We retrospectively identified 41 patients with NICM and 58 control patients with preserved systolic function and without clinical heart failure who had undergone comprehensive adenosine stress CMR perfusion between 2011 and 2016 at a single academic institution. NICM was defined by left ventricular ejection fraction (LVEF) 50% without significant CAD. Coronary artery disease was defined as the presence of 50% coronary artery stenosis on invasive or CT coronary angiography, prior coronary artery revascularization, the presence of a segmental perfusion defect on CMR, or the presence of infarct scar on late gadolinium enhancement (LGE) imaging. A control cohort was identified by selecting patients with LVEF 50% who were referred for clinical stress CMR exam. Control patients were excluded if they had any prior history of obstructive CAD on coronary angiography, prior coronary artery revascularization, prior myocardial infarction, or a history of heart failure. Control patients were selected to match risk factors for microvascular dysfunction. Additionally, patients with infarct scar by LGE or focal perfusion defects on first pass stress perfusion were excluded. In the control cohort patients, the indication for stress CMR was chest pain in 38 (66%), ventricular ectopy or ventricular tachycardia in 7 (12%), dyspnea in 3 (5%), syncope in 2 (3%), and other in 8 (14%) patients.
Clinical patient characteristics and comorbidities were established through a review of the electronic medical record. The following baseline clinical characteristics were collected: age, gender, ethnicity, body mass index, New York Heart Association Class, NICM etiology, serum creatinine, hematocrit, BNP, and troponin. The Ohio State University Institutional Review Board approved this retrospective study and agreed to waive informed consent. All investigators have full access to the data and take responsibility for its integrity and the data analysis.
CMR Imaging and Analysis:
Patients underwent clinical CMR exams using a 1.5 Tesla scanner (Magnetom Avanto or Espree, Siemens Medical Solutions, Erlangen, Germany). LV volumes, mass, and EF were assessed using steady state free precession (SSFP) sequences. Ventricular volumes and function were quantified from endocardial and epicardial tracing of serial short axis slices at end diastole and end systole. LV mass was calculated by multiplying the total myocardial volume at end diastole by the specific gravity of the myocardium (1.05 g/ml)18.
Vasodilator stress CMR was performed using a 140 mcg/kg/min adenosine infusion for 2 minutes prior to first-pass perfusion imaging, and continued until completion of the perfusion imaging data acquisition. First-pass perfusion imaging was performed using a 0.05 mmol/kg bolus of gadolinium based contrast agent (GBCA). A rest perfusion study was performed using the same protocol. Myocardial perfusion defects were assessed by both visual and quantitative analysis. Quantification was performed by manually delineating endocardial and epicardial left ventricular borders in the mid-short axis slice during both stress and rest first-pass perfusion with care to exclude blood pool activity (Cvi42, Circle Cardiovascular Imaging, Calgary, Canada). Only mid-short axis slices were used out of concern for partial volume effects related to thin distal segments in the NICM group. Signal intensity curves of segmental myocardium were automatically generated. MPRI was defined as: MPRI = RUstress/RUrest. RU is defined as the ratio between the maximum upslope of the first-pass myocardial perfusion time-intensity curve divided by the maximum upslope of the first-pass LV cavity time-intensity curve (Figure 1). MVD was defined quantitatively as MPRI <1.51 which was the lower interquartile range for the entire cohort and is similar to that used in the WISE subanalysis19. Qualitative MVD was defined as the presence of a circumferential subendocardial perfusion defect on first pass stress imaging20. Per guidelines, defects which occurred prior to contrast arrival in the LV myocardium, persisted <10 heart beats, or were <2 pixels wide were considered to be due to dark rim artifact and were not identified as true perfusion defects21.
Late gadolinium enhancement imaging was performed using gradient-echo inversion recovery sequences and phase sensitive inversion recovery (PSIR) reconstructions 10 minutes after administration of an additional 0.1 mmol/kg of GBCA22. The presence of LGE was assessed by 2 expert level 3 trained operators blinded to clinical data and had to be present in either two consecutive short axis slices or in two orthogonal imaging planes. LGE was scored according to its presence and extent based on the number of American Heart Association segments23.
Categorical data are presented as frequency with percentage, and comparisons between groups were performed using the chi-square test or Fisher exact test. Skewness, kurtosis, and visual inspection of the histogram and QQ plot were checked to assess the distribution of continuous variables. Continuous variables are presented as mean ± standard deviation (SD) for normal distribution or expressed as median (interquartile range) for non-normal distribution. Continuous variables were compared using Student's t-test or the Wilcoxon rank-sum test, as appropriate. Univariate and multivariable linear regression was performed to assess the relationship between the presence of NICM and MPRI after controlling for significant covariates. Because of non-normal distributed residual in multivariable analysis, logarithmic transformation was performed. To test the robustness of association of non-ischemic cardiomyopathy and RPP, the bootstrap method with 2,000 resampling technique was performed to estimate 95% bias-corrected and accelerated confidence intervals. Further, gamma regression model with an identity link function was applied to assess the robustness of result. Regression diagnostics were performed to test model assumptions. Statistical analyses were performed using R software, version 4.03 (The R Foundation, Vienna, Austria).