Prevalence and association of advanced atherosclerotic lesions in cerebral and coronary arteries: An autopsy study

INTRODUCTION

Cardiovascular diseases, along with other non-communicable conditions such as diabetes and cancer, account for a substantial proportion of global mortality. Cardiovascular diseases, such as ischemic heart disease and cerebrovascular stroke, were the leading causes of almost 17.6 million deaths in a year.^[1] According to the World Health Organization (WHO), India is responsible for one-fifth of these global deaths, particularly among the younger population. According to the Global Burden of Disease study findings, India has an age-standardized cardiovascular disease (CVD) death rate of 272/100,000 people, significantly higher than the global average of 235. Indians are affected by CVD 10 years earlier than people in the West.^[2]

Atherosclerosis is a progressive condition characterized by arterial plaque deposition, leading to vascular stiffening and potential occlusion. This pathology is a well-established contributor to CVD-related mortality. Individuals with multi-arterial atherosclerotic involvement face significantly elevated risks of adverse outcomes. Data indicate that within 3 years of diagnosis, patients with atherosclerosis in multiple arterial territories exhibit a 40% incidence of myocardial infarction, stroke, vascular death, or rehospitalization.^[3] Despite extensive research, only a limited number of autopsy studies have explored the relationship between cerebral and coronary atherosclerosis. Given the evolving lifestyle and environmental factors contributing to early-onset atherosclerosis, a comprehensive investigation into this association is warranted.

MATERIALS AND METHODS

This research was conducted at the Department of Forensic Medicine and Toxicology and the Department of Pathology and Laboratory Medicine at AIIMS Bhopal, an Institute of National Importance in Madhya Pradesh, Central India. This study was approved by the Institutional Human Ethics Committee of All India Institute of Medical Sciences, Bhopal (letter of permission number IHEC-PGR/2020/PG/July/15, dated August 27^th, 2021).

A prospective observational design was employed, encompassing 64 autopsy cases of individuals aged 10 years and older. The selection criteria included cases with intact arterial specimens. Cases with known cardiovascular causes of death were not excluded from this study, as one of our objectives was to examine the relationship between atherosclerotic burden and cause of death, particularly sudden natural death. Cases were categorized into sudden natural death (defined as death within 24 h of symptom onset as per the WHO criteria) and other medicolegal deaths to analyze the relationship between atherosclerotic burden and cause of death. The study focused on analyzing arteries forming the circle of Willis – comprising the basilar artery (BA), middle cerebral artery (MCA), posterior cerebral artery (PCA), and the intracranial segment of the internal carotid arteries (ICAs) – along with the three major coronary arteries: The right coronary artery (RCA), left circumflex artery (LCX), and left anterior descending (LAD) artery. These specimens were meticulously collected using appropriate dissection techniques and subsequently preserved in 10% neutral buffered formalin.^[4] Then, all the arteries were examined by making a series of cross-incisions along the course of the vessel, spaced 2–3 mm apart, using a scalpel to observe any narrowing due to plaque or antemortem thrombus. If any gross atheromatous changes were seen, the site was selected for further histopathological examination. Likewise, two samples from each artery were taken for analysis. If no gross atheromatous changes were seen, two representative samples from the proximal portion of the artery were taken for analysis. Since there were four intracranial arteries to be studied for each case, two blocks were allotted, with two arteries in each block. Of that, one of the arteries was painted with black acrylic to differentiate it from the other.

The slides were evaluated under compound microscopes using 4×, 10×, and 40× objectives to identify the presence of atherosclerosis. The atherosclerosis was graded according to the American Heart Association classification published in 2000, which provides eight distinct grades (I–VIII).^[5] We chose this detailed eight-grade classification over the current simplified six-stage classification because it allows for more precise characterization of lesion progression and severity, which was essential for our study’s objective of analyzing age-specific progression patterns and inter-arterial correlations. The eight-grade system provides better discrimination between intermediate lesion types (III–V) that are crucial for understanding disease progression across different age groups. These grades are outlined below:

• Grade I: Isolated intimal foamy cells

• Grade II: Numerous intimal foamy cells, often in layers (fatty streaks)

• Grade III: Pools of extracellular lipid without a well-defined core (pre-atheroma)

• Grade IV: Well-defined lipid core with the luminal surface covered by normal intima (atheroma or fibro plaque)

• Grade V: Lipid core with a fibrous cap, with or without calcification (fibro-atheroma)

• Grade VI: Fibro-atheroma with cap defects such as hemorrhage and thrombosis

• Grade VII: Prominent calcification

• Grade VIII: Prominent fibrous tissue changes.

In the context of histopathological examination, when multiple types of lesions were observed within an artery, the highest-grade lesion was chosen for study. The lesion gradings are further classified based on their severity, which are mentioned in Table 1.

All data were imported into the Integrated development environment IDE (Posit) and analyzed using the R programming language. The analysis involved tidyverse, gtsummary, readxl, markdown, and relevant dependencies. Continuous data underwent scrutiny for normal distribution and were summarized and analyzed accordingly. Normally distributed variables were summarized using mean and standard deviation, and analyzed using analysis of variance or t-test. Non-normally distributed continuous variables were summarized using median and interquartile ranges and analyzed using Kruskal–Wallis and Mann–Whitney U tests. Categorical variables were analyzed using Pearson’s Chi-squared test. Logistic modeling was applied, and odds ratios with corresponding confidence intervals (CIs) were presented. Probability values equal to or below 0.05 were deemed statistically significant. For multivariable analyses, P-values were adjusted to 0.1.

RESULTS

A total of 64 cases that met the inclusion criteria were included in the study, consisting of 49 (77%) males and 15 (23%) females. The mean age was 39. The mean age was slightly lower for females at 36.07 and higher for males at 40.16. The age range of the subjects spanned from 11 to 85 years. The majority of cases were in the 41–50 age group, and no cases were available in the 71–80 age group. Details of the case distribution across different age groups can be found in Table 2. Histopathological grading revealed significant variations in lesion distribution across different arterial territories:

• Cerebral arteries: Advanced lesions were most prevalent in the internal carotid artery (ICA) (24.19%), followed by the BA (16.13%), MCA (11.29%), and PCA (4.84%) [Table 3]. BA, ICA, and MCA showing grade III and PCA showing grade II lesions [Figure 1].

• Coronary arteries: The highest prevalence of advanced lesions was observed in the LAD artery (46.88%), followed by the RCA (23.44%) and LCX (18.75%) [Table 4]. RCA, LCX showing grade V, and (LAD) LAD artery showing grade VII lesions [Figure 1].

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Figure 1:

Grading of lesions in different arteries. BA: Basilar artery (grade III), PCA: Posterior cerebral artery (grade II), ICA: Internal carotid artery (grade III), MCA: Middle cerebral artery (grade III), RCA: Right coronary artery (grade V), LAD: Left anterior descending artery (grade VII), LCX: Left circumflex artery (grade V).

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Advanced lesions were first observed in the second decade of life in the LCX (13%) and extracranial carotid artery (13%). From the third decade onward, a step-wise progression was evident across most arterial territories. In the third decade (21–30 years), advanced lesions appeared in LAD (36%), RCA (18%), and ICA (10%) were noted. During the fourth decade (31–40 years), there was a marked increase in all territories, with LAD showing 44% prevalence. The fifth decade (41–50 years) showed peak prevalence in multiple arteries – LAD (53%), ICA (35%), and RCA (35%). In the sixth decade (51–60 years), LAD reached 71% prevalence, with continued progression in all territories.

Multivariate analysis demonstrated that individuals with advanced coronary artery lesions were 7.14 times more likely to have advanced lesions in intracerebral arteries (95% CI: 1.73, 38.9; P = 0.011). Univariable analysis further supported this finding, indicating an 8.36-fold increased likelihood of cerebral lesions in patients with coronary atherosclerosis (95% CI: 2.79, 28.3; P < 0.001) [Table 5]. The “unknown” parameter in our tables (n = 2) represents cases where intracranial arteries underwent autolysis, preventing reliable histopathological examination. These cases were excluded from the statistical analysis of intracranial atherosclerosis.

DISCUSSION

Our study contributes to the growing body of evidence linking cerebral and coronary atherosclerosis. The presence of advanced coronary lesions significantly correlates with intracranial atherosclerosis, emphasizing the systemic nature of the disease. Notably, the highest prevalence of cerebral lesions was observed in the ICA, aligning with previous research highlighting its vulnerability to atherosclerotic changes.

Age-specific trends were also evident, with individuals aged 41–50 and 51–60 exhibiting markedly elevated odds of advanced intracranial lesions. These findings underscore the importance of early detection and targeted interventions to mitigate cerebrovascular risks in middle-aged populations.

Moreover, our findings support earlier studies such as those by Uehara et al.^[6] who demonstrated the significance of intracranial atherosclerosis in ischemic heart disease patients. In addition, studies by Uekita et al.^[7] suggest that patients undergoing coronary artery bypass grafting frequently exhibit co-existing intracranial atherosclerosis. The implications of such findings highlight the necessity of comprehensive cardiovascular assessments in individuals presenting with cerebrovascular risk factors.

Interestingly, the relationship between systemic atherosclerosis and neurologic outcomes is further emphasized by recent research indicating that increased coronary arterial calcification is predictive of future cardiovascular events. This aligns with findings by Ohuchi et al.^[8] suggesting that preoperative evaluations of carotid and intracranial arteries should be incorporated into routine cardiovascular assessments. Furthermore, our study corroborates existing evidence on the progression of atherosclerosis from extracranial to intracranial arteries, as proposed by researchers such as Solberg et al.^[9]

Our findings align with those of Mathur et al.^[10] who observed that advanced lesions typically appear in the fourth decade of life. Similarly, Fisher et al.^[11] demonstrated that stenosis was present in both the anterior and posterior portions of the circle of Willis, suggesting a widespread distribution of atherosclerotic involvement. In addition, Kim et al.^[12] found that the MCA was the most frequently affected in Asian populations, while Keche and Keche^[13] emphasized the predominant involvement of the left coronary artery in atherosclerotic progression.

In our study, coronary artery disease was the predominant cause (77.78%) among sudden natural deaths. Sudden death cases showed significantly higher prevalence of advanced lesions across all arterial territories compared to other medicolegal deaths.

The limitations of our study include a relatively small sample size, which may affect the generalizability of findings. The absence of anthropometric data (height, weight, and body mass index [BMI]) represents a significant limitation that affects our understanding of the relationship between obesity-related factors and atherosclerotic progression patterns. Recent studies have established strong correlations between BMI, metabolic syndrome, and accelerated atherosclerosis^[14,15] and the inclusion of these parameters in future studies would enhance understanding of disease progression. Future research should incorporate larger datasets and employ advanced imaging modalities like high-resolution magnetic resonance imaging (MRI) for noninvasive atherosclerotic plaque characterization. Further, an in-depth assessment of inflammatory markers and genetic predispositions to atherosclerosis could provide valuable insights into individual risk stratification. Virtual autopsy using computed tomography and MRI could significantly enhance sample sizes and data quality in future studies. Recent advances in post-mortem imaging allow detailed assessment of atherosclerotic plaques with excellent correlation to histopathology.^[16,17] Virtual autopsy could overcome consent limitations and enable larger population studies, particularly important for studying age-specific progression patterns. This technological advancement could address the sample size limitations noted in our study and provide more comprehensive population data. Integration of molecular autopsy techniques for sudden death cases could identify genetic predispositions to early atherosclerosis.^[18]

CONCLUSIONS

This autopsy-based investigation provides compelling evidence of the association between cerebral and coronary atherosclerosis. Our findings highlight the early onset and widespread prevalence of advanced lesions, underscoring the need for integrated preventive strategies targeting both cardiovascular and cerebrovascular health. Future studies should explore novel imaging techniques to improve the detection and management of atherosclerosis in high-risk populations.