Kathryn J. Ascah

Sympathetic nervous dysregulation in the absence of systolic left ventricular dysfunction in a rat model of insulin resistance with hyperglycemia

BackgroundDiabetes mellitus is strongly associated with cardiovascular dysfunction, derived in part from impairment of sympathetic nervous system signaling. Glucose, insulin, and non-esterified fatty acids are potent stimulants of sympathetic activity and norepinephrine (NE) release. We hypothesized that sustained hyperglycemia in the high fat diet-fed streptozotocin (STZ) rat model of sustained hyperglycemia with insulin resistance would exhibit progressive sympathetic nervous dysfunction in parallel with deteriorating myocardial systolic and/or diastolic function.MethodsCardiac sympathetic nervous integrity was investigated in vivo via biodistribution of the positron emission tomography radiotracer and NE analogue [11C]meta-hydroxyephedrine ([11C]HED). Cardiac systolic and diastolic function was evaluated by echocardiography. Plasma and cardiac NE levels and NE reuptake transporter (NET) expression were evaluated as correlative measurements.ResultsThe animal model displays insulin resistance, sustained hyperglycemia, and progressive hypoinsulinemia. After 8 weeks of persistent hyperglycemia, there was a significant 13-25% reduction in [11C]HED retention in myocardium of STZ-treated hyperglycemic but not euglycemic rats as compared to controls. There was a parallel 17% reduction in immunoblot density for NE reuptake transporter, a 1.2 fold and 2.5 fold elevation of cardiac and plasma NE respectively, and no change in sympathetic nerve density. No change in ejection fraction or fractional area change was detected by echocardiography. Reduced heart rate, prolonged mitral valve deceleration time, and elevated transmitral early to atrial flow velocity ratio measured by pulse-wave Doppler in hyperglycemic rats suggest diastolic impairment of the left ventricle.ConclusionsTaken together, these data suggest that sustained hyperglycemia is associated with elevated myocardial NE content and dysregulation of sympathetic nervous system signaling in the absence of systolic impairment.

Comparison of accuracy of transesophageal versus transthoracic echocardiography for the detection of mitral valve prolapse with ruptured chordae tendineae (flail mitral leaflet)

The accuracy of transesophageal echocardiography was compared with that of transthoracic echocardiography in the detection of ruptured chordae tendineae (flail mitral leaflet) in 27 patients with mitral valve prolapse (MVP) who underwent valve repair or replacement for mitral regurgitation. Confirmation of the presence of ruptured chordae resulting in a flail leaflet was available at surgery in all cases. The echocardiographic studies were read blindly by 2 independent observers with any differences resolved by a third. Mean (+/- standard deviation) age was 63 +/- 13 years. Men (n = 20) outnumbered women (n = 7) (p less than 0.02), and tended to be younger (p = 0.06). Flail leaflets were identified in 20 of 27 patients. In 1 patient, both leaflets were involved and in the remaining 19 patients posterior leaflets (15 patients) were more frequently affected than anterior leaflets (4 patients). Transesophageal echocardiography correctly identified all 20 patients with flail leaflets, but 1 false positive study occurred among the 7 patients without a flail leaflet. In contrast, transthoracic echocardiography identified only 12 of 20 patients with flail leaflets, with no false positive studies. Transesophageal echocardiography was more accurate, correctly classifying 26 of 27 (96%) cases versus 19 of 27 (70%) by the transthoracic approach (p less than 0.01). This study suggests a higher incidence of chordal rupture to the posterior leaflet in patients with MVP and demonstrates improved accuracy of transesophageal over transthoracic echocardiography in the detection of flail leaflets.

Effects of mitral valve surgery on myocardial energetics in patients with severe mitral regurgitation.

Background—Hemodynamically significant mitral regurgitation (MR) may alter left ventricular (LV) myocardial energy requirements. The effects of MR and subsequent corrective mitral valve (MV) surgery on myocardial energetics are not well understood. A better understanding of myocardial energetics and the LV responses to changes in preload and afterload may assist with the understanding of mitral regurgitation and its effect on the LV. We sought to determine the effects of MV surgery on forward stroke work, myocardial oxidative metabolism, and myocardial efficiency. Methods and Results—Prospectively enrolled patients with chronic, severe, nonischemic mitral regurgitation underwent echocardiography, radionuclide angiography, and C-11 acetate positron emission tomography to measure LV volumes, ejection fraction, and oxidative metabolism before and 1 year after MV surgery. Forward and total stroke work corrected for oxidative metabolism was used to estimate efficiency using the work metabolic index. Fourteen patients (age, 59± 8 years) with myxomatous MV were enrolled. One year after MV surgery, there was a reduction in LV end-diastolic and end-systolic volumes (231±86 to 131±21 mL; P<0.01 and 98±53 to 55±17 mL; P<0.01). Forward stroke volume increased (58.1±15.0 to 75.5±23 mL; P<0.01), LV ejection fraction was preserved without a significant change in oxidative metabolism. Forward work metabolic index improved (4.99±1.32×106 to 6.59±2.45×106 mm Hg×mL/m2; P=0.02). This was not at the expense of total work metabolic index, which was preserved. Conclusions—MV surgery has a beneficial effect on forward stroke volume and forward work metabolic index without adverse effects on oxidative metabolism or total work metabolic index.

Preclinical Evaluation of Biopolymer-Delivered Circulating Angiogenic Cells in a Swine Model of Hibernating Myocardium

Background—Vasculogenic cell–based therapy combined with tissue engineering is a promising revascularization approach targeted at patients with advanced coronary artery disease, many of whom exhibit myocardial hibernation. However, to date, no experimental data have been available in this context; we therefore examined the biopolymer-supported delivery of circulating angiogenic cells using a clinically relevant swine model of hibernating myocardium. Methods and Results—Twenty-five swine underwent placement of an ameroid constrictor on the left circumflex artery. After 2 weeks, animals underwent echocardiography, rest and stress ammonia-positron emission tomography perfusion, and fluorodeoxyglucose positron emission tomography viability scans. The following week, swine were randomized to receive intramyocardial injections of PBS control (n=10), circulating angiogenic cells (n=8), or circulating angiogenic cells+collagen-based matrix (n=7). The imaging protocol was repeated after 7 weeks. Baseline positron emission tomography myocardial blood flow and myocardial flow reserve were reduced in the left circumflex artery territory (both P<0.001), and hibernation (mismatch) was observed. At follow-up, stress myocardial blood flow had increased (P⩽0.01) and hibernation decreased (P<0.01) in the cells+matrix group only. Microsphere-measured myocardial blood flow validated the perfusion results. Arteriole density and wall motion abnormalities improved in the cells+matrix group. There was also a strong trend toward an improvement in ejection fraction (P=0.07). Conclusions—In this preclinical swine model of ischemic and hibernating myocardium, the combined delivery of circulating angiogenic cells and a collagen-based matrix restored perfusion, reduced hibernation, and improved myocardial wall motion.

Mobile ventricular thrombus arising from the mitral annulus in patients with dense mitral annular calcification

Mitral annular calcification (MAC) has been considered a risk factor for thrombo-embolic disease. Superimposed thrombus formation on MAC has not been well described as a possible underlying mechanism for this association. We report three patients with mobile left ventricular (LV) thrombus arising from the LV aspect of severe calcified mitral annulus in the setting of normal LV function, mitral valve function, and sinus rhythm.

Single coronary artery in a patient with apical variant hypertrophic cardiomyopathy.

Computed tomographic coronary angiography can noninvasively provide valuable anatomical information that may delineate the mechanism of ischemia (1). The resting electrocardiogram of a 70-year-old woman with a history of hypertension, dyslipidemia and chest pain is shown in Figure 1A. Dipyridamole stress myocardial perfusion imaging revealed distal anterior wall and apical ischemia. Computed tomographic angiography demonstrated the presence of Yamaguchi’s apical variant of hypertrophic cardiomyopathy. The characteristic spade-like configuration of the left ventricular cavity is shown in multiplanar and three-dimensional volume-rendered two-chamber views of the left atrium and left ventricle during diastasis (Figures 1B and ​and1C).1C). A single coronary artery arising from the right sinus of Valsalva is shown in Figures 1C and ​and1D.1D. The left main artery (elongated arrow) coursed posterior to the aortic root, supplying a very small left anterior descending artery (right ventricular outflow tract [short arrow]). A large posterior interventricular artery supplied most of the apex. No significant coronary obstructions were detected. Figure 1 Both apical hypertrophic cardiomyopathy and anomalous coronary arteries are rare. Yamaguchi’s variant accounts for less than 10% of hypertrophic cardiomyopathy cases in some reports (2) and anomalous coronary arteries occur in less than 1% of live births (3).

Comparison of Tc-99m sestamibi perfusion imaging and echocardiography using an arbutamine infusion for the detection of coronary artery disease

Arbutamine, a synthetic catecholamine, coupled with a closed-loop, computerized delivery system was evaluated in conjunction with technetium-99m sestamibi scintigraphy and echocardiography for the detection of coronary artery disease. Concordance between the imaging methods was 68%, with a similar sensitivity for coronary disease using echocardiography (78%) and technetium-99m sestamibi (76%), although more arbutamine-induced ischemia was noted with perfusion imaging.

A fenestrated aortic valve contributing to iatrogenic aortic insufficiency post mitral valve replacement

A case of an unusual local complication of cardiac valvular surgery is presented. Distortion of the geometry of the aortic valve base by a prosthetic mitral valve sewing ring allowed aortic insufficiency through the aortic valves central orifice, as well as through an aortic valve cusp fenestration. During the 6 years after valve surgery, this patient developed chronic left heart failure contributed to by the aortic insufficiency and eventually, at age 65, required cardiac transplantation. Surgeons and pathologists should be aware of this unusual local complication of cardiac valve surgery, as it may have serious consequences.

Atypical Pseudoaneurysm After Mitral Valve Replacement: Doppler Echocardiographic Diagnosis

Ventricular pseudoaneurysm is a rare complication of mitral valve replacement or myocardial infarction. Typically, a ventricular pseudoaneurysm appears as an echocardiographic lucency posterior and lateral to the left ventricle and is best seen from the parasternal long axis and apical four-chamber views. We present an atypical case of left ventricular pseudoaneurysm that tracts posterior and lateral to the right ventricle that was best visualized from the subcostal and low parasternal windows with medial angulation. Doppler imaging confirmed the diagnosis by demonstrating to-and-fro flow between the left ventricle and the cavity located behind the right ventricle. This case emphasizes the importance of the use of multiple echocardiographic windows.

Randomized Trial Comparing the Effects of Ticagrelor Versus Clopidogrel on Myocardial Perfusion in Patients With Coronary Artery Disease

Background Ticagrelor is a P2Y12 receptor inhibitor used in acute coronary syndromes to reduce platelet activity and to decrease thrombus formation. Ticagrelor is associated with a reduction in mortality incremental to that observed with clopidogrel, potentially related to its non–antiplatelet effects. Evidence from animal models indicates that ticagrelor potentiates adenosine‐induced myocardial blood flow (MBF) increases. We investigated MBF at rest and during adenosine‐induced hyperemia in patients with stable coronary artery disease treated with ticagrelor versus clopidogrel. Methods and Results This randomized double‐blinded crossover study included 22 patients who received therapeutic interventions of ticagrelor 90 mg orally twice a day for 10 days and clopidogrel 75 mg orally once a day for 10 days, with a washout period of at least 10 days between the treatments. Global and regional MBF and myocardial flow reserve were measured using rubidium 82 positron emission tomography/computed tomography at baseline and during intermediate‐ and high‐dose adenosine. Global MBF was significantly greater with ticagrelor versus clopidogrel (1.28±0.55 versus 1.13±0.47 mL/min per gram, P=0.002) at intermediate‐dose adenosine and not different at baseline (0.65±0.19 versus 0.60±0.15 mL/min per gram, P=0.084) and at high‐dose adenosine (1.64±0.40 versus 1.61±0.19 mL/min per gram, P=0.53). In regions with impaired myocardial flow reserve (<2.5), MBF was greater with ticagrelor compared with clopidogrel during intermediate and high doses of adenosine (P<0.0001), whereas the differences were not significant at baseline. Conclusions Ticagrelor potentiates global and regional adenosine‐induced MBF increases in patients with stable coronary artery disease. This effect may contribute to the incremental mortality benefit compared with clopidogrel. Clinical Trial Registration URL: http://www.clinicaltrials.gov. Unique identifier: NCT01894789.