiomyocyte width ratio (C) for inner, middle, and outer regions of left ventricle sections from male and female decedents with either CAD and noncardiac death (open columns) or CAD and SAD (closed columns). Data are shown as mean±SD: n=22 for men and n=20 for women with noncardiac death, and n=23 for men and women with SAD. Mean differences (95% CIs) between men and women and between decedents with either noncardiac death or SAD were calculated for all regions and for the inner, middle, and outer regions of each section: *P<0.05; **P<0.01; ***P<0.001. The higher capillary length density (P=0.0028) and lower diffusion radius (P=0.0053) of decedents with SAD were confirmed in multivariable linear regression analysis with cause of death, sex, and age category as independent predictor or explanatory variables. CAD indicates coronary artery disease; and SAD, sudden arrhythmic death.

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  Figure 7. Correlations between capillary length density, diffusion radius, and cardiomyocyte width in decedents with CAD and either sudden noncardiac death or SAD. Shown are correlations between capillary length density and cardiomyocyte width in decedents with CAD and noncardiac death (A), capillary length density and cardiomyocyte width in decedents with CAD and SAD (B), diffusion radius and cardiomyocyte width in decedents with CAD and noncardiac death (C), and diffusion radius and cardiomyocyte width in decedents with CAD and SAD (D). Each dot represents either the inner, middle, or outer region of each section for each decedent: n=126 (22 men and 20 women) for noncardiac death, and n=138 (23 men and 23 women) for SAD. Also shown are Pearson correlation coefficients: all P values <0.0001. CAD indicates coronary artery disease; and SAD sudden arrhythmic death.

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  Figure 8. Correlations between cardiomyocyte width and cumulative stenosis per decedent in decedents with CAD and either sudden noncardiac death or SAD. Shown are correlations between cardiomyocyte width and the cumulative stenosis per decedent in decedents with CAD and either noncardiac death (A) or SAD (B). Cumulative stenosis represents the sum of percent area stenosis for each of the left main, left anterior descending, left circumflex, and right coronary arteries. Each dot represents the inner, middle, or outer region of each section for each decedent: n=144 (inner, middle, or outer regions for 25 men and 23 women) for noncardiac death, and n=150 (inner, middle, or outer regions for 25 men and 25 women) for SAD. Also shown are Pearson correlation coefficients: all P values not significant. CAD indicates coronary artery disease; and SAD, sudden arrhythmic death.

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  Figure 9. Hypothetical schema of the evolution of the atherosclerotic plaque and its dynamic interaction with the myocardium in the absence of acute coronary thrombosis and myocardial infarction. The atherosclerotic plaque may release microemboli, causing myocardial micronecrosis, fibrosis, and coronary microvascular rarefaction, and plaque erosion and rupture may produce acute coronary thrombosis, myocardial infarction, and chronic nonocclusive thrombosis. Moreover, greater atherosclerotic plaque burden may be associated with increased susceptibility to ischemia (supply–demand mismatch), cardiomyocyte atrophy, and sudden arrhythmic death.