A recent large-scale clinical trial found that an initial invasive strategy does not improve cardiac outcomes beyond optimized medical therapy in patients with stable coronary artery disease (CAD). Novel methods to stratify at-risk patients may refine therapeutic decisions to improve outcomes.
Methods and Results
In a cohort of 815 consecutive patients referred for evaluation of myocardial ischemia, we determined the net reclassification improvement of the risk of cardiac death or nonfatal MI (MACE) incremental to clinical risk models, using guideline–based low (<1%), moderate (1–3%), and high (>3%) annual risk categories. In the whole cohort, inducible ischemia demonstrated strong association with MACE (hazard ratio 14.66, P<0.0001) with low negative event rates of MACE and cardiac death (0.6% and 0.4%). This prognostic robustness maintained in patients with prior CAD (hazard ratio 8.17, P<0.0001, and 1.3% and 0.6%, respectively). Adding inducible ischemia to the multivariable clinical risk model (age and prior CAD adjusted) improved discrimination of MACE (C-statistic 0.81 to 0.86, P=0.04; Adjusted hazard ratio 7.37, P<0.0001) and reclassified 91.5% of patients at moderate pre-test risk (65.7% to low risk; 25.8% to high risk) with corresponding changes in the observed event rates (0.3%/year and 4.9%/year, for low and high risk post-test, respectively). Categorical net reclassification index was 0.229 (95% CI 0.063–0.391). Continuous NRI was 1.11 (95% CI 0.81–1.39).
Stress CMR effectively reclassifies patient risk beyond standard clinical variables, specifically in patients at moderate to high pre-test clinical risk and in patients with prior CAD.
Clinical Trial Registration Information
http://clinicaltrials.gov/. Identifier: NCT01821924.
chronic ischemia; cardiac magnetic resonance imaging
High-fidelity 12-lead Electrocardiogram (ECG) is important for physiological monitoring of patients during MR-guided intervention and cardiac MR imaging. Issues in obtaining non-corrupted ECGs inside MRI include a superimposed Magneto-Hydro-Dynamic (MHD) voltage, gradient-switching induced-voltages, and radiofrequency (RF) heating. These problems increase with magnetic field. We intended to develop and clinically validate a 1.5T MRI-conditional 12-lead ECG system.
The system was constructed, including transmission-lines to reduce radio-frequency induction, and switching-circuits to remove induced voltages. Adaptive filters, trained by 12-lead measurements outside MRI and in two orientations inside MRI, were used to remove MHD. The system was tested on ten (one exercising) volunteers and four arrhythmia patients.
Switching circuits removed most imaging-induced voltages (residual noise <3% of the R-wave). MHD removal provided intra-MRI ECGs that varied by <3.8% from those outside the MRI, preserving the true ST segment. In premature-ventricular-contraction (PVC) patients, clean ECGs separated PVC and sinus-rhythm beats. Measured heating was <1.5 C0. The system reliably acquired multiphase (SSFP) wall-motion-cine and phase-contrast-cine scans, including in subjects where 4-lead gating failed. The system required a minimum TR of 4ms to allow robust ECG processing.
High-fidelity intra-MRI 12-lead ECG is possible.
ECG; Magneto-Hydro-Dynamic effect; Cardiac MRI; MRI-guided interventions
We assessed in the Multi-Ethnic Study of Atherosclerosis (MESA) whether impaired fasting glucose, insulin resistance, and waist-to-hip ratio had effects on cardiac remodeling, independent of obesity.
Recent studies suggest that central obesity and insulin resistance may be primary mediators of obesity-related cardiac remodeling independent of body mass index (BMI).
We investigated 4,364 individuals without diabetes in MESA. Impaired fasting glucose (IFG: 100-125 mg/dl) or insulin resistance (by homeostatic model assessment of insulin resistance, HOMA-IR) and waist-to-hip ratio (WHR) were used for cardiometabolic phenotyping. Multivariate linear regression analysis was used to determine the effects of the cardiometabolic markers on LV remodeling, assessed primarily through the LV mass-to-volume ratio obtained by cine cardiac magnetic resonance imaging.
Individuals with IFG were more likely to be older, hypertensive, with increased prevalence of cardiometabolic risk factors regardless of BMI. In each quartile of BMI, individuals with above-median HOMA-IR, above-median WHR, or IFG had a higher LV mass-to-volume ratio (p<0.05 for all). HOMA-IR (p<0.0001), WHR (p<0.0001), and the presence of IFG (p=0.04), but not BMI (p=0.24), were independently associated with LV mass-to-volume ratio after adjustment for age, gender, hypertension, race, and dyslipidemia.
Insulin resistance and waist-to-hip ratio are associated with concentric LV remodeling independent of BMI. These results support the emerging hypothesis that the cardiometabolic phenotype, defined by insulin resistance and central obesity, may play a critical role in LV remodeling independently of BMI.
obesity; metabolic syndrome; LV remodeling; MESA
This study sought to determine feasibility and prognostic performance of stress cardiac magnetic resonance (CMR) in obese patients (body mass index [BMI] ≥30 kg/m2).
Current stress imaging methods remain limited in obese patients. Given the impact of the obesity epidemic on cardiovascular disease, alternative methods to effectively risk stratify obese patients are needed.
Consecutive patients with a BMI ≥30 kg/m2 referred for vasodilating stress CMR were followed for major adverse cardiovascular events (MACE), defined as cardiac death or nonfatal myocardial infarction. Univariable and multivariable Cox regressions for MACE were performed to determine the prognostic association of inducible ischemia or late gadolinium enhancement (LGE) by CMR beyond traditional clinical risk indexes.
Of 285 obese patients, 272 (95%) completed the CMR protocol, and among these, 255 (94%) achieved diagnostic imaging quality. Mean BMI was 35.4 ± 4.8 kg/m2, with a maximum weight of 200 kg. Reasons for failure to complete CMR included claustrophobia (n = 4), intolerance to stress agent (n = 4), poor gating (n = 4), and declining participation (n = 1). Sedation was required in 19 patients (7%; 2 patients with intravenous sedation). Sixteen patients required scanning by a 70-cm-bore system (6%). Patients without inducible ischemia or LGE experienced a substantially lower annual rate of MACE (0.3% vs. 6.3% for those with ischemia and 6.7% for those with ischemia and LGE). Median follow-up of the cohort was 2.1 years. In a multivariable stepwise Cox regression including clinical characteristics and CMR indexes, inducible ischemia (hazard ratio 7.5; 95% confidence interval: 2.0 to 28.0; p = 0.002) remained independently associated with MACE. When patients with early coronary revascularization (within 90 days of CMR) were censored on the day of revascularization, both presence of inducible ischemia and ischemia extent per segment maintained a strong association with MACE.
Stress CMR is feasible and effective in prognosticating obese patients, with a very low negative event rate in patients without ischemia or infarction.
cardiac magnetic resonance; obesity; stress testing
Myocardial extracellular matrix expansion and reduced coronary flow reserve (CFR) occur in patients with type 2 diabetes mellitus without heart failure or coronary artery disease. Because aldosterone is implicated in the pathophysiology of cardiac fibrosis and vascular injury, the aim of this study was to test the hypothesis that aldosterone is associated with extracellular matrix expansion and reduced CFR in type 2 diabetes mellitus. Patients with type 2 diabetes mellitus without evidence of coronary artery disease were recruited. Blood pressure, lipid management, and glycemic control were optimized over 3 months. Cardiac magnetic resonance imaging with T1 mapping was used to measure myocardial extracellular volume (ECV). Cardiac positron emission tomography was used to assess CFR. On a liberal, 250 mEq/day sodium diet, 24-hour urinary aldosterone and change in serum aldosterone with angiotensin II stimulation were measured. Fifty-three participants with type 2 diabetes (68% men, mean age 53 ± 7 years, mean body mass index 32.2 ± 4.3 kg/m2, mean glycosylated hemoglobin 6.8 ± 0.7%, mean systolic blood pressure 126 ± 14 mm Hg) without infarction or ischemia by cardiac magnetic resonance and positron emission tomography were studied. Subjects had impaired CFR (2.51 ± 0.83) and elevated ECV (0.36 ± 0.05), despite normal echocardiographic diastolic function and normal left ventricular function. Myocardial ECV, but not CFR, was positively associated with 24-hour urinary aldosterone excretion (r = 0.37, p = 0.01) and angiotensin II–stimulated aldosterone increase (r = 0.35, p = 0.02). In a best-overall multivariate model (including age, gender, body mass index, glycosylated hemoglobin, and blood pressure), 24-hour urinary aldosterone was the strongest predictor of myocardial ECV (p = 0.004). In conclusion, in patients with type 2 diabetes mellitus without coronary artery disease, aldosterone is associated with myocardial extracellular matrix expansion. These results implicate aldosterone in early myocardial remodeling in type 2 diabetes mellitus.
We aimed to test the characteristics of the myocardial extracellular volume (ECV) fraction derived from pre and post-contrast T1 measurements among healthy volunteers.
Cardiac magnetic resonance (CMR) T1 measurements of myocardium and blood before and after contrast allow quantification of the ECV, a tissue parameter that has been shown to change in proportion to the connective tissue fraction.
Healthy volunteers underwent a standard CMR with administration of gadolinium. T1 measurements were performed with a Look-Locker sequence followed by gradient-echo acquisition. We tested the segmental, inter-slice, inter-, intra-, and test-retest characteristics of the ECV, as well as the association of the ECV with other variables. Juvenile and aged mice underwent a similar protocol and cardiac sections were harvested for measurement of fibrosis.
In healthy volunteers (n=32, 56% female; ages 21 to 72), the ECV averaged 0.28 ± 0.03 (range 0.23 to 0.33). The intra-class coefficients for the intra-observer, inter-observer, and test-retest absolute agreements of the ECV were 0.94 (95% confidence interval, 0.84 to 0.98), 0.93 (95% confidence interval, 0.80 to 0.98), and 0.95 (95% confidence interval, 0.52 to 0.99), respectively. In volunteers, the ECV was associated with age (r=0.74, p< 0.001), maximal LA volume index (r=0.67, p< 0.001), and indexed LV mass. There were no differences in the ECV between segments in a slice or between slices. In mice (n=12) the myocardial ECV ranged from 0.20 to 0.32 and increased with age (0.22 ± 0.02 vs. 0.30 ± 0.02, juvenile vs. aged mice, p< 0.001). In mice, the ECV correlated with the extent of myocardial fibrosis (r=0.94, p< 0.001).
In healthy volunteers, the myocardial ECV ranges from 0.23 to 0.33, has acceptable test characteristics, and is associated with age, LA volume, and LV mass. In mice, the ECV also increases with age and strongly correlates with the extent of myocardial fibrosis.
Myocardial Fibrosis; Cardiac Magnetic Resonance; T1 measurements; Extracellular Matrix
Nearly 50% of patients with heart failure (HF) have preserved LV ejection fraction, with interstitial fibrosis and cardiomyocyte hypertrophy as early manifestations of pressure overload. However, methods to assess both tissue characteristics dynamically and noninvasively with therapy are lacking. We measured the effects of mineralocorticoid receptor blockade on tissue phenotypes in LV pressure overload using cardiac magnetic resonance (CMR).
Methods and Results
Mice were randomized to l‐nitro‐ω‐methyl ester (l‐NAME, 3 mg/mL in water; n=22), or l‐NAME with spironolactone (50 mg/kg/day in subcutaneous pellets; n=21). Myocardial extracellular volume (ECV; marker of diffuse interstitial fibrosis) and the intracellular lifetime of water (τic; marker of cardiomyocyte hypertrophy) were determined by CMR T1 imaging at baseline and after 7 weeks of therapy alongside histological assessments. Administration of l‐NAME induced hypertensive heart disease in mice, with increases in mean arterial pressure, LV mass, ECV, and τic compared with placebo‐treated controls, while LV ejection fraction was preserved (>50%). In comparison, animals receiving both spironolactone and l‐NAME (“l‐NAME+S”) showed less concentric remodeling, and a lower myocardial ECV and τic, indicating decreased interstitial fibrosis and cardiomyocyte hypertrophy (ECV: 0.43±0.09 for l‐NAME versus 0.25±0.03 for l‐NAME+S, P<0.001; τic: 0.42±0.11 for l‐NAME groups versus 0.12±0.05 for l‐NAME+S group). Mice treated with a combination of l‐NAME and spironolactone were similar to placebo‐treated controls at 7 weeks.
Spironolactone attenuates interstitial fibrosis and cardiomyocyte hypertrophy in hypertensive heart disease. CMR can phenotype myocardial tissue remodeling in pressure‐overload, furthering our understanding of HF progression.
cardiac magnetic resonance imaging; hypertension; hypertrophy/remodeling
The authors investigated the utility of an intravascular magnetic resonance (MR) contrast agent, poly-L-lysine-gadolinium diethylenetriaminepentaacetic acid (DTPA), for differentiating acutely ischemic from normally perfused myocardium with first-pass MR imaging. Hypoperfused regions, identified with microspheres, on the first-pass images displayed significantly decreased signal intensities compared with normally perfused myocardium (P < .0007). Estimates of regional myocardial blood content, obtained by measuring the ratio of areas under the signal intensity-versus-time curves in tissue regions and the left ventricular chamber, averaged 0.12 mL/g ± 0.04 (n = 35), compared with a value of 0.11 mL/g ± 0.05 measured with radiolabeled albumin in the same tissue regions. To obtain MR estimates of regional myocardial blood flow, in situ calibration curves were used to transform first-pass intensity-time curves into content-time curves for analysis with a multiple-pathway, axially distributed model. Flow estimates, obtained by automated parameter optimization, averaged 1.2 mL/min/g ± 0.5 [n = 29), compared with 1.3 mL/min/g ± 0.3 obtained with tracer microspheres in the same tissue specimens at the same time. The results represent a combination of T1-weighted first-pass imaging, intravascular relaxation agents, and a spatially distributed perfusion model to obtain absolute regional myocardial blood flow and volume.
Contrast agent, blood pool; Contrast enhancement; Coronary vessels, diseases, 54.76; Heart, flow dynamics; Heart, MR, 51.12143; Model, mathematical; Myocardium, blood supply, 511.12143; Myocardium, MR, 511.12143; Perfusion studies
Myocardial fibrosis is a hallmark of hypertrophic cardiomyopathy (HCM) and a potential substrate for arrhythmias and heart failure. Sarcomere mutations appear to induce profibrotic changes before left ventricular hypertrophy (LVH) develops. To further evaluate these processes, we used cardiac magnetic resonance (CMR) with T1 measurements on a genotyped HCM population to quantify myocardial extracellular volume (ECV).
Methods and Results
Sarcomere mutation carriers with LVH (G+/LVH+, n = 37) and without LVH (G+/LVH−, n = 29); HCM patients without mutations (sarcomere-negative HCM, n = 11); and healthy controls (n = 11) underwent contrast CMR, measuring T1 times pre- and post-gadolinium infusion. Concurrent echocardiography and serum biomarkers of collagen synthesis, hemodynamic stress, and myocardial injury were also available in a subset. Compared to controls, ECV was increased in patients with overt HCM, as well as G+/LVH− mutation carriers (ECV= 0.36±0.01, 0.33±0.01, 0.27±0.01 in G+/LVH+, G+/LVH−, controls, respectively, P≤0.001 for all comparisons). ECV correlated with NT-proBNP levels (r = 0.58, P<0.001) and global E’ velocity (r = −0.48, P<0.001). Late gadolinium enhancement (LGE) was present in >60% of overt HCM patients but absent from G+/LVH− subjects. Both ECV and LGE were more extensive in sarcomeric HCM than sarcomere-negative HCM.
Myocardial ECV is increased in HCM sarcomere mutation carriers even in the absence of LVH. These data provide additional support that fibrotic remodeling is triggered early in disease pathogenesis. Quantifying ECV may help characterize the development myocardial fibrosis in HCM and ultimately assist in developing novel disease-modifying therapy, targeting interstitial fibrosis.
hypertrophic cardiomyopathy; genetics; magnetic resonance imaging; fibrosis; gadolinium
Cardiovascular MRI has effectively become a reference standard for quantifying ventricular volumes and function and for measuring the myocardial scar burden after myocardial infarction. Imaging of late gadolinium enhancement and microvascular obstruction carries strong prognostic information for identifying patients who would benefit from anti-remodeling therapy. The combination of gadolinium enhancement, perfusion, and cine imaging should make MRI the modality of choice in the assessment of left ventricular dysfunction and remodeling. The use of MRI in clinical trials of heart failure could help reduce sample size requirements because of its accuracy and reproducibility. This review describes the use of MRI in assessing ventricular remodeling and viability and summarizes the few studies that have relied on MRI for image-based markers of ventricular remodeling.
Purpose of review
This review is meant as a balanced summary of the current state of cardiac magnetic resonance (CMR) perfusion imaging in assessing alterations in myocardial blood flow due to coronary artery disease (CAD). We aim to provide first an accessible technical overview of first-pass CMR perfusion imaging and contrast it with other conventional perfusion imaging modalities, and then address the potential advantages of CMR for a qualitative assessment of perfusion defects, as well as quantitative blood flow measurements. Most recent results from clinical trials on the utility of CMR perfusion and novel directions will be explored.
Recent results of the first multicenter multivendor CMR perfusion study demonstrated superior diagnostic utility in detecting CAD by CMR compared with conventional nuclear single-photon emission computed tomography. Several large clinical trials provide additional evidence indicating the strong prognostic implications when CMR perfusion was performed in a clinical setting in patients with an intermediate clinical likelihood of CAD. A negative adenosine stress CMR perfusion study conferred a favorable 3-year prognosis towards nonfatal myocardial infarction or cardiac death.
CMR perfusion imaging during the first pass of gadolinium-based contrast agents has undergone many technical improvements and levels of clinical validation. Rapidly increasing clinical use worldwide over the last years in diagnosing chest pain syndromes supports the role of CMR in a comprehensive and efficient noninvasive assessment of altered myocardial physiology in CAD.
first-pass myocardial perfusion; gadolinium; ischemia; mortality; myocardial blood flow; myocardial infarction
Editorials; imaging; diagnostic; magnetic resonance imaging; ventricular remodeling
Assessment of myocardial ischemia in symptomatic patients remains a common and challenging clinical situation faced by physicians. Risk stratification by presence of ischemia provides important utility for both prognostic assessment and management. Unfortunately, current noninvasive modalities possess numerous limitations and have limited prognostic capacity. More recently, ischemia assessment by cardiovascular magnetic resonance (CMR) has been shown to be a safe, available, and potentially cost-effective alternative with both high diagnostic and prognostic accuracy. Cardiovascular magnetic resonance has numerous advantages over other noninvasive methods, including high temporal and spatial resolution, relatively few contraindications, and absence of ionizing radiation. Furthermore, studies assessing the clinical utility and cost effectiveness of CMR in the short-term setting for patients without evidence of an acute myocardial infarction have also demonstrated favorable results. This review will cover techniques of ischemia assessment with CMR by both stress-induced wall motion abnormalities as well as myocardial perfusion imaging. The diagnostic and prognostic performance studies will also be reviewed, and the use of CMR for ischemia assessment will be compared with other commonly used noninvasive modalities.
Acute coronary syndrome; Adenosine; Cardiac magnetic resonance imaging (CMR); Chest pain; Coronary artery disease; Dobutamine; Echocardiography; Ischemia; Myocardial infarction; Perfusion; Persantine; Regadenoson; Positron emission tomography; Single-photon emission computed tomography; Vasodilators
The aim of this study was to perform direct quantification of myocardial extracellular volume fraction (ECF) with T1-weighted cardiac magnetic resonance (CMR) imaging in patients suspected to have infiltrative heart disease.
Infiltrative heart disease refers to accumulation of abnormal substances within the myocardium. Qualitative assessment of late gadolinium enhancement (LGE) remains the most commonly used method for CMR evaluation of patients suspected with myocardial infiltration. This technique is widely available and can be performed in a reproducible and standardized manner. However, the degree of extracellular matrix expansion due to myocardial infiltration in the intercellular space has, to date, not been amenable to noninvasive quantification with LGE.
We performed 3-T CMR in 38 patients (mean age 68 ± 15 years) who were referred for assessment of infiltrative heart disease and also in 9 healthy volunteers as control subjects. The T1 quantification by Look-Locker gradient-echo before and after contrast determined segmental myocardial partition coefficients. The ECF was obtained by referencing the tissue partition coefficient for gadolinium to the plasma volume fraction in blood, derived from serum hematocrit. Cine CMR and LGE imaging in matching locations were also performed.
Seventeen patients (45%) had cardiac amyloidosis (CA) (biopsy-confirmed or clinically highly probable), 20 (53%) had a non-amyloid cardiomyopathy, and 1 had lysosomal storage disease. Median global ECF was substantially higher in CA patients (0.49) compared with non-amyloid cardiomyopathy patients (0.33, p < 0.0001) and volunteers (0.24, p < 0.0001). The ECF strongly correlated with visually assessed segmental LGE (r = 0.80, p < 0.0001) and LV mass index (r = 0.69, p < 0.0001), reflecting severity of myocardial infiltration. In patients with CA, ECF was highest in segments with LGE, although it remained elevated in segments without qualitative LGE.
The CMR ECF quantification identified substantial expansion of the interstitial space in patients with CA compared with volunteers. Further studies using this technique for diagnosis and assessment of the severity of myocardial infiltration are warranted.
amyloid; infiltrative cardiomyopathy; left ventricular mass; myocardial delayed enhancement; T1 mapping
The major aim of this study is to test the hypothesis that stress cardiac magnetic resonance (CMR) imaging can provide robust prognostic value in women presenting with suspected ischemia, to the same extent as in men.
Compelling evidence indicates that women with coronary artery disease (CAD) experience worse outcomes than men owing to a lack of early diagnosis and management. Numerous clinical studies have shown that stress CMR detects evidence of myocardial ischemia and infarction at high accuracy. Compared to nuclear scintigraphy, CMR is free of ionizing radiation, has high spatial resolution for imaging small hearts, and overcomes breast attenuation artifacts, which are substantial advantages when imaging women for CAD.
We performed stress CMR in 405 patients (168 women, mean age 58 ± 14 years) referred for ischemia assessment. CMR techniques included cine cardiac function, perfusion imaging during vasodilating stress, and late gadolinium enhancement imaging. All patients were followed for major adverse cardiac events (MACE).
At a median follow-up of 30 months, MACE occurred in 36 patients (9%) including 21 cardiac deaths and 15 acute myocardial infarctions. In women, CMR evidence of ischemia (ISCHEMIA) demonstrated strong association with MACE (unadjusted hazard ratio: 49.9, p < 0.0001). While women with ISCHEMIA(+) had an annual MACE rate of 15%, women with ISCHEMIA(−) had very low annual MACE rate (0.3%), which was not statistically different from the low annual MACE rate in men with ISCHEMIA(−) (1.1%). CMR myocardial ischemia score was the strongest multivariable predictor of MACE in this cohort, for both women and men, indicating robust cardiac prognostication regardless of sex.
In addition to avoiding exposure to ionizing radiation, stress CMR myocardial perfusion imaging is an effective and robust risk-stratifying tool for patients of either sex presenting with possible ischemia.
cardiac magnetic resonance; infarction; major cardiac adverse events; mortality; myocardial ischemia; women