Authors: Parag Bawaskar (1Cardiovascular Division, Department of Medicine, University of Minnesota Medical School, Minneapolis, Minnesota, USA), Nicholas Thomas (1Cardiovascular Division, Department of Medicine, University of Minnesota Medical School, Minneapolis, Minnesota, USA), Khaled Ismail (1Cardiovascular Division, Department of Medicine, University of Minnesota Medical School, Minneapolis, Minnesota, USA), Yugene Guo (1Cardiovascular Division, Department of Medicine, University of Minnesota Medical School, Minneapolis, Minnesota, USA), Sanya Chhikara (1Cardiovascular Division, Department of Medicine, University of Minnesota Medical School, Minneapolis, Minnesota, USA), Pal Satyajit Singh Athwal (1Cardiovascular Division, Department of Medicine, University of Minnesota Medical School, Minneapolis, Minnesota, USA), Alison Ranum (1Cardiovascular Division, Department of Medicine, University of Minnesota Medical School, Minneapolis, Minnesota, USA), Achal Jadhav (1Cardiovascular Division, Department of Medicine, University of Minnesota Medical School, Minneapolis, Minnesota, USA), Abel Hooker Mendez (1Cardiovascular Division, Department of Medicine, University of Minnesota Medical School, Minneapolis, Minnesota, USA), Ishan Nadkarni (1Cardiovascular Division, Department of Medicine, University of Minnesota Medical School, Minneapolis, Minnesota, USA), Dominic Frerichs (1Cardiovascular Division, Department of Medicine, University of Minnesota Medical School, Minneapolis, Minnesota, USA), Pratik Velangi (1Cardiovascular Division, Department of Medicine, University of Minnesota Medical School, Minneapolis, Minnesota, USA), Tesfatsiyon Ergando (1Cardiovascular Division, Department of Medicine, University of Minnesota Medical School, Minneapolis, Minnesota, USA), Hassan Akram (1Cardiovascular Division, Department of Medicine, University of Minnesota Medical School, Minneapolis, Minnesota, USA), Adinan Kanda (1Cardiovascular Division, Department of Medicine, University of Minnesota Medical School, Minneapolis, Minnesota, USA), Chetan Shenoy (1Cardiovascular Division, Department of Medicine, University of Minnesota Medical School, Minneapolis, Minnesota, USA)
Categories: Article, Coronary artery disease, cardiac magnetic resonance imaging, ischemic cardiomyopathy, non-ischemic cardiomyopathy, dual cardiomyopathy, etiology, prognosis, outcomes
Source: Circulation
Authors: Parag Bawaskar, Nicholas Thomas, Khaled Ismail, Yugene Guo, Sanya Chhikara, Pal Satyajit Singh Athwal, Alison Ranum, Achal Jadhav, Abel Hooker Mendez, Ishan Nadkarni, Dominic Frerichs, Pratik Velangi, Tesfatsiyon Ergando, Hassan Akram, Adinan Kanda, Chetan Shenoy
Randomized trials in obstructive coronary artery disease (CAD) have largely shown no prognostic benefit from coronary revascularization. While there are several potential reasons for the lack of benefit, an underexplored possible reason is the presence of coincidental non-ischemic cardiomyopathy (NICM). We investigated the prevalence and prognostic significance of NICM in patients with CAD (CAD-NICM).
We conducted a registry study of consecutive patients with obstructive CAD on coronary angiography who underwent contrast-enhanced cardiovascular magnetic resonance imaging (CMR) for the assessment of ventricular function and scar at 4 hospitals from 2004 to 2020. We identified the presence and cause of cardiomyopathy using CMR and coronary angiography data, blinded to clinical outcomes. The primary outcome was a composite of all-cause death or heart failure (HF) hospitalization, and secondary outcomes were all-cause death, HF hospitalization, and cardiovascular death.
Among 3,023 patients (median age 66 years, 76% men), 18.2% had no cardiomyopathy (CAD+noCM), 64.8% had ischemic cardiomyopathy (CAD+ICM), 9.3% had CAD+NICM, and 7.7% had dual cardiomyopathy (CAD+dualCM) defined as both ICM and NICM. Thus, 16.9% had CAD+NICM or dualCM. During a median follow-up of 4.8 years (interquartile range, 2.9, 7.6), 1,116 patients experienced the primary outcome. In Cox multivariable analysis, CAD+NICM or dualCM was independently associated with a higher risk of the primary outcome compared with CAD+ICM [adjusted hazard ratio (HR) 1.23; 95% confidence interval (CI) 1.06-1.43; P = 0.007] after adjustment for potential confounders. The risks of the secondary outcomes of all-cause death and HF hospitalization were also higher with CAD+NICM or dualCM (HR 1.21; 95% CI 1.02-1.43; P = 0.032 and HR 1.37; 95% CI 1.11-1.69; P = 0.003 respectively), while the risk of cardiovascular death did not differ from that of CAD+ICM (HR 1.15; 95% CI 0.89-1.48; P = 0.28).
In patients with CAD referred for clinical CMR, NICM or dualCM was identified in 1 of every 6 patients and was associated with worse long-term outcomes compared with ICM. In patients with obstructive CAD, coincidental NICM or dualCM may contribute to the lack of prognostic benefit from coronary revascularization.
In patients with obstructive coronary artery disease (CAD), multiple randomized clinical trials including COURAGE (Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation)^1^, ISCHEMIA (International Study of Comparative Health Effectiveness With Medical and Invasive Approaches)^2^, BARI-2D (Bypass Angioplasty Revascularization Investigation 2 Diabetes)^3^, and REVIVED-BCIS2 (REVascularization for Ischemic VEntricular Dysfunction)^4^ have failed to demonstrate improved outcomes after coronary revascularization. Potential explanations for these results include the remarkable effectiveness of modern CAD treatments^5,6^ and the confounding implications of coronary microvascular dysfunction^7^.
An underexplored reason for the lack of benefit from coronary revascularization may be the occurrence of coincidental non-ischemic cardiomyopathy (NICM) in some patients with obstructive CAD, sometimes misclassified as ischemic cardiomyopathy (ICM). In a clinicopathologic study of 170 patients who had cardiac transplantation and obstructive coronary stenoses on examination of their explanted hearts, 22 (13%) were found to have NICM on examination of the myocardium^8^. Of the 22 with CAD and NICM, 11 (50%) were clinically diagnosed and treated as ICM until transplantation. Patients with obstructive CAD and NICM may not respond optimally to coronary revascularization because it solely targets CAD, not the cause of their cardiomyopathy. Yet, there is a lack of large-scale data on the epidemiology and clinical significance of NICM in patients with obstructive CAD. These data could provide valuable insights into how coincidental NICM may contribute to the lack of benefit from coronary revascularization. Such insights could help refine the selection of patients for coronary revascularization and improve outcomes for all CAD patients.
Cardiovascular magnetic resonance imaging (CMR) has been used for over 2 decades to distinguish between ICM and NICM by characterizing the myocardium, largely independent of coronary angiography findings^9-11^. CMR offers a unique tool to investigate NICM in patients with obstructive CAD. We aimed to investigate the prevalence and prognostic significance of NICM in a large cohort of patients with obstructive CAD who had CMR.
To protect patient confidentiality, only a limited dataset may be made available to other researchers on reasonable request.
We assembled a retrospective cohort of consecutive patients with obstructive CAD who underwent clinical CMR with late gadolinium enhancement (LGE) imaging for the assessment of ventricular function and scar from 2004 to 2020 at 4 hospitals within the University of Minnesota M Health Fairview system (the UMNCMRCAD Registry). Eligible patients were aged 18 or older, with documented atherosclerotic obstructive CAD, defined as ≥70% stenosis in ≥1 of the left anterior descending artery (LAD), circumflex artery (Cx), or right coronary artery (RCA) and/or ≥50% stenosis of the left main (LM) coronary artery identified on invasive coronary angiography at any time prior to, or up to 1 year after CMR. Patients were included irrespective of whether the CAD was revascularized at the time of the CMR. Exclusion criteria included cardiac transplantation prior to the CMR, complex congenital heart disease, and cardiac tumors (Figure 1).
Demographic data, medical history, comorbidities, medications, and outcome data were collected while blinded to CMR data from the electronic medical record by study investigators. Details of CAD were collected from coronary angiography reports. In those who had coronary revascularization, data from the coronary angiography prior to revascularization were included, and in those who did not have revascularization, data from the coronary angiography closest to the CMR were included. For outcome analyses, the severity of CAD was classified using a modified Duke prognostic index^12^ into the following 4 1) obstructive disease in 1 coronary artery other than in the proximal LAD or the LM coronary artery; 2) obstructive disease in 2 coronary arteries other than the LM coronary artery, or in the proximal LAD; 3) obstructive disease in 3 coronary arteries other than the LM coronary artery, or 2 coronary arteries including the proximal LAD; and 4) obstructive disease in the LM coronary artery. Patients were assigned to the highest disease category.
Mitral regurgitation severity was obtained from reports of echocardiography studies done closest to and within 1 year of the CMR. In patients without echocardiography within 1 year of the CMR (16% of the study cohort), the severity of mitral regurgitation was assessed from the cine CMR images using parameters established by Heitner et al^13^.
This retrospective cohort study was approved by the institutional review board at the University of Minnesota with a waiver of informed consent owing to the retrospective nature of the study.
Patients underwent CMR on clinical 1.5 Tesla (97%) or 3.0 Tesla (3%) Siemens scanners using phased-array receiver coils according to standard recommendations^14^. The standard protocol was as follows. First, localizers were acquired to identify the cardiac position. Next, steady-state free precession cine CMR images were acquired in multiple short-axis views (every 10 mm to cover the entire left ventricle (LV) from the mitral valve plane through the apex) and 3 long-axis views (2-, 3-, and 4-chamber). Standard LGE imaging was performed 10-15 minutes after administration of gadolinium contrast (0.10-0.15 mmol/kg), using a 2-dimensional segmented inversion-recovery gradient-echo sequence in identical views as cine CMR imaging^15^. Single-shot LGE imaging with steady-state free precession readout was also performed as a backup for patients with irregular rhythm, and/or difficulty breath holding^15^. Typical inversion delay times were 280-360 milliseconds.
CMR analyses were performed in a core laboratory fashion blinded to all other patient information by the consensus of 2 investigators with expertise in CMR. LV and right ventricular (RV) volumes and ejection fraction (LVEF and RVEF) were determined from the short-axis cine images by quantitative analysis according to standard recommendations^16^. The presence of LGE was assessed visually. We assessed the extent of left ventricular LGE semiquantitatively on a 17-segmental basis from the area of hyperenhanced myocardium on LGE images on a 5-point scale as previously 0, no hyperenhancement; 1, 1% to 25% hyperenhancement; 2, 26% to 50% hyperenhancement; 3, 51% to 75% hyperenhancement; and 4, 76% to 100% hyperenhancement^15,17,18^. We calculated the global LGE extent as a percentage of the LV myocardium by adding the segmental scores weighted by the midpoint of the range of hyperenhancement and dividing by 17 for the total number of segments^15,17,18^. This method of LGE quantification has been shown to have a high correlation with and similar reproducibility as automated quantification methods^17^. To verify this in our cohort, we performed automated quantification using the full-width at half-maximum (FWHM) algorithm in 50 random patients.
The presence and the cause of cardiomyopathy were determined blinded to clinical outcomes by the consensus of 2 investigators with expertise in CMR, cardiomyopathies, and clinical cardiology, using coronary angiography data, and CMR data, in an approach adapted from Assomull et al^11^.
We defined cardiomyopathy as the presence of 1 or more of the abnormal LVEF (defined as LVEF<50%), LGE, or morphological abnormalities of NICM [moderate or severe LV hypertrophy (LVH), moderate or severe LV dilatation, and regional wall motion abnormalities consistent with stress cardiomyopathy]. Patients without any of these abnormalities were classified as having no cardiomyopathy (CAD+noCM). In patients with a cardiomyopathy, the cause was classified as ICM (CAD+ICM), NICM (CAD+NICM), or dual (both ischemic and non-ischemic) cardiomyopathy (CAD+dualCM) using an interpretation algorithm (Figure 2) incorporating these the presence and pattern of LGE, morphological features of NICM (listed earlier), abnormal LVEF, disproportionate dysfunction, unrevascularized obstructive CAD at the time of the CMR, and recent acute myocardial infarction (MI) or cardiac arrest. Definitions of the data used in the interpretation algorithm and other relevant details are provided in the Supplement.
In patients with CAD+NICM or CAD+dualCM, the cause of NICM was determined by incorporating the results of all non-imaging diagnostic investigations, e.g., endomyocardial biopsy, genetic testing, performed after the CMR. Definitions of the causes of NICM are listed in Table S1 in the Supplement.
To define the incremental value of CMR, we reviewed the electronic medical records to determine the proportion of patients with CAD+NICM or CAD+dualCM in whom it was clinically not suspected prior to the CMR.
The primary outcome was a composite of all-cause death or heart failure (HF) hospitalization. The secondary outcomes were all-cause death, HF hospitalization, and cardiovascular death.
Details of survival status and HF hospitalizations were collected by review of the electronic medical records blinded to the CMR findings. HF hospitalization was defined as a hospitalization lasting >24 hours primarily for symptoms of HF, with clinical and/or radiographic signs of HF, treated with at least 1 of the intravenous diuretic therapy, intravenous vasodilators, inotropic support, left ventricular assist device, or cardiac transplantation^4^.
Mortality status and death dates were collected from the electronic medical records and cross-verified with the Minnesota State Department of Health's Office of Vital Records. The cause of death was adjudicated as cardiovascular, non-cardiovascular, or of undetermined cause by 2 cardiologist investigators blinded to the cause of the cardiomyopathy using data from electronic medical records and death certificates as outlined in the Online Supplement.
Follow-up started at the date of CMR and was truncated after 10 years because <10% of the cohort was still under follow-up after this time point^19^.
Categorical variables were expressed as counts with percentages. Normally distributed continuous variables were expressed as mean ± standard deviation, and non-normally distributed continuous variables were presented as medians with interquartile range (IQR).
Patients with LVEF disproportionately lower than the extent of LGE were identified using standardized residuals in a linear regression model^20^. Residuals represent the vertical distance between each data point and the regression line. By analyzing the magnitude of residuals, outliers that deviate significantly from the expected pattern can be identified using a threshold value. The threshold was determined by the investigators based on the inclusion of cases deemed to have disproportionate dysfunction by the expert investigators on review of a subgroup of a random 10% sample of eligible patients. Thus, patients with standardized residuals larger than 15 were considered outliers with disproportionately worse dysfunction relative to the extent of LGE.
Interobserver variability was assessed in a subgroup of 30 patients interpreted by 2 independent investigators using Cohen’s kappa (κ) for LGE presence and Pearson correlation coefficient for LGE extent.
Survival analyses were performed to compare outcomes by the cause of cardiomyopathy. The number of patient-years of follow-up was calculated by adding the follow-up time in years for all patients starting from the date of the CMR until the primary outcome or the end of follow-up. To capture the prognostic significance of NICM, we combined the CAD+NICM and CAD+dual CM groups into a single group named CAD+NICM or dualCM. The cumulative incidence of the primary outcome and the secondary outcome of all-cause mortality were estimated using the Kaplan-Meier method. Pairwise unadjusted comparisons were made using the log-rank test with P value adjustment for multiple testing using the Benjamini and Hochberg method^21^. Multivariable analyses of event-free survival were performed using Cox proportional hazards regression.
For the secondary outcomes of HF hospitalization and cardiovascular mortality, competing risk analyses were performed with an estimation of cumulative incidence function and Fine-Gray subdistribution hazard modeling. All-cause death was considered as the competing risk for HF hospitalization analyses and non-cardiovascular death was considered the competing risk for cardiovascular mortality analyses. Deaths of undetermined cause were considered non-cardiovascular for these analyses.
Covariates for inclusion in the multivariable models were chosen a priori based on prior published literature and the investigators’ clinical experience and included age, sex, body mass index, hypertension, diabetes mellitus, current or former smoking, coronary revascularization prior to the CMR, cerebrovascular disease, peripheral vascular disease, severity of CAD, and moderate or severe mitral regurgitation.
The assumption of proportional hazards was assessed by plotting the scaled Schoenfeld residuals for each independent variable against time; these correlations were found to be nonsignificant for all variables included in the multivariable models.
All eligible variables were tested for collinearity using the variance inflation factor measure before being included in the final multivariable models. All multivariable models showed acceptably low multicollinearity.
Statistical significance was defined as a 2-tailed p-value of <0.05. Analyses were done in RStudio 2023.06.1+524.
The study cohort consisted of 3,023 consecutive patients identified after screening 13,306 patients for obstructive CAD (Figure 1).
Patient characteristics at the time of the CMR are provided in Table 1. The median age was 66 years and 76% were men. The prevalence of cardiovascular risk factors was expectedly high with 82% and 35% having diagnoses of hypertension and diabetes mellitus respectively. Fifty-nine percent had a history of MI, 62% had a history of percutaneous coronary intervention (PCI), and 20% had a history of coronary artery bypass grafting (CABG) prior to the CMR. Overall, 91% had coronary angiography prior to the CMR. With respect to CAD severity, 11% had left main (LM) coronary artery disease, and the remaining had a nearly equal distribution of 1 vessel, 2 vessels or proximal LAD, and 3 vessels or 2 vessels with proximal LAD disease. Eight percent of patients were identified to have moderate or severe mitral regurgitation.
CMR findings are listed in Table 2. The median LVEF for the overall cohort was 46%; 44% of patients had LVEF ≥50% and 40% had LVEF ≤40%. The prevalence of LGE was 74.9%; 70.1% had LGE in an MI pattern and 6.3% had LGE in a non-MI pattern. The median global LGE extent was 10.5%.
We found a strong correlation between the scar extent determined by visual scoring and semiautomated quantification, with Pearson correlation coefficient r = 0.89; P<0.001. Reproducibility analysis of visual scoring between 2 independent investigators demonstrated perfect agreement for LGE presence (κ = 1.00) and a very strong correlation for LGE extent (Pearson correlation coefficient r = 0.96; P<0.001).
Among the 3,023 study patients, 551 (18.2%) had CAD+noCM, 1,960 (64.8%) had CAD+ICM, 280 (9.3%) had CAD+NICM, and 232 (7.7%) had CAD+dualCM. Thus, 512 (16.9%) had CAD+NICM or dualCM.
Among the study patients, 1,709 (56.5%) had LVEF <50%, of whom 1,404 (82.2%) had CAD+ICM, 139 (8.1%) had CAD+NICM, and 166 (9.7%) had CAD+dualCM. Thus, 305 (17.8%) had LV EF <50% and CAD+NICM or dualCM.
Table S2 in the Supplement provides a breakdown of the numbers and proportions of patients aligned with the interpretation algorithm.
Figure S1 in the Supplement shows how patients with disproportionate LV dysfunction were identified from patients with MI LGE and LVEF<50%.
Examining more conservative definitions of severe CAD to define CAD+ICM with hibernating myocardium, the prevalence of CAD+ICM decreased to 63.8% and the prevalence of CAD+NICM or dualCM increased to 17.9% when severe CAD was defined as at least 1 proximal non-revascularized 80% stenosis of an epicardial coronary artery or 60% stenosis of the LM coronary artery. The prevalence of CAD+ICM decreased further to 63.2% and the prevalence of CAD+NICM or dualCM increased further to 18.6% when severe CAD was defined as at least 1 proximal non-revascularized 90% stenosis of an epicardial coronary artery or 70% stenosis of the LM coronary artery.
Among patients with CAD+NICM or dualCM, the most common identifiable causes of NICM (Table S3 in the Supplement) were hypertrophic cardiomyopathy, hypertensive cardiomyopathy, and valvular dysfunction-related cardiomyopathy. In 21.3% of cases, the specific cause of NICM could not be determined.
Among 102 patients with hypertrophic cardiomyopathy (including 4 with a second cause of NICM), the median maximal wall thickness was 1.7 cm (IQR 1.5, 1.9). Genetic testing was performed on 4 patients with no pathological variants identified.
Out of 46 patients with tachyarrhythmia-related cardiomyopathy, 33 had atrial tachyarrhythmia (26 atrial fibrillation, 5 atrial flutter, and 2 atrial tachycardia), while 13 had frequent premature ventricular contractions.
Out of 30 patients with cardiac amyloidosis, 26 had confirmation of their diagnosis, including 23 with ATTR cardiac amyloidosis [confirmed by endomyocardial biopsy in 14, technetium Tc 99m pyrophosphate (99mTc-PYP) scanning in 8, and both methods in 1 patient] and 3 with AL-type amyloidosis (2 confirmed by bone marrow biopsy and 1 through endomyocardial biopsy).
Out of 11 patients with genetic/familial dilated cardiomyopathy, 2 had a family history of cardiomyopathy and 1 had a family history of sudden cardiac death. Genetic testing was performed on 3 patients, revealing a TTN truncating mutation in 1 patient, while 2 patients had variants of uncertain significance.
Among 4 patients with cardiac sarcoidosis, 2 had confirmation of their diagnosis by endomyocardial biopsy, while the other 2 had extracardiac histologically proven sarcoidosis.
All 3 patients with Fabry cardiomyopathy were confirmed through genetic testing.
Examples of patients from the cardiomyopathy categories are provided in Figure 3 and Figure S2 in the Supplement.
Among patients with CAD+NICM or dualCM, 51% (38% of CAD+NICM and 67% of CAD+dualCM) were not clinically suspected to have a cardiomyopathy other than CAD+ICM prior to the CMR.
The median LVEF was 40% (IQR 29, 51) among patients with CAD+ICM, while it was 46% (IQR 31, 59) among patients with CAD+NICM or dualCM. Out of 1,960 patients with CAD+ICM, 1,914 (97.7%) had LGE, compared with 348 (68.0%) of the 512 patients with CAD+NICM or dualCM. The median global LGE extent among patients with CAD+ICM was 17.9% (IQR 8.9, 28.9) of the LV mass, whereas the median global LGE extent among patients with CAD+NICM or dualCM was 3.1% (IQR 0.0, 9.1).
The study cohort was followed for a median of 4.8 years (IQR 2.9, 7.6), totaling 15,393 patient-years of follow-up. Treatments and procedures performed during follow-up are listed in Table S4 in the Supplement. During this period, 856 patients died. Among them, the cause of death was cardiovascular in 399 (46.6%), non-cardiovascular in 388 (45.3%), and undetermined in 69 (8.1%). Five hundred and seventy-one patients had HF hospitalization, during which 32 patients received a left ventricular assist device and 30 patients underwent cardiac transplantation. Overall, 1,116 patients had the primary outcome of all-cause death or HF hospitalization (Table 3).
Among the 30 patients who had cardiac transplantation, the cause of the cardiomyopathy identified using the study algorithm was accurate in all patients when compared to the cause determined on pathology review of the explanted heart. Additional details are provided in the Supplement.
On Kaplan-Meier analyses (Figure 4 Panels A and B), patients with CAD+NICM or dualCM had a higher risk of the primary outcome of all-cause death or HF hospitalization and the secondary outcome of all-cause death (log-rank P<0.001 for both comparisons) compared with patients with CAD+ICM. Similarly, on cumulative incidence function analyses accounting for competing risks (Figure 4 Panels C and D), compared with patients with CAD+ICM, those with CAD+NICM or dualCM had a higher risk of the secondary outcomes of HF hospitalization and cardiovascular death (Gray’s P<0.001 and P = 0.030 respectively).
The same unadjusted analyses showed lower risk of all 4 outcomes for patients with CAD+noCM compared with patients with CAD+ICM.
On Cox multivariable proportional hazards regression analysis (Table 4), patients with CAD+NICM or dualCM had a higher risk of the primary outcome of all-cause death or HF hospitalization [adjusted hazard ratio (HR) 1.23; 95% confidence interval (CI) 1.06-1.43; P = 0.007] compared with patients with CAD+ICM. The risks of the secondary outcomes of all-cause death and HF hospitalization were also higher with CAD+NICM or dualCM (HR 1.21; 95% CI 1.02-1.43; P = 0.032 and HR 1.37; 95% CI 1.11-1.69; P = 0.003 respectively), while the risk of cardiovascular death did not differ from that of CAD+ICM (HR 1.15; 95% CI 0.89-1.48; P = 0.28).
The same adjusted analyses showed lower risk of all 4 outcomes for patients with CAD+noCM compared with patients with CAD+ICM.
In a subgroup analysis of patients with LV EF<50% (Table S5 in the Supplement), those with CAD+NICM or dualCM had a higher risk of the primary outcome (all-cause death or HF hospitalization) and the secondary outcome of HF hospitalization, whereas the risk of the secondary outcomes of all-cause death and cardiovascular death did not differ from patients with CAD+ICM.
In sensitivity analyses, patients with CAD+NICM had a higher risk of the primary outcome compared with patients with CAD+ICM (adjusted HR 1.35; 95% CI 1.11-1.63; P = 0.002), but patients with CAD+dualCM did not differ in the risk of the primary outcome compared to patients with CAD+ICM (adjusted HR 1.10; 95% CI 0.90-1.36; P = 0.33).
In additional sensitivity analyses defining severe CAD as at least 1 proximal non-revascularized 80% stenosis of an epicardial coronary artery or 60% stenosis of the LM coronary artery, CAD+NICM was associated with a higher risk of the primary outcome with an adjusted HR of 1.19; 95% CI 1.03-1.38; P = 0.018. Using the definition of at least 1 proximal non-revascularized 90% stenosis of an epicardial coronary artery or 70% stenosis of the LM coronary artery, CAD+NICM was associated with a non-statistically significant higher risk of the primary outcome with an adjusted HR of 1.14; 95% CI 0.99-1.33; P = 0.065.
In a large cohort of 3,023 consecutive patients with obstructive CAD who had CMR for clinical reasons over 17 years, we identified CAD+NICM or dualCM in 17%. These patients experienced worse long-term outcomes with a higher long-term risk of all-cause death or HF hospitalization compared with those with CAD+ICM. In the subgroup of patients with LVEF <50%, the proportion of patients with CAD+NICM or dualCM was 18%; these patients again had a higher risk of long-term outcomes of all-cause death or HF hospitalization compared with those with CAD+ICM.
The occurrence of NICM in patients with CAD was first described in necropsy studies in the late 1980s. In 1986, Ross and Roberts described 18 patients with HF who had idiopathic dilated cardiomyopathy and coincidental obstructive CAD^22^. Three years later, Atkinson and Virmani published a necropsy study of 54 consecutive patients with HF, of whom, 26 (48%) had obstructive CAD and MI and were deemed to have ICM, 19 (35%) had no CAD or MI, and were deemed to have NICM, and 9 (17%) had obstructive CAD but no MI and were deemed to have idiopathic dilated cardiomyopathy and coincidental obstructive CAD^23^. More recently, in the DAPA-HF (Dapagliflozin And Prevention of Adverse Outcomes in Heart Failure) trial, among the patients with non-ischemic HF, 7.4% had MI, 8.5% had PCI, and 3.0% had CABG^24^.
Traditionally the cause of cardiomyopathy has been determined as ICM or NICM by inference from the presence or absence of obstructive CAD on coronary angiography^25,26^. In the past 2 decades, CMR has made it possible to identify the cause of cardiomyopathy by allowing the characterization of the myocardium directly^9-11^. Cardiomyopathies often manifest with distinct patterns of myocardial damage, which can be seen as LGE on CMR and help identify the cause of the cardiomyopathy^10,27^. Following the pathophysiology of ischemic injury, myocardial damage due to an MI always involves the subendocardium and is either subendocardial or transmural and located in a coronary artery perfusion territory^10^. Conversely, NICMs have other patterns of LGE such as subepicardial or midmyocardial LGE^10,27^.
Small CMR studies have reproduced the findings from the pathology studies of the 1980s by describing patients with obstructive CAD on coronary angiography who had NICM on CMR characterization of the myocardium. Among 58 with obstructive CAD on coronary angiography, Assomull et al. described 4 (6.9%) patients with dilated cardiomyopathy based on CMR^11^. Kim et al. studied 34 patients with obstructive CAD and LVEF<35% using CMR and identified NICM in 3 (8.8%) patients and dualCM in 4 (11.8%)^28^. Using a large cohort of consecutive patients with obstructive CAD undergoing CMR for clinical purposes, we provide a reliable estimate of the real-world prevalence of CAD+NICM or dualCM. Our algorithm to determine the cause of cardiomyopathy was validated by the demonstration of 100% accuracy when compared to pathology of the explanted hearts in 30 patients who had cardiac transplantation during follow-up.
Compared to ICM, NICM has been shown to be associated with better long-term outcomes in several studies^24,29-34^. However, the classification of cardiomyopathy in all these studies was based on coronary angiography findings, and patients with NICM were classified as such based on the absence of obstructive CAD. While there have been no prior studies about the long-term outcomes of patients with CAD+NICM, a couple of studies have examined the outcomes of patients with NICM and non-obstructive CAD. Braga et al. showed that patients with HF with reduced LVEF and non-obstructive CAD, defined as the presence of 1-69% stenosis in ≥1 of the LAD, Cx, or RCA and/or 1-49% stenosis of the LM, had a higher risk of all-cause death and a composite endpoint of cardiovascular death, nonfatal acute MI, nonfatal stroke, or HF hospitalization compared with patients with HF with reduced LVEF and normal coronary arteries^35^. Similarly, Raja et al. showed that patients with NICM and moderate CAD, defined as 50-75% stenosis of the LAD, Cx, or RCA and/or 30-50% stenosis of the LM, had higher mortality compared with patients with NICM and no or mild CAD^36^. They also found that the mortality of patients with NICM and moderate CAD was not different from that of patients with ICM. We demonstrate that, unlike patients with no CAD+NICM or nonobstructive CAD+NICM, those with (obstructive) CAD+NICM have a higher hazard of HF hospitalization or death compared with patients with CAD+ICM.
The mechanisms underlying the worse outcomes for CAD+NICM or dualCM compared with CAD+ICM are unknown. While a logical explanation would be that the coincidental occurrence of CAD and NICM pathologies entails risk from dual atherosclerotic and non-ischemic cardiomyopathic processes, this explanation is not supported by the observation that only patients with CAD+NICM had higher risk, not those with CAD+dualCM. More work is needed to understand the mechanisms driving the long-term outcomes in CAD+NICM and CAD+dualCM patients.
While electrocardiography and echocardiography may raise suspicion for CAD+NICM in some patients with CAD, we found that NICM was clinically not suspected prior to the CMR in half of our cohort, underscoring the incremental value of CMR over routine tests.
Guideline-directed medical therapies for atherosclerosis such as aspirin and statin are indicated for reducing the risk of atherosclerotic events in all patients with CAD^37^. Similarly, therapies broadly directed at the management of HF such as beta-blocker, ARNI, mineralocorticoid receptor antagonist, and SGLT2i are indicated for reducing HF-related adverse outcomes in patients with CAD and LV dysfunction, regardless of the cause of cardiomyopathy^24,37-41^. Our findings of worse outcomes in patients with CAD+NICM or dualCM raise the possibility that coronary revascularization may not be as effective in them as it is in patients with CAD+ICM. The presence of NICM or dualCM in patients with CAD and LV dysfunction may limit the recovery of LV function after coronary revascularization. Thus, not recognizing NICM or dualCM in patients with CAD, or misclassifying it as ICM, may result in suboptimal outcomes after coronary revascularization.
It is plausible that the presence of CAD+NICM or dualCM in some patients may have contributed to the lack of prognostic benefit from coronary revascularization in prior randomized trials^42^. In REVIVED-BCIS2, CMR was 1 of the tests performed to assess viability, and of 2,695 patients screened for eligibility, 326 (12.1%) were deemed ineligible because they had NICM with extensive CAD (CAD+NICM)^43^. Of note, 30% of patients enrolled in the trial did not undergo CMR^4,43^.
Separately, patients with NICM or dualCM may benefit from therapies specifically directed at the cause of the NICM, such as valve surgery for valvular-dysfunction-related cardiomyopathy, control of tachyarrhythmia for tachyarrhythmia-related cardiomyopathy, tafamidis for aTTR cardiac amyloidosis, immunosuppressive therapy for cardiac sarcoidosis, etc. Thus, not recognizing NICM or dualCM in patients with CAD, or misclassifying it as ICM, may result in missed benefits from therapies specifically directed at the cause of the NICM.
Future research should investigate whether NICM or dualCM in patients with CAD influences outcomes specifically after coronary revascularization. If NICM or dualCM does influence outcomes after coronary revascularization, the logical next step would be to investigate whether increased recognition of NICM and dualCM through the routine use of CMR before coronary revascularization improves the selection of patients for coronary revascularization and overall long-term outcomes compared with the standard of care, where CMR is not routinely performed before coronary revascularization. Our study demonstrates that a coronary artery-focused approach using coronary angiography to identify the cause of cardiomyopathy—a disease of the myocardium—could result in the misclassification of up to 1 of every 6 patients with CAD. Instead, a more logical myocardium-focused approach primarily using CMR would avoid this issue.
Another hypothesis generated from our study is that increased recognition of NICM and dualCM through routine use of CMR in all patients with CAD improves long-term outcomes through the increased use of therapies specifically directed at the cause of the NICM.
Our retrospective study of patients referred for a clinically indicated CMR has limitations inherent to the study design, such as referral bias. We included patients from 4 hospitals including an academic tertiary care and 3 community hospitals, minimizing referral bias to some degree. However, ascertainment bias from the preferential referral of patients with CAD+NICM or CAD+dualCM suspected prior to the CMR influenced the prevalence of CAD+NICM or dualCM in our study. Nevertheless, 51% of patients in whom CAD+NICM or dualCM was identified were not suspected to have NICM or dualCM prior to the CMR.
Because our study period spanned over 17 years, encompassing a period of many advances in medical therapy, not all patients had the opportunity to benefit from contemporary guideline-directed medical therapy.
The threshold of severity of CAD required to induce hibernating myocardium is unknown. We used criteria from the seminal work on hibernating myocardium by Rahimtoola et al.^44^ and performed sensitivity analyses using 2 more conservative definitions for severe CAD, with the prevalence of NICM ranging from 16.9% to 18.6% for the 3 definitions.
Finally, stress perfusion CMR was not included in our interpretation algorithm because it was not available in most patients. Identification of ischemia related to epicardial CAD may have helped to determine the cause of cardiomyopathy more accurately in the small minority of patients with LV dysfunction and no LGE, or disproportionate dysfunction.
In patients with CAD referred for clinical CMR, NICM or dualCM was identified in 1 of every 6 patients and was associated with worse long-term outcomes when compared with ICM. In patients with obstructive CAD, coincidental NICM or dualCM may contribute to the lack of prognostic benefit from coronary revascularization.