Authors: Francesco Prati, Giovanni Gurguglione, Flavio Biccire, Luigi Cipolloni, Michela Ferrari, Alessandro Di Toro, Eloisa Arbustini
Categories: CCC 2023 - State of the Art Cardiology Supplement Paper, Atherosclerotic plaques, Ischaemic heart disease (IHD), Myocardial fibrosis, Sudden cardiac death (SCD), AcademicSubjects/MED00200
Source: European Heart Journal Supplements : Journal of the European Society of Cardiology
The mechanisms underlying sudden cardiac death (SCD) in patients with ischaemic heart disease (IHD) caused by coronary atherosclerosis are not yet clarified. For decades, acute coronary causes have been sought as the main triggers of SCD in these patients. In fact, angiographic and pathological studies in cardiac arrest survivors and SCD victims, respectively, consistently show that acute plaque events occur in ∼50% of SCD of patients with IHD. Among the acute events, plaque rupture and erosion triggering acute coronary thrombosis remain the main substrates; however, a significant percentage of plaque haemorrhage (20%) is identified by pathological studies. Its role in acute coronary thrombosis is unknown and deserves future intravascular imaging developments. In the remaining 50% of SCD, the atherosclerotic coronary disease shows the characteristics of structural stability. More recent studies have focused attention not only on the coronary tree and on the search for acute complications of atherosclerotic plaques but also on myocardial tissue, identifying replacement and patchy fibrosis as the most frequent findings in the post-mortem hearts of these patients, a feature followed by cardiac hypertrophy, as assessed by the heart weight, usually associated with fibrosis. The possibility of characterizing myocardial fibrosis in vivo, besides confirming the pathological data, now offers new risk stratification perspectives to prevent SCD in IHD, alongside the consolidated secondary prevention criteria based on left ventricular dysfunction.
Keywords: Sudden cardiac death (SCD), Ischaemic heart disease (IHD), Atherosclerotic plaques, Myocardial fibrosis
The risk of sudden cardiac death (SCD) has a central role in secondary prevention pathways in patients with ischaemic heart disease (IHD). The causes of cardiac arrest in this clinical context are still a matter of fatal arrhythmias are generally attributed to the acute destabilization and thrombotic occlusions of an atherosclerotic plaque. However, recent studies have questioned this pathophysiological aspect, placing the emphasis on other causes of ventricular arrhythmias underlying cardiac arrest. The latter can be identified in the heart muscle and not only in the coronary bed.
In 1997, Burke et al.^1^ described the pathology findings of 113 male subjects with coronary artery disease (CAD) who died suddenly. The authors identified acute coronary thrombosis in 59 subjects (52%), and severe coronary narrowing in the absence of thrombosis, indicating stable plaque, in 48% of cases. Furthermore, only, 36% of cases with acute thrombosis had an underlying ruptured vulnerable plaque, while in 16% of cases, the lesion underlying the thrombosis was a plaque erosion. Pathology features of acute myocardial infarction (AMI) were observed in 19% of cases with acute thrombosis, 11% of cases with erosion, and 4% of cases with stable plaques. In the multivariate analysis, cigarette smoking emerged as the only risk factor associated with acute thrombosis.
The study by Burke et al.^1^ mainly aimed at identifying atherosclerotic plaques as a possible cause of AMI; however, it also highlighted the common association between SCD and ‘stable’ plaques with non-vulnerable morphology. Two years later, the same group investigated the role of effort in the destabilization of atherosclerotic plaque in subjects who died suddenly.^2^ Plaque rupture was the most common mechanism associated with coronary thrombosis in the presence of intense effort (68%), while rupture was less common in victims of SCD at rest (23%) (P < 0.001).^2^ Acute myocardial infarction was never diagnosed during exercise and only in 13% of subjects with SCD in resting conditions.
For decades, pathological and imaging studies that explored the causes of SCD in CAD have focused on atherosclerotic plaques and strove to identify ‘acute plaque lesions’ matching the acute clinical event. All past studies emphasized the role of plaque vulnerability as a contributor to the risk of SCD. Whereas it was proved that culprit plaques with acute thrombosis were often ulcerated, had a thin fibrous cap, were lipid-rich, and showed inflammation, it was also proved that in 50% of cases, coronary thrombosis was absent and there was no acute coronary lesion underlying the fatal arrhythmic event. These findings should not be in 50% of cases of SCD in IHD, only stable atherosclerotic plaques were present. In these cases, the mechanism of the fatal arrhythmia could not be attributed to an acute occlusive coronary thrombosis; an alternative mechanism had to be considered.
More recently, in vivo studies performed in cardiac arrest survivors have expanded the pathophysiological aspects of SCD in IHD. The COACT study^3^ randomized 552 patients to investigate the results of an aggressive strategy based on an immediate coronary angiography procedure vs. a wait-and-see solution based on a deferred coronary angiography. Immediate coronary angiography had no clinical benefit. The coronary angiography results agreed with the pathological observations of Burke et al.^1,2^ Coronary angiography, performed in 97% of cases, showed thrombotic coronary occlusion in only 3.4% of subjects in the group with immediate coronary angiography vs. 7.6% of patients in the group with deferred coronary angiography. Overall, coronary thrombosis occurred in a very low percentage of cases (8.1%). In line with this observation, angiographically unstable coronary lesions were found in 15% of cases, while severe CAD was common and observed in 66% of cases. Therefore, most subjects showed angiographically severe but stable atherosclerotic disease.
These ‘negative’ clinical results excluded the benefit deriving from an immediate coronary angiography with possible revascularization and were explained by the low rate of coronary thrombosis. In fact, the reason why primary angioplasty is effective in AMI is the recanalization of the occluded coronary artery, i.e. the removal of the occluding intracoronary thrombus.
The conclusions of the COACT^3^ were confirmed by the TOMAHAWK study.^4^ This randomized study, with a design similar to the COACT,^3^ compared an aggressive strategy with immediate angiography with a more conservative solution in cardiac arrest survivors. A culprit lesion potentially responsible for the arrhythmic event was only observed in 40% of cases.
Pathological and angiographic studies concordantly show that AMI caused by the destabilization of atherosclerotic plaques is not the unique pathophysiological mechanism underlying SCD in subjects with IHD. Therefore, the open question is what the other causes are. The recent study by Holmström et al.^5^ helps to clarify these aspects. The study was performed on 600 subjects who died of SCD in the presence of CAD and included histological analysis of both coronary arteries and myocardial tissue. Heart weight was higher than normal values in 78% of subjects, and fibrosis was present in 93% of cases. In 58% of cases, the fibrosis was substitutive and attributable to prior healed AMI. In 56% of cases, however, there was an AMI, a percentage higher than those previously reported in subjects with SCD and CAD.^1–4^
The latter finding agrees with the rate of thrombosis and/or plaque ulceration observed in autopsy studies. In fact, the study of the coronary arteries showed signs of plaque rupture or erosion in 24% of cases, plaque haemorrhage in 24%, and stable plaque in the remaining 52.3% of cases. In confirmation of previous studies, ‘plaque destabilization’ was present in less than half of the cases. Finally, plaque rupture and erosion, which commonly trigger acute coronary thrombosis, were more frequent in subjects with sudden death that occurred during exercise. The pathological study of the myocardium has explored alternative mechanisms to plaque destabilization as a trigger for fatal myocardial fibrosis was present in over 93% of cases. Fibrosis was of a substantial degree in 13% of cases and of a moderate degree (patchy) in 68% of cases.
In addition to the fibrosis, a relevant finding was the presence of hypertrophy (weight above normal values) in 78% of cases. Only 2.7% of the victims had neither fibrosis nor ventricular hypertrophy. In the subgroup of patients with stable atherosclerotic plaques, i.e. in the absence of plaque rupture, erosion, or haemorrhage, fibrosis was found in 92% of cases and was substantial in 11.8% and patchy in 66.2%. Hypertrophy was rarely an isolated finding and was observed in association with fibrosis in almost all cases.
Studies performed with cardiac magnetic resonance (CMR) imaging (MRI) have correlated the extent of fibrosis with ventricular arrhythmias or the risk of SCD. Zegard et al.^6^ performed CMR in 979 patients with IHD. The presence of fibrosis on MRI was significantly associated with the risk of SCD [hazard ratio (HR): 10.1; confidence interval (CI): 1.42–1278.9] and the composite arrhythmic endpoint of SCD, resuscitated cardiac arrest, sustained ventricular tachycardia, ventricular fibrillation, or appropriate defibrillator shock (HR: 28.0; 95% CI: 4.07–3,52). The presence of significant myocardial fibrosis, defined as fibrosis on visual assessment and greyzone fibrosis (GZF) > 5 g on CMR, was associated with the risk of SD and the arrhythmic endpoint (respectively sHR: 10.8; 95%, CI: 3.74–30.9 and sHR: 7.40; 95% CI: 4.29–12.8). Furthermore, the burden of fibrosis was more closely associated with SCD than was observed for reduced ejection fraction. The data, obtained in a population including patients with preserved left ventricular systolic function, confirm other studies carried out in patients with reduced ejection fraction that correlated the extent of fibrosis on CMR expressed as GZF with the risk of SCD.^7–9^
Overall, pathological, angiographic, and CMR studies of SCD in IHD consistently dichotomize the causes into coronary plaque complications and myocardial scarring, in roughly similar proportions (Figure 1). Investigation of plaque vulnerability in secondary prevention remains a key clinical issue. There is no doubt that recurrences of MI and cardiac death increase significantly in subjects with ‘vulnerable’ plaques with thin fibrous caps, large lipid pools, and inflammation. This mechanism, however, accounts for no more than 50% of SCD in IHD. The remaining 50% is likely attributable to myocardial scars. Each mechanism requires targeted prevention and treatment strategies. In the former, the mechanism is likely the acute thrombotic occlusion complicating a vulnerable plaque. In the latter, the most likely mechanism is ventricular arrhythmias due to re-entrant circuits with arrhythmogenic potential in border zones (electrically active) between the transmural infarct scar (electrically silent) and spared myocardium. Similarly, non-transmural ischaemia may also trigger ventricular arrhythmias whose pathological substrate is that of border scar areas. Preferential sites of arrhythmogenesis in post-AMI are the conducting channels in the border zones of scars, where fibrosis is mixed with still viable myocytes and adipocytes.^10^ Cardiac magnetic resonance is the key diagnostic tool for myocardial fibrosis. Finally, hypertrophy can play a role; however, the hypertrophy as an isolated finding does not seem to be essential or sufficient to trigger fatal arrhythmias in IHD; in the series by Holmström et al.,^5^ isolated hypertrophy was present in a low percentage (2% of cases) of cases of SCD and stable atherosclerosis.
Figure 1 Dual etiopathogenesis of sudden cardiac death in ischaemic heart acute plaque pathology (left panels) vs. myocardial scarring in post-acute myocardial infarction (right panels).
Prior imaging and pathology evidence and the recent study by Holmström et al.^5^ call for new considerations and questions in SCD of patients with IHD:
Studies on coronary atherosclerotic plaques, risk factors and ischemic heart disease are supported by CLI Foundation (F.P. and F.B.) and by grants from the Ministry of Health to the National IRCCS Cardiology Network (RCR-2022-23682288) and from FRRB grant CP2_14/2018, INTESTRAT-CAD, Lombardia Region, Italy (E.A.).
Francesco Prati, CLI Foundation Onlus, Cli Foundation, Rome, Italy; UniCamillus—Saint Camillus International University of Health Sciences, Rome, Italy.
Giovanni Gurguglione, Dipartimento di Medicina Clinica e Sperimentale, Università di Foggia, Foggia, Italy.
Flavio Biccire, CLI Foundation Onlus, Cli Foundation, Rome, Italy; UniCamillus—Saint Camillus International University of Health Sciences, Rome, Italy.
Luigi Cipolloni, Dipartimento di Medicina Clinica e Sperimentale, Università di Foggia, Foggia, Italy.
Michela Ferrari, Centre for Inherited Cardiovascular Diseases, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy.
Alessandro Di Toro, Centre for Inherited Cardiovascular Diseases, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy.
Eloisa Arbustini, Centre for Inherited Cardiovascular Diseases, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy.
None declared.
No new data were generated or analysed in support of this research.
No new data were generated or analysed in support of this research.