Juliet Varghese

Renin-sensitive microRNAs correlate with atherosclerosis plaque progression

Recent trials with inhibition of the renin–angiotensin–aldosterone system (RAAS) in patients with established atherosclerosis have been equivocal. MicroRNAs (miRs) are known to affect multiple pathways relevant to atherosclerosis, including RAAS. We postulated that the use of a direct renin antagonist would result in differential regulation of miRs. We examined monocyte miR expression before and after treatment with renin antagonist, Aliskiren, in patients with established cardiovascular disease as part of a prospective, single-center, randomized, double-blind and placebo-controlled clinical trial (NCT01417104). After screening, patients (mean age 62±3 years) were randomized to placebo or Aliskiren. Three-dimensional dark-blood magnetic resonance imaging assessment of atherosclerosis in the thoracic and abdominal aorta was conducted at baseline and at study completion (19–36 weeks). MiR expression arrays were performed on RNA from peripheral blood mononuclear cells collected at baseline and 12 weeks following randomization to placebo or Aliskiren and showed that hsa-miR-106b-5p, 27a-3p and 18b-5p were significantly downregulated with Aliskiren. Baseline expression of these miRs positively correlated with normalized total wall volume in subjects taking Aliskiren (miR-106b, R=0.62; miR-27a, R=0.63; miR-18b, R=0.77; P<0.05). Hsa-miR-106b-5p, 27a-3p and 18b-5p may represent pathway-specific adaptations to renin inhibition relevant to atherosclerosis.

Aliskiren Effect on Plaque Progression in Established Atherosclerosis Using High Resolution 3D MRI (ALPINE): A Double‐Blind Placebo‐Controlled Trial

Background The renin–angiotensin system is well recognized as a mediator of pathophysiological events in atherosclerosis. The benefits of renin inhibition in atherosclerosis, especially when used in combination with angiotensin-converting enzyme inhibitors/angiotensin receptor blockers (ACEIs/ARBs) are currently not known. We hypothesized that treatment with the renin inhibitor aliskiren in patients with established cardiovascular disease will prevent the progression of atherosclerosis as determined by high-resolution magnetic resonance imaging (MRI) measurements of arterial wall volume in the thoracic and abdominal aortas of high-risk patients with preexisting cardiovascular disease. Methods and Results This was a single-center, randomized, double-blind, placebo-controlled trial in patients with established cardiovascular disease. After a 2-week single-blind placebo phase, patients were randomized to receive either placebo (n=37, mean±SD age 64.5±8.9 years, 3 women) or 150 mg of aliskiren (n=34, mean±SD age 63.9±11.5 years, 9 women). Treatment dose was escalated to 300 mg at 2 weeks and maintained during the remainder of the study. Patients underwent dark-blood, 3-dimensional MRI assessment of atherosclerotic plaque in the thoracic and abdominal segments at baseline and on study completion or termination (up to 36 weeks of drug or matching placebo). Aliskiren use resulted in significant progression of aortic wall volume (normalized total wall volume 5.31±6.57 vs 0.15±4.39 mm3, P=0.03, and percentage wall volume 3.37±2.96% vs 0.97±2.02%, P=0.04) compared with placebo. In a subgroup analysis of subjects receiving ACEI/ARB therapy, atherosclerosis progression was observed only in the aliskiren group, not in the placebo group. Conclusions MRI quantification of atheroma plaque burden demonstrated that aliskiren use in patients with preexisting cardiovascular disease resulted in an unexpected increase in aortic atherosclerosis compared with placebo. Although preliminary, these results may have implications for the use of renin inhibition as a therapeutic strategy in patients with cardiovascular disease, especially in those receiving ACEI/ARB therapy. Clinical Trial Registration URL: http://ClinicalTrials.gov Unique identifier: NCT01417104.

Reproducibility of thoracic and abdominal aortic wall measurements with three-dimensional, variable flip angle (SPACE) MRI

To evaluate the reproducibility and repeatability of high‐resolution, isotropic thoracic and abdominal aortic wall measurements, and determine the implications they have on the number of subjects necessary for future clinical trials.

Rapid assessment of quantitative T1, T2 and T2* in lower extremity muscles in response to maximal treadmill exercise

MRI provides a non‐invasive diagnostic platform to quantify the physical and physiological attributes of skeletal muscle at rest and in response to exercise. MR relaxation parameters (T1, T2 and T2*) are characteristic of tissue composition and metabolic properties. With the recent advent of quantitative techniques that allow rapid acquisition of T1, T2 and T2* maps, we posited that an integrated treadmill exercise–quantitative relaxometry paradigm can rapidly characterize exercise‐induced changes in skeletal muscle relaxation parameters. Accordingly, we investigated the rest/recovery kinetics of T1, T2 and T2* in response to treadmill exercise in the anterior tibialis, soleus and gastrocnemius muscles of healthy volunteers, and the relationship of these parameters to age and gender. Thirty healthy volunteers (50.3 ± 16.6 years) performed the Bruce treadmill exercise protocol to maximal exhaustion. Relaxometric maps were sequentially acquired at baseline and for approximately 44 minutes post‐exercise. Our results show that T1, T2 and T2* are significantly and differentially increased immediately post‐exercise among the leg muscle groups, and these values recover to near baseline within 30–44 minutes. Our results demonstrate the potential to characterize the kinetics of relaxation parameters with quantitative mapping and upright exercise, providing normative values and some clarity on the impact of age and gender. Copyright

Cardiopulmonary exercise testing in the MRI environment.

Maximal oxygen consumption ([Formula: see text]max) measured by cardiopulmonary exercise testing (CPX) is the gold standard for assessment of cardiorespiratory fitness. Likewise, cardiovascular magnetic resonance (CMR) is the gold standard for quantification of cardiac function. The combination of CPX and CMR may offer unique insights into cardiopulmonary pathophysiology; however, the MRI-compatible equipment needed to combine these tests has not been available to date. We sought to determine whether CPX testing in the MRI environment, using equipment modified for MRI yields results equivalent to those obtained in standard exercise physiology (EP) lab. Ten recreationally trained subjects completed [Formula: see text]max tests in different locations; an EP laboratory and an MRI laboratory, using site specific equipment. CMR cine images of the heart were acquired before and immediately after maximal exercise to measure cardiac function. Subjects in all tests met criteria indicating that peak exercise was achieved. Despite equipment modifications for the MRI environment, [Formula: see text]max was nearly identical between tests run in the different labs (95% lower confidence limit (LCL)  =  0.8182). The mean difference in [Formula: see text]max was less than 3.40 ml (kg/min)(-1), within the variability expected for tests performed on different days, in different locations, using different metabolic carts. MRI performed at rest and following peak exercise stress indicated cardiac output increased from 5.1  ±  1.0 l min(-1) to 16.4  ±  5.6 l min(-1), LVEF increased from 65.2  ±  3.3% to 78.4  ±  4.8%, while RVEF increased from 52.8  ±  5.3% to 63.4  ±  5.3%. Regression analysis revealed a significant positive correlation between [Formula: see text]max and stroke volume (R  =  0.788, P  =  0.006), while the correlation with cardiac output did not reach statistical significance (R  =  0.505, P  =  0.137). [Formula: see text]max CPX testing can be effectively performed in the MRI environment, enabling direct combination of physiological data with advanced post-exercise imaging in the same test session.

Integrated treadmill stress testing and MR relaxometry (T1, T2, T2*): response in healthy calf muscles

Background Peripheral arterial disease (PAD) is accompanied by a complex lower limb pathophysiology resulting in reduced functional capacity and quality of life. We aim to characterize the exercise recovery kinetics in the calf muscle of healthy volunteers by combining treadmill exercise and magnetic resonance (MR) relaxometry (T1, T2 and T2*), and to investigate their relation with age and treadmill exercise duration.

Venous oxygen saturation estimation from multiple T2 maps with varying inter-echo spacing

Background Dependence of blood T2 on O2 saturation has led to noninvasive MRI-based techniques for determining venous O2 saturation (SvO2) [1-3]. However, applying a general calibration factor derived from in vitro experiments can lead to inaccurate and largely varying SvO2 estimates in the target population. We aim to show that based on the Luz-Meiboom relation 1/T2 = 1/T2o + Hct(1-Hct) τex [(1-%SO2/100)aω0] (1-2*τex/τ180 tanh(τ180/2*τex))[4], individual SvO2 can be determined from multiple T2 maps, each acquired at a specific inter-echo spacing (τ180).

Monocyte DPP4 Expression in Human Atherosclerosis Is Associated With Obesity and Dyslipidemia

Studies including ours indicate that systemic inhibition of dipeptidyl peptidase 4 (DPP4), an ubiquitously expressed peptidase, by pharmaceutical inhibitors improved atherosclerosis (1,2). However, the role of immune cell–derived DPP4 is not well defined in atherosclerosis. Our previous work demonstrated that DPP4 expression on monocytes/macrophages was increased in obesity and associated with the degree of insulin resistance (3). To test if the obesity-related increase of monocyte DPP4 plays a role in vascular disease, we investigated the relationship of monocyte DPP4 expression with human aortic atherosclerosis, obesity, and lipid metabolism. A total of 14 control volunteers and 27 atherosclerotic patients without diagnosed heart, lung, or liver diseases and without prescription drugs (except ACE inhibitors and angiotensin receptor blockers) were selected from Aliskiren Effect on Aortic Plaque Progression (ALPINE), a phase 4 clinical trial (clinical trial reg. no. NCT01417104, clinicaltrials.gov). Presence of aortic atherosclerotic plaque (Fig. 1 A ) was confirmed by high-resolution three-dimensional MRI. Figure 1 A : High-resolution three-dimensional dark-blood MRI was used to confirm the aortic atherosclerotic plaque in patients with atherosclerotic disease. Arrows indicate the thickening of the aortic wall. Scale bars, 10 mm. B and C : DPP4 expression on circulating immune cells. Peripheral blood mononuclear cells were isolated from healthy volunteers, and CD11b+ monocyte and CD3+ T cells were gated for …

Simultaneous VO2 and cardiac output measurement to estimate oxygen extraction (a-v)O2

Background Chronic heart failure (CHF) is the leading hospital discharge diagnosis in patients over age 65 [1]. Emerging techniques in cardiovascular magnetic resonance (CMR) have resulted in unique opportunity for improvement of non-invasive assessment of the physiologic and anatomic effects of CHF. We have previously demonstrated the accuracy and feasibility of V̇O2 max measurements in the MRI environment using a modified metabolic cart [2]. Additionally, V̇O2 measures acquired within the MRI have been reported [3]. Existing methods describe non-invasive MRI measurement of whole body oxygen consumption via T2 imaging [4]. The Fick principle states V̇O2 = CO × (A-V)O2; where V̇O2 is oxygen consumption, CO is cardiac output, and (A-V)O2 is arteriovenous oxygen difference. Current modifications required for metabolic cart measures of oxygen consumption in the MRI environment present clinical challenges in widespread application. Using the Fick principle we sought to quantify and compare non-invasive MRI derived V̇O2 (MRI-V̇O2) quantification with metabolic cart measures of V̇O2 .

An improved preparation pulse for quantitative t2 mapping of blood in the cardiac chambers

Background T2 is sensitive to hemoglobin oxygen saturation (%HbO2). Non-invasive, rapid in-vivo quantification of %HbO2 based on the T2 of blood may be useful in patients with congenital heart disease. Although singleshot, T2-prepared SSFP enables rapid myocardial T2 quantification [1], flow sensitivity of the T2 preparation, especially at later echo times, may cause an underestimation of T2 values in flowing blood. We aim to reduce flow sensitivity of the T2 preparation pulse for rapid and accurate quantification of T2 in blood.