Robert C. Touchon

Agonists of epoxyeicosatrienoic acids reduce infarct size and ameliorate cardiac dysfunction via activation of HO-1 and Wnt1 canonical pathway

Myocardial infarction (MI) is complicated by ventricular fibrosis and associated diastolic and systolic failure. Emerging studies implicate Wnt1 signaling in the formation of new blood vessels. Epoxyeicosatrienoic acids (EETs)-mediated up-regulation of heme oxygenase-1 (HO-1) protects against the detrimental consequences of MI in several animal models, however, the mechanism(s) by which this occurs remains unclear. The aim of this study was to examine these mechanisms in the LAD ligation animal model of post infarcted heart failure. Specifically, we sought to clarify the mechanistic basis of the interactions of the Wnt1 canonical pathway, HO-1 and associated angiogenesis. Human microvascular endothelial cells (HMECs) were exposed to anoxia and treated with the EET agonist, NUDSA, in the presence and absence of tin mesoporphyrin (SnMP). Increased capillary density, and Wnt1 and HO-1 expression occurred in cells treated with NUDSA. Anoxic HMECs treated with NUDSA and Wnt1 siRNA, exhibited decreased in the expression of β-catenin and the Wnt1 target gene, PPARδ (p<0.05 vs. NUDSA). Furthermore, blocking the Wnt 1 antagonist, Dickkopf 1, by siRNA increased β-catenin and PPARδ expression, and this effect was further enhanced by the concurrent administration of NUDSA. In in vivo experiments, C57B16 mice were divided into 4 groups: sham, mice with MI via LAD ligation and mice with MI treated with NUDSA, with and without SnMP. Increased fractional area change (FAC) and myocardial angiogenesis were observed in mice treated with NUDSA (p<0.05 vs. MI). Increased expression of HO-1, Wnt1, β-catenin, adiponectin, and phospho-endothelial nitric oxide synthetase (p-eNOS), and a decrease in the glycosylated subunit of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, gp91(phox) expression occurred in cardiac tissue of mice treated with NUDSA (p<0.05 vs. MI). SnMP reversed these effects. This novel study demonstrates that increasing the canonical Wnt1 signaling cascade with the subsequent increase in HO-1, adiponectin and angiogenesis ameliorates fibrosis and cardiac dysfunction in a mouse model of MI and supports the hypothesis that HO-1 is an integral component of the EETs-adiponectin axis and is central for the control of resistance to fibrosis and vascular dysfunction and in part determine how they influence the cellular/vascular homeostasis and provides insight into the mechanisms involved in vascular dysfunction as well as potential targets for the treatment of CVD.

Late potentials in mitral valve prolapse

To determine the incidence and significance of late potentials in patients with mitral valve prolapse, we performed surface signal-averaged electrocardiography and 24-hour ambulatory electrocardiographic (ECG) monitoring in 41 patients with moderate to severe mitral valve prolapse on two-dimensional echocardiograms. Late potentials were defined as the presence of either a root mean square voltage of the last 40 msec of the QRS (RMS-40) of less than 20 mu v or a low-amplitude signal duration (LAS-40) of greater than 39 msec. Despite the absence of clinically significant ventricular tachycardia by history and on ambulatory ECG monitoring, 12 patients had late potentials on their signal-averaged electrocardiograms. Clinical characteristics could not differentiate patients with from patients without late potentials, and all patients were doing well at a mean follow-up of 34 months except for one noncardiac death. We conclude that late potentials on the surface signal-averaged electrocardiogram are a common and benign finding in patients with mitral valve prolapse and their clinical significance should be determined only in the presence of other findings.

The Role of Two-Dimensional Echocardiography in the Diagnosis of Ineffective Endocarditis

Two-dimensional echocardiography has had a significant impact on and is considered the technique of choice for the diagnosis and management of infec tive endocarditis. Over a thirty-six month period, 106 patients were evaluated by echocardiography for the possibility of endocarditis. The diagnosis of en docarditis was determined by strict clinical and laboratory criteria. All clinical histories, blood cultures, echocardiograms, and autopsy results were reviewed. Five echocardiograms were technically inadequate, resulting in a study popula tion of 101 patients. The age of the patients ranged from forty-five days to eighty-eight years (mean fifty-seven years). The clinical manifestations of endocarditis included fever (83%), chills (60%), congestive heart failure (25%), and splenomegaly (18%). Twelve patients had preexisting valvular or congenital heart disease. Gram-positive cocci were the most common microorganisms. Complications included mitral regurgitation, subarachnoid hemorrhage, renal infarction, stroke, and a pulmo nary embolus. The patients were divided into two groups: Group I consisted of 36 patients with definite vegetations by echocardiography, and Group II had 65 patients with no vegetations. In Group I, acute infective endocarditis was present in 35 patients, whereas only 4 patients had endocarditis in Group II. The sensitivity of two-dimensional echocardiography for detecting endocarditis was 90%. The specificity was 98%. The predictive accuracy for a positive test was 97%, and the predictive accuracy for a negative test was 94%. Thus, two-dimensional echocardiography appears to have a high sensitivity, specificity, and predictive value in the evaluation of patients with suspected endocarditis.

Coronary venous retroperfusion of arterial blood for the treatment of acute myocardial ischemia

Synchronized coronary venous retroperfusion of autologous arterial blood was offered to patients referred for medically refractory unstable angina or evolving myocardial infarction with contraindications to thrombolytic therapy. Primary endpoints of angina, ST segment deviation, and two-dimensional echocardiographic systolic wall motion were followed to determine the efficacy of retroperfusion in patients prior to and then during angioplasty, surgical intervention, or pharmacological management, as the clinical picture warranted. Over a 12 month period, 21 patients were referred and 15 received retroperfusion. All experienced full relief of angina (p = 0.008). ST segment deviations and systolic wall motion of ischemic zones were observed to improve (p = 0.06 ST changes; p = 0.0001 wall motion changes) with synchronized retrograde perfusion. During attempts to remove patients from retroperfusion, statistically significant (p < 0.01) reproducible changes in these same endpoints were documented. Retroperfusion appears to improve acute myocardial ischemia. This technique functions well in the intensive care unit environment with only fluoroscopy as technical imaging support.

Aortic atherosclerosis and stroke

METHODS Studies using transesophageal echocardiography (TEE) suggest aortic atherosclerosis may be a risk factor for stroke, particularly stroke of undetermined mechanism, but controls in prior studies were not balanced for vascular risk factors. We used TEE to evaluate aortic atherosclerosis in 60 patients with stroke compared with a high-risk control population of 46 subjects. We also examined the possible association of plasma viscosity and fibrinogen levels to aortic atherosclerosis. RESULTS The mean maximal plaque thickness (MMPT) was similar for the control (2.8 +/- 3.6 mm) and the stroke group (3.3 +/- 3.5 mm), but varied with stroke mechanism. The MMPT was similar in stroke of undetermined and atherosclerotic mechanism [3.5 +/- 4 mm (n = 25) and 4.2 +/- 4.3 mm (n = 16), respectively], significantly greater than in stroke of other mechanisms (1.7 +/- 1.2 mm, P < .05, n = 19). Patients with stroke of undetermined mechanism were four times more likely (95% confidence interval [CI] 1.2-12) to have plaques >/=5 mm compared with controls. Ulcerated plaque was associated with plaque thickness (P < .001) and plasma viscosity (P < .001). CONCLUSIONS Aortic atherosclerosis is associated with stroke of undetermined cause suggesting atherosclerosis is a cause of stroke of undetermined etiology. Plaque ulceration was associated with the thickness of aortic plaque and plasma viscosity.

THERAPY OF ISCHEMIC CARDIOMYOPATHY WITH PENTOXIFYLLINE

Abnormal blood rheology is a known characteristic of coronary artery disease. The authors evaluated the effects of pentoxifylline on the exercise capacity ejection fraction and symptoms of 9 patients with ischemic cardiomyopathy. All patients had signs and symptoms of left ventricular dysfunction. All had at least two major vessels obstructed as determined by coronary angiography. Pentoxifylline 400 mg three times daily was administered for twelve weeks. Seven of 9 patients re sponded with increases in ejection fraction and exercise tolerance. Exercise tolerance correlated with improvement or lack of improvement in ejection frac tion. For all patients at twelve weeks post-therapy mean ejection fraction in creased 9.8% over baseline (p = .07), total treadmill time increased 15 % (p = .27), and mean double product increased 13% (p = .03). Anginal symptoms were significantly improved over baseline at twelve weeks of therapy (p>.001), as well as dyspnea on exertion (p = .03). Pentoxifylline was well tolerated. Pentoxifylline may benefit ischemic cardiomyopathy by improving coronary perfusion owing to favorable alterations in hemorheologic properties.

Impact of a preventive cardiology curriculum on knowledge and attitudes of first‐year medical students

This study examined the impact of a preventive cardiology curriculum on the knowledge and attitudes of first‐year medical students. Questionnaires assessing knowledge and attitudes were self‐administered to classes entering in 1988 and 1989 at the beginning and end of each academic year. Data from 54 students were analyzed. All statistical analyses were significant, indicating that students showed increases in both knowledge and attitudes regarding preventive cardiology. We concluded that the preventive cardiology curriculum had a significant impact on student learning. Future research is needed to address the long‐term effect of the increases in knowledge and attitudes on the future practice of medicine.

The acute and chronic effects of G-lasing on femoral vein grafts in dogs

Each year, 5 % of all coronary artery bypass operations are repeat procedures, and 15 % -30 % of coronary artery vein grafts occlude within the first eighteen months postoperatively. To evaluate the macroscopic and histologic effects of G-lasing on vein grafts and their patency, femoral veins were used to bypass bilaterally induced stenoses of femoral arteries in 10 dogs. The left vein grafts were G-lased with a 1.5 mm, hot-tipped argon laser at 5 watts for ninety seconds, while the right grafts were used as the controls. Acutely, each vein graft demonstrated no evidence of charring or perforation. The percentage of endothelium present in the G-lased vein grafts was consistently less than 5 %, whereas the control vein grafts had an average of 70%. After ten weeks, the animals were sacrificed, and the vein grafts were evaluated for histologic changes and patency. There were no significant microscopic differences between the G-lased and control vein grafts. A statistically significant difference in graft patency was not achieved between G-Lased and control vein grafts at 10 weeks, but only a small number of grafts were studied. Further studies will be needed to evaluate the effects of G-lasing on the long-term patency of vein grafts.

Left ventricular pseudoaneurysm after myocardial infarction

As is evident from our case and others, post-myocardial infarction pericarditis with the formation of pericardial adhesions creates a suitable milieu for left ventricular pseudoaneurysm. Although the conditions for pseudoaneurysm formation are rarely met, the clinician should be aware of this diagnosis, even long after myocardial infarction, because of its associated mortality and also because it is surgically curable.