Judith Meadows

Stress Cardiac Magnetic Resonance Imaging Provides Effective Cardiac Risk Reclassification in Patients With Known or Suspected Stable Coronary Artery Disease

Background— 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. 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 myocardial infarction (major adverse cardiac events) incremental to clinical risk models, using guideline-based low (<1%), moderate (1% to 3%), and high (>3%) annual risk categories. In the whole cohort, inducible ischemia demonstrated a strong association with major adverse cardiac events (hazard ratio=14.66; P<0.0001) with low negative event rates of major adverse cardiac events and cardiac death (0.6% and 0.4%, respectively). This prognostic robustness was maintained in patients with previous coronary artery disease (hazard ratio=8.17; P<0.0001; 1.3% and 0.6%, respectively). Adding inducible ischemia to the multivariable clinical risk model (adjusted for age and previous coronary artery disease) improved discrimination of major adverse cardiac events (C statistic, 0.81–0.86; P=0.04; adjusted hazard ratio=7.37; P<0.0001) and reclassified 91.5% of patients at moderate pretest risk (65.7% to low risk; 25.8% to high risk) with corresponding changes in the observed event rates (0.3%/y and 4.9%/y for low and high risk posttest, respectively). Categorical net reclassification index was 0.229 (95% confidence interval, 0.063–0.391). Continuous net reclassification improvement was 1.11 (95% confidence interval, 0.81–1.39). Conclusions— Stress cardiac magnetic resonance imaging effectively reclassifies patient risk beyond standard clinical variables, specifically in patients at moderate to high pretest clinical risk and in patients with previous coronary artery disease. Clinical Trial Registration:— URL: http://www.clinicaltrials.gov. Unique identifier: NCT01821924.

Confluence of depression and acute psychological stress among patients with stable coronary heart disease: effects on myocardial perfusion.

Background Depression is prevalent in coronary heart disease (CHD) patients and increases risk for acute coronary syndrome (ACS) recurrence and mortality despite optimal medical care. The pathways underlying this risk remain elusive. Psychological stress (PS) can provoke impairment in myocardial perfusion and trigger ACS. A confluence of acute PS with depression might reveal coronary vascular mechanisms of risk. We tested whether depression increased risk for impaired myocardial perfusion during acute PS among patients with stable CHD. Methods and Results Patients (N=146) completed the Beck Depression Inventory‐I (BDI‐I), a measure of depression linked to recurrent ACS and post‐ACS mortality, and underwent single‐photon emission computed tomography myocardial perfusion imaging at rest and during acute PS. The likelihood of new/worsening impairment in myocardial perfusion from baseline to PS as a function of depression severity was tested. On the BDI‐I, 41 patients scored in the normal range, 48 in the high normal range, and 57 in the depressed range previously linked to CHD prognosis. A BDI‐I score in the depressed range was associated with a significantly greater likelihood of new/worsening impairment in myocardial perfusion from baseline to PS (odds ratio =2.89, 95% CI: 1.26 to 6.63, P=0.012). This remained significant in models controlling ACS recurrence/mortality risk factors and medications. There was no effect for selective serotonin reuptake inhibitor medications. Conclusions Depressed patients with CHD are particularly susceptible to impairment in myocardial perfusion during PS. The confluence of PS with depression may contribute to a better understanding of the depression‐associated risk for ACS recurrence and mortality.

Endothelial biology in the post-menopausal obese woman

Women generally have a reduced risk of cardiovascular disease (CVD). However, this protection of gender diminishes rapidly after menopause and with advancing age, particularly in obese women. Alterations in vascular function are thought to a key early step in the development of atherosclerosis. In this review, we will describe the features of endothelial dysfunction in the post-menopausal obese female and discuss the interplay of aging, estrogen withdrawal, and obesity. The objectives include (1) a review of endothelial biology and endothelial dysfunction, and (2) a discussion how the endothelial function is altered in the context of aging, hormonal changes and insulin resistance. The clinical consequences of endothelial dysfunction and CVD will also be reviewed.

Imaging Atherosclerotic Plaque Calcification: Translating Biology

Calcification of atherosclerotic lesions was long thought to be an age - related, passive process, but increasingly data has revealed that atherosclerotic calcification is a more active process, involving complex signaling pathways and bone-like genetic programs. Initially, imaging of atherosclerotic calcification was limited to gross assessment of calcium burden, which is associated with total atherosclerotic burden and risk of cardiovascular mortality and of all cause mortality. More recently, sophisticated molecular imaging studies of the various processes involved in calcification have begun to elucidate information about plaque calcium composition and consequent vulnerability to rupture, leading to hard cardiovascular events like myocardial infarction. As such, there has been renewed interest in imaging calcification to advance risk assessment accuracy in an evolving era of precision medicine. Here we summarize recent advances in our understanding of the biologic process of atherosclerotic calcification as well as some of the molecular imaging tools used to assess it.

Rac2 Modulates Atherosclerotic Calcification by Regulating Macrophage Interleukin-1β Production

Objective— The calcium composition of atherosclerotic plaque is thought to be associated with increased risk for cardiovascular events, but whether plaque calcium itself is predictive of worsening clinical outcomes remains highly controversial. Inflammation is likely a key mediator of vascular calcification, but immune signaling mechanisms that promote this process are minimally understood. Approach and Results— Here, we identify Rac2 as a major inflammatory regulator of signaling that directs plaque osteogenesis. In experimental atherogenesis, Rac2 prevented progressive calcification through its suppression of Rac1-dependent macrophage interleukin-1&bgr; (IL-1&bgr;) expression, which in turn is a key driver of vascular smooth muscle cell calcium deposition by its ability to promote osteogenic transcriptional programs. Calcified coronary arteries from patients revealed decreased Rac2 expression but increased IL-1&bgr; expression, and high coronary calcium burden in patients with coronary artery disease was associated with significantly increased serum IL-1&bgr; levels. Moreover, we found that elevated IL-1&bgr; was an independent predictor of cardiovascular death in those subjects with high coronary calcium burden. Conclusions— Overall, these studies identify a novel Rac2-mediated regulation of macrophage IL-1&bgr; expression, which has the potential to serve as a powerful biomarker and therapeutic target for atherosclerosis.

Novel Molecular Imaging Approaches to Abdominal Aortic Aneurysm Risk Stratification

Selection of patients for abdominal aortic aneurysm repair is currently based on aneurysm size, growth rate, and symptoms. Molecular imaging of biological processes associated with aneurysm growth and rupture, for example, inflammation and matrix remodeling, could improve patient risk stratification and lead to a reduction in abdominal aortic aneurysm morbidity and mortality. 18F-fluorodeoxyglucose-positron emission tomography and ultrasmall superparamagnetic particles of iron oxide magnetic resonance imaging are 2 novel approaches to abdominal aortic aneurysm imaging evaluated in clinical trials. A variety of other tracers, including those that target inflammatory cells and proteolytic enzymes (eg, integrin &agr;v&bgr;3 and matrix metalloproteinases), have proven effective in preclinical models of abdominal aortic aneurysm and show great potential for clinical translation.

Serial Native T1 Mapping to Monitor Cardiac Response to Treatment in Light-Chain Amyloidosis

Amyloidosis is a condition in which misfolded proteins form insoluble deposits in the extracellular space of various tissues and organs, leading to interstitial expansion and disruption of structure and function. Light-chain (AL) amyloidosis is caused by an underlying plasma cell dyscrasia; cardiac involvement is common, is present in ≈50% of patients at presentation, and is a principal driver of morbidity and mortality.1 In practice, there has been reliance on ECG and echocardiographic features, as well as serum cardiac biomarkers, such as pro-brain natriuretic peptide and troponin T concentrations, for prognostic purposes and correlation to clinical response to treatment. However, these parameters can be of limited use because of concomitant etiologies for left ventricular (LV) hypertrophy and coexisting renal impairment. T1 relaxation time for hydrogen magnetization in the myocardium, an intrinsic characteristic of tissue, has been studied in a variety of pathologies with diffuse processes, including amyloidosis. Native, also known as noncontrast or precontrast, T1 mapping can be performed without the use of gadolinium-based contrast in patients with significantly reduced glomerular filtration rate. The technique of T1 mapping with cardiovascular magnetic resonance (CMR), in which T1 relaxation times for all pixels in the acquired image of the heart are measured, has been used for purposes of tissue characterization in regards to the diagnosis of cardiac involvement2 and prognosis in AL amyloidosis3 at single time point evaluations. Here we present a case using serial CMR native T1 mapping to assess treatment response of AL amyloidosis in a patient with renal failure. A 60-year-old …

Assessment of diastolic function and atrial remodeling by MRI – validation and correlation with echocardiography and filling pressure

Atrial fibrosis can be estimated noninvasively by magnetic resonance imaging (MRI) using late gadolinium enhancement (LGE), but diastolic dysfunction is clinically assessed by transthoracic echocardiography (TTE), and rarely by MRI. This study aimed to evaluate well‐established diastolic parameters using MRI, and validate them with TTE and left ventricular (LV) filling pressures, and to study the relationship between left atrial (LA) remodeling and parameters of diastolic function. The study retrospectively included 105 patients (53 ± 16 years, 39 females) who underwent 3D LGE MRI between 2012 and 2016. Medical charts were reviewed for the echocardiographic diastolic parameters E, A, and e′ by TTE, and pressure catheterizations. E and A were measured from in‐plane phase‐contrast cardiac MRI images, and e′ by feature‐tracking, and validated with TTE. Interobserver and intraobserver variability was examined. Furthermore, LA volumes, function, and atrial LGE was correlated with diastolic parameters. Evaluation of e′ in MRI had strong agreement with TTE (r = 0.75, P < 0.0001), and low interobserver and intraobserver variability. E and A by TTE showed strong agreement to MRI (r = 0.77, P = 0.001; r = 0.73, P = 0.003, for E and A, respectively). Agreement between E/e′ by TTE and MRI was strong (r = 0.85, P = 0.0004), and E/e′ by TTE correlated moderately to invasive pressures (r = 0.59, P = 0.03). There was a strong relationship between LA LGE and pulmonary capillary wedge pressure (r = 0.81, P = 0.01). In conclusion, diastolic parameters can be measured with good reproducibility by cardiovascular MRI. LA LGE exhibited a strong relationship with pulmonary capillary wedge pressure, an indicator of diastolic function.

Body mass index and risk for mental stress induced ischemia in coronary artery disease.

Acute emotionally reactive mental stress (MS) can provoke prognostically relevant deficits in cardiac function and myocardial perfusion, and chronic inflammation increases risk for this ischemic phenomenon. We have described parasympathetic withdrawal and generation of inflammatory factors in MS. Adiposity is also associated with elevated markers of chronic inflammation. High body mass index (BMI) is frequently used as a surrogate for assessment of excess adiposity and associated with traditional coronary artery disease (CAD) risk factors and CAD mortality. BMI is also associated with autonomic dysregulation and adipose tissue-derived proinflammatory cytokines, which are also attendant to emotion-provoked myocardial ischemia. Thus, we sought to determine if BMI contributes to risk of developing myocardial ischemia provoked by MS. We performed a prospective interventional study in a cohort of 161 patients with stable CAD. They completed an assessment of myocardial blood flow with single-photon emission computed tomography simultaneously during two conditions: laboratory MS and at rest. Multivariate logistic regression determined the independent contribution of BMI to the occurrence of MS-induced ischemia. Mean age was 65.6 ± 9.0 years, 87.0% had a history of hypertension and 28.6% had diabetes. Mean BMI was 30.4 ± 4.7. Prevalence of MS ischemia was 39.8%. BMI was an independent predictor of MS ischemia, odds ratio (OR) = 1.10, 95% confidence interval (CI) [1.01–1.18] for 1-point increase in BMI and OR = 1.53, 95% CI [1.06–2.21] for a 4.7-point increase in BMI (one standard deviation beyond the cohort BMI mean), p = 0.025 for all. These data suggest that BMI may serve as an independent risk marker for MS ischemia. The factors attendant with greater BMI, which include autonomic dysregulation and inflammation, may represent pathways by which high BMI contributes to this risk and serves as a conceptual construct to replicate these findings in larger CAD populations.

Relative predictive value of lung cancer screening CT versus myocardial perfusion attenuation correction CT in the evaluation of coronary calcium

Coronary artery calcium scores (CACS) from lung cancer screening computed tomography (LCSCT) or myocardial perfusion attenuation correction computed tomography (ACCT) are not routinely performed or reported. CACS from LCSCT and ACCT have not been directly compared in the same patient population. We identified 66 patients who underwent both LCSCT (non-gated) and ECG-gated cardiac CT (CCT) within a 2-year span. Of this population, 40 subjects had also undergone ACCT. Using the Agatston method, CACS for 264 individual vessels from the LCSCT population and for 160 vessels from ACCT population were calculated and evaluated for agreement with ECG-gated CCT as the gold standard. Secondary analysis included a comparison of individual vessel contribution to variations in agreement and a comparison of total CACS from CCT, LCSCT, and ACCT for respective MACE prediction. CACS from LCSCT demonstrated a strong Pearson correlation, r = 0.9017 (0.876–0.9223), with good agreement when compared to CACS from CCT. CACS from ACCT demonstrated a significantly (P < 0.00001) weaker correlation, r = 0.5593 (0.4401–0.6592). On an individual vessel basis, CACS from all major vessels (LM, LAD, LCX, and RCA) contributed to the weaker correlation. For total vessel CACS, LCSCT demonstrated comparable area under the curve (AUC) for the receiver operating characteristic (ROC) curve (LCSCT AUC = 0.8133 and CCT AUC = 0.8302, P = 0.691) for prediction of MACE. Although ACCT demonstrated a similar AUC (ACCT AUC = 0.7969, P = 0.662) for MACE prediction the cutoff value for elevated risk was extremely low. In conclusion, LCSCT outperformed ACCT at calcium scoring by providing better agreement and comparable risk assessment to CCT despite the absence of ECG-gating. It is therefore reasonable to use LCSCT images to derive and report Agatston-based CACS for cardiovascular risk assessment, whereas the use of ACCT images to report Agatston-based CACS is not currently practical.