Stuart W. Jamieson

Early Expression of Angiogenesis Factors in Acute Myocardial Ischemia and Infarction

BACKGROUND When the myocardium is deprived of blood, a process of ischemia, infarction, and myocardial remodeling is initiated. Hypoxia-inducible factor 1 (HIF-1) is a transcriptional activator of vascular endothelial growth factor (VEGF) and is critical for initiating early cellular responses to hypoxia. We investigated the temporal and spatial patterns of expression of the alpha subunit of HIF-1 (HIF-1alpha) and VEGF in specimens of human heart tissue to elucidate the early molecular responses to myocardial hypoxia. METHODS Ventricular-biopsy specimens from 37 patients undergoing coronary bypass surgery were collected. The specimens were examined by microscopy for evidence of ischemia, evolving infarction, or a normal histologic appearance. The specimens were also analyzed with the reverse-transcriptase polymerase chain reaction for HIF-1alpha and VEGF messenger RNA (mRNA) expression and by immunohistochemical analysis for the location of the HIF-1alpha and VEGF proteins. RESULTS HIF-1alpha mRNA was detected in myocardial specimens with pathological evidence of acute ischemia (onset, <48 hours before surgery) or early infarction (onset, <24 hours before surgery). In contrast, VEGF transcripts were seen in specimens with evidence of acute ischemia or evolving infarction (onset, 24 to 120 hours before surgery). Patients with normal ventricles or evidence of infarction in the distant past had no detectable levels of either VEGF mRNA or HIF-1alpha mRNA. HIF-1alpha immunoreactivity was detected in the nuclei of myocytes and endothelial cells, whereas VEGF immunoreactivity was found in the cytoplasm of endothelial cells lining capillaries and arterioles. CONCLUSIONS An increase in the level of HIF-1alpha is an early response to myocardial ischemia or infarction. This response defines, at a molecular level, one of the first adaptations of human myocardium to a deprivation of blood. HIF-1alpha is a useful temporal marker of acutely jeopardized myocardium.

Pulmonary endarterectomy: experience and lessons learned in 1,500 cases

BACKGROUND The incidence of pulmonary hypertension resulting from chronic thrombotic occlusion of the pulmonary arteries is significantly underestimated. Although medical therapy for the condition is supportive only, surgical therapy is curative. Our pulmonary endarterectomy program was begun in 1970, and 188 patients were operated on in the subsequent 20 years. With the increased recognition of the disease and the success of operative therapy, however, more than 1,400 operations have been done since 1990 at our center. METHODS The safety and efficacy of the operation was assessed with changes made through increased experience. We examined in detail the results of our last 500 consecutive patients. RESULTS Median sternotomy, cardiopulmonary bypass, profound hypothermia, and circulatory arrest were found to be essential to the success of the operation. All occluding material could be removed at operation. We currently believe that there is no degree of embolic occlusion within the pulmonary vascular tree that is inaccessible and no degree of right ventricular impairment or any level of pulmonary vascular resistance that is inoperable. With shorter cardiac arrest periods and the use of a cooling jacket to the head, cerebral impairment has been eliminated. The pulmonary artery pressures and pulmonary vascular resistance in a recent cohort of 500 patients is examined. The mortality rate for the operation has been reduced steadily, and was 22 of the last 500 patients operated on (4.4%). CONCLUSIONS The operation is considered curative and therefore greatly superior to transplantation for this condition. Current techniques of operation make the procedure relatively safe.

Pulmonary Endarterectomy: Recent Changes in a Single Institution's Experience of More Than 2,700 Patients

BACKGROUND Chronic thromboembolic pulmonary hypertension (CTEPH) is a known sequela of acute pulmonary embolic disease and yet remains underdiagnosed. Although nonsurgical options for patients with CTEPH have become increasingly available, including pulmonary artery hypertensive medical therapy, surgical endarterectomy provides the most appropriate intervention as a potential cure for this debilitating disorder. This article summarizes the most recent outcomes of pulmonary endarterectomy at a single institution over the past 12 years, with emphasis on the surgical approach to segmental-level chronic thromboembolic disease. METHODS More than 2,700 pulmonary endarterectomy operations have been performed at the University of California, San Diego Medical Center. Because of recent changes in the patient population and in surgical results, 1,500 patients with symptomatic chronic thromboembolic disease who underwent pulmonary endarterectomy between March 1999 and December 2010 were analyzed. The outcomes for the more recent 500 patients, compared with the previous 1,000 were studied. RESULTS In-hospital mortality for the cohort of 1,000 patients (group 1) was 5.2% compared with 2.2% for the last 500 operations (group 2) (p < 0.01). There was no mortality in the last 260 consecutive patients undergoing isolated pulmonary endarterectomy. More patients presented with segmental type III disease in the more recent 500 patients (21.4% versus 13.1%; p < 0.001). Between the 2 patient groups, there was a comparable decline in pulmonary vascular resistance (PVR) (group 1: 861.2 ± 446.2 to 94.8 ± 204.2 dynes/sec/cm(-5); group 2: 719.0 ± 383.2 to 253.4 ± 148.6 dynes/sec/cm(-5)) and mean pulmonary artery (PA) pressures (group 1: 46.1 ± 11.4 to 28.7 ± 10.1 mm Hg; group 2: 45.5 ± 11.6 to 26.0 ± 8.4 mm Hg) after endarterectomy. CONCLUSIONS Despite a patient population with more distal disease, results continue to improve. Pulmonary endarterectomy for patients with CTEPH results in significant pulmonary hemodynamic improvement, with favorable outcomes achievable even in patients with distal segmental-level chronic thromboembolic disease.

Notch3 signaling promotes the development of pulmonary arterial hypertension

Notch receptor signaling is implicated in controlling smooth muscle cell proliferation and in maintaining smooth muscle cells in an undifferentiated state. Pulmonary arterial hypertension is characterized by excessive vascular resistance, smooth muscle cell proliferation in small pulmonary arteries, leading to elevation of pulmonary vascular resistance, right ventricular failure and death. Here we show that human pulmonary hypertension is characterized by overexpression of NOTCH3 in small pulmonary artery smooth muscle cells and that the severity of disease in humans and rodents correlates with the amount of NOTCH3 protein in the lung. We further show that mice with homozygous deletion of Notch3 do not develop pulmonary hypertension in response to hypoxic stimulation and that pulmonary hypertension can be successfully treated in mice by administration of N-[N-(3,5-difluorophenacetyl)-L-alanyl]-S-phenylglycine t-butyl ester (DAPT), a γ-secretase inhibitor that blocks activation of Notch3 in smooth muscle cells. We show a mechanistic link from NOTCH3 receptor signaling through the Hairy and enhancer of Split-5 (HES-5) protein to smooth muscle cell proliferation and a shift to an undifferentiated smooth muscle cell phenotype. These results suggest that the NOTCH3–HES-5 signaling pathway is crucial for the development of pulmonary arterial hypertension and provide a target pathway for therapeutic intervention.

Induction of pulmonary hypertension by an angiopoietin 1/TIE2/serotonin pathway

Smooth muscle cell proliferation around small pulmonary vessels is essential to the pathogenesis of pulmonary hypertension. Here we describe a molecular mechanism and animal model for this vascular pathology. Rodents engineered to express angiopoietin 1 (Ang-1) constitutively in the lung develop severe pulmonary hypertension. These animals manifest diffuse medial thickening in small pulmonary vessels, resulting from smooth muscle cell hyperplasia. This pathology is common to all forms of human pulmonary hypertension. We demonstrate that Ang-1 stimulates pulmonary arteriolar endothelial cells through a TIE2 (receptor with tyrosine kinase activity containing IgG-like loops and epidermal growth factor homology domains) pathway to produce and secrete serotonin (5-hydroxytryptamine), a potent smooth muscle mitogen, and find that high levels of serotonin are present both in human and rodent pulmonary hypertensive lung tissue. These results suggest that pulmonary hypertensive vasculopathy occurs through an Ang-1/TIE2/serotonin paracrine pathway and imply that these signaling molecules may be targets for strategies to treat this disease.

PATHOGENESIS AND PREVENTION OF GRAFT ARTERIOSCLEROSIS IN AN EXPERIMENTAL HEART TRANSPLANT MODEL

Accelerated graft arteriosclerosis is a major cause of death in human heart transplantation. Despite many investigations, the pathogenesis of this disease remains undetermined and its control inadequate. In this study using a rat heart transplant model and cyclosporin A, a new immunosuppressant, acute rejection was prevented but arteriosclerotic-like vessel disease still developed consistently as early as 20 days postoperatively. The combination of cyclosporin A and dipyridamole prevented the development of this vessel disease in transplanted hearts at 20 and 50 days postoperatively. Sulfinpyrazone and cyclosporin A reduced but did not prevent the disease. These findings suggest that immunologically induced graft arteriosclerosis can be prevented in transplanted rat hearts by the combination of cyclosporin A and dipyridamole.

Continuous intravenous epoprostenol for chronic thromboembolic pulmonary hypertension

Pathophysiological findings in chronic thromboembolic pulmonary hypertension (CTEPH) have suggested that a secondary small vessel arteriopathy may contribute to the haemodynamic impairment observed in these patients. It was hypothesised that this element of the elevated vascular resistance may be responsive to continuous intravenous epoprostenol therapy. Retrospectively, the clinical and haemodynamic responses to continuous intravenous epoprostenol were evaluated in nine CTEPH patients who subsequently underwent pulmonary thromboendarterectomy (PTE). Cardiopulmonary haemodynamics were determined prior to the initiation of epoprostenol, while on epoprostenol, prior to PTE, and after PTE. Six patients, treated for 2–26 months prior to PTE, experienced either clinical stability or improvement that was associated with a mean reduction in pulmonary vascular resistance (PVR) of 28% (median 33%, range 0–46%). Three patients, treated for 3–9 months, experienced clinical deterioration during epoprostenol administration, with a significant increase in PVR in two patients. Subsequent PTE resulted in a highly significant improvement of cardiac index, mean pulmonary artery pressure and total pulmonary resistance. To conclude, selected patients with chronic thromboembolic pulmonary hypertension may benefit clinically and haemodynamically from continuous intravenous epoprostenol treatment prior to pulmonary thromboendarterectomy. Factors predictive of a beneficial response, and whether this intervention influences either morbidity or mortality associated with pulmonary thromboendarterectomy, remain to be established.

A Reconsideration of Cerebral Perfusion in Aortic Arch Replacement

Ten patients underwent aortic arch replacement for aneurysmal disease from 1970 to 1985 using a simplified cardiopulmonary bypass (CPB) technique with partial brachiocephalic perfusion, low CPB flow (30 to 50 ml/kg/min), moderate systemic cooling (26 degrees to 28 degrees C), and topical hypothermic myocardial protection. The arterial line from a single pump head has a Y shape to perfuse the femoral artery (20F cannula) and either the innominate or left carotid artery (14F). Of the 10 patients (mean age, 58 years) with arch aneurysm (6 atherosclerotic, 2 dissections, and 2 degenerative), 3 had previously undergone major cardiovascular operations. Concomitant procedures included aortic valve replacement in 4 and coronary artery bypass grafting in 3. Eight patients survived the procedure, and 1 died three weeks after operation of a ruptured abdominal aneurysm. Among the survivors, CPB time was 119 +/- 36 minutes (+/- standard deviation), myocardial ischemia time was 79 +/- 32 minutes, and intraoperative blood requirement was 5.9 +/- 3.4 units. There were no postoperative strokes. Neurological complications were only minor and included an asymptomatic miosis and ulnar nerve paresthesias in 1 patient and transient vocal cord palsy in another. Applicable in most patients undergoing elective resection of degenerative and atherosclerotic arch aneurysms and in selected patients with arch dissections, this simplified technique of brachiocephalic perfusion without circulatory arrest provides an attractive and safe alternative; the potential advantages are technical simplicity, reduced CPB and operating times, and satisfactory cerebral protection.

Primary pulmonary artery sarcoma: A report of six cases

Pulmonary artery tumors are rare and a frequently overlooked cause of pulmonary artery occlusion. The presentation is one of progressive pulmonary dysfunction and right ventricular failure. The diagnosis seldom is made preoperatively. We report 6 cases of primary sarcoma of the pulmonary artery identified at operation, which were treated surgically. Resection with or without adjuvant therapy currently offers the only chance for survival. Emphasis must be placed on earlier identification of these tumors.

Infectious complications in heart-lung transplant recipients

Infectious complications were studied in 14 patients who received heart-lung transplants at Stanford University Medical Center from March 1981 to November 1983. Twenty-nine infections occurred in 12 patients: 18 bacterial, nine viral, and two fungal. Sixteen (89 percent) of the bacterial infections occurred in the lung. Because of frequent colonization of the lower respiratory tract, the specificity of transtracheal aspiration and bronchoscopy was low. Empiric broad-spectrum antibiotic therapy was usually successful, and no patient died of bacterial infection. Cytomegalovirus infection occurred in six and herpes simplex virus infection in three patients. Two patients had invasive candidiasis at postmortem examination. This series emphasizes the importance of infection, particularly of the lung, in causing morbidity and mortality in heart-lung transplant recipients.