Stromal cell-derived factor-1alpha improves infarcted heart function through angiogenesis in mice.

BACKGROUND: Local delivery of stromal cell-derived factor-1alpha (SDF-1) has been demonstrated to improve hind limb ischemia through enhanced neovascularization in animals. It was hypothesized that local administration of SDF-1 also contributes to neovascularization of ischemic heart. METHOD: Acute myocardial infarction was created by left coronary artery ligation in C57BL/6J mice. Immediately after infarction induction, mice were treated by injection directly into the center of ischemic myocardium either with saline (control group) or SDF-1 (SDF-1 group). Cardiac function was measured on echocardiogram 2 and 4 weeks after infarction. On week 4 mice were killed to evaluate infarction size and capillary vessel density. To determine the contribution of bone marrow cells to angiogenesis, the same procedures were performed on C57BL/6J chimeric mice reconstituted with green fluorescent protein-positive bone marrow cells. RESULTS: Fractional shortening was greater in the SDF-1 group at 4 weeks (0.31 +/- 0.06% vs 0.23 +/- 0.03%, P = 0.037). The infarct area was smaller in the SDF-1 group compared to the control group (9.31 +/- 2.76% vs 18.07 +/- 5.69%, P = 0.028). Green fluorescent protein-positive cells accumulated predominantly at the peri-infarction site, and were located with the capillary vessels. Capillary vessel density was significantly increased in the SDF-1 group (13.08 +/- 4.11 vessels/mm(2) vs 34.50 +/- 7.59 vessels/mm(2), P = 0.014). CONCLUSIONS: SDF-1 protects against deterioration of cardiac function after acute myocardial infarction by promoting angiogenesis. The safety and long-term prognosis of this treatment remains to be determined.

Remodeling of gap junctions in ischemic and nonischemic forms of heart disease.

Electrical activation of the myocardium to produce effective pumping of blood depends on the orderly coordinated spatial and temporal transfer of current from one cell to another via gap junctions. Normal ventricular myocytes are extensively coupled by gap junctions and have the capacity to rapidly increase the amount of connexin within gap junction plaques to meet physiological demands for enhanced cell-cell communication. However, myocytes can also rapidly uncouple in response to injury or disease. In general, both acute and chronic forms of heart disease caused by diverse etiologies are associated with changes in the expression of connexins and remodeling of gap junctions. Such remodeling may have both adaptive and maladaptive consequences and contribute to major clinical processes such as heart failure and sudden cardiac death. Our laboratory has investigated mechanisms regulating cell-cell electrical coupling in the heart under physiological and pathophysiological conditions. This review is focused on selected aspects of this work pertaining to changes in coupling in response to acute and chronic ischemic heart disease and in familial cardiomyopathies caused by mutations in genes encoding desmosomal proteins.

Map-guided surgery for atrial fibrillation.

BACKGROUND: Although current surgical procedures result in a high success rate for atrial fibrillation, they are not guided by electrophysiologic findings in individual patients and thus might include unnecessary incisions in some patients or be inappropriate for other patients. We sought to determine whether intraoperative mapping is beneficial for the surgical treatment of atrial fibrillation. METHODS: A 256-channel 3-dimensional dynamic mapping system with custom-made epicardial patch electrodes was used to examine the atrial activation during atrial fibrillation and to determine the optimal procedure in 37 patients with continuous and 9 patients with intermittent atrial fibrillation intraoperatively. RESULTS: Surgical intervention for atrial fibrillation was not indicated in 3 patients in whom the atrial electrograms had a low voltage over a broad area. Concurrent, multiple, and repetitive activations arising from the pulmonary veins or left atrial appendage were observed in all patients. A simple left atrial procedure consisting of pulmonary vein isolation and left atrial incisions without any right atrial incisions was performed in 8 patients in whom the right atrial activation was passive, and all (100%) were cured of atrial fibrillation. The radial procedure was performed in the remaining 35 patients, and 31 (89%) of the patients were cured of atrial fibrillation. In this subset of patients, 10 exhibited reentrant or focal activation in the posterior left atrium between the right and left pulmonary veins and required an additional linear ablation on the posterior left atrium. The total amount of postoperative bleeding after the simple left atrial procedure was significantly less than after the radial procedure (378 +/- 135 vs 711 +/- 364 mL, P = .03). The right and left atrial transport functions were well preserved after both the radial and simple left atrial procedures. CONCLUSION: Intraoperative mapping facilitates determining the optimal procedure for atrial fibrillation in each patient.

Spontaneous and inducible ventricular arrhythmias after myocardial infarction in mice.

INTRODUCTION: Remodeling of gap junctions has been implicated in development of ventricular arrhythmias following myocardial infarction (MI) but the specific contribution of reduced electrical coupling is not known. We addressed this question using hearts from mice heterozygous for a connexin43 null allele (Cx43(+/-)). METHODS: To determine whether Cx43-deficient mice exhibit increased spontaneous ventricular arrhythmias in the setting of chronic ischemic heart disease, radiofrequency transmitters were implanted in wild-type and Cx43(+/-) mice 2 days or 9 weeks after left anterior descending coronary artery ligation or sham operations. ECGs were recorded from unanesthetized, unrestrained mice 1 and 10 weeks after MI. Isolated, perfused hearts excised 1 and 10 weeks after MI were subjected to programmed electrical stimulation to induce arrhythmias. RESULTS AND CONCLUSIONS: Hearts with infarcts exhibited more spontaneous and inducible arrhythmias, but there was no significant difference between wild-type and Cx43-deficient mice. Fewer hearts exhibited spontaneous ventricular tachycardia (VT) in vivo than were inducible in vitro, suggesting that structural and functional substrates for inducible VT in isolated hearts may not be sufficient for initiation and maintenance of sustained VT in vivo. Previous studies have shown that Cx43-deficient mice exhibit more VT than wild-type mice during acute regional ischemia. Mice with MI exhibit increased arrhythmias. However, reduced coupling in Cx43-deficient mice does not significantly enhance spontaneous or inducible VT after MI.

Coronary artery bypass grafting without cardiopulmonary bypass: a five-year experience.

The current drive to practice less invasive surgery is changing surgical practice towards safer and simpler procedures. The practice of coronary artery bypass grafting (CABG) on a beating heart without cardiopulmonary bypass (CPB), off-pump CABG or OPCAB, has been gaining great attention as an alternative approach to conventional CABG. Since the first adoption of OPCAB in 1997 at our department, 181 patients have undergone OPCAB. OPCAB was indicated for patients who were possibly at risk for CPB, i.e., those who were elderly, who had a history of cerebrovascular disease, whose ascending aorta was severely atherosclerotic with calcification, whose respiratory function was compromised, or whose renal function was compromised. A patient with a concomitant malignant neoplastic disorder was also a candidate for OPCAB because of the possible deleterious effect of CPB on the immune system. More recently, when the coronary anatomy was suitable for OPCAB, even in younger or less risky patients, OPCAB was indicated. The OPCAB procedure was performed through a median sternotomy in 146 patients (80.6%), a left thoracotomy in 27 (14.9%), a subxiphoid approach in 6 and a combined one in 2. One hundred and eleven patients (61.3%) received 1 or 2 grafts (Group I) and 70 (38.7%) received 3 or more grafts (Group II). The number of grafted vessels in Group II patients was 3 to 5 with a mean of 3.44. The mean operative time was 163 minutes in Group I and 209.5 minutes in Group II. The frequency of the use of arterial grafts such as LITA, RITA and RA was significantly higher in Group II than in Group I. Death occurred in 3 patients with acute coronary syndrome who had to undergo urgent surgery. Angiographic examination was performed within 3 months, postoperatively, in 98 patients (54.1%) revealing the overall patency rate of each graft: LITA82/83 (98.8%), RITA 33/33 (100%), GEA 15/16 (93.8%), RA 20/20 (100%), and SVG 15/16 (93.8%). We conclude that, in light of our 5-year experience, off-pump CABG on a beating heart can be safely and effectively performed, with acceptable angiographic results even in patients with multi-vessel coronary disease requiring multiple revascularization. This procedure enables us to perform successful coronary bypass surgery for those who otherwise would not have been candidates for conventional CABG.

Connexin43 as a determinant of myocardial infarct size following coronary occlusion in mice.

OBJECTIVES: The purpose of this study was to define the role of cell-cell coupling as an independent determinant of infarct size following coronary occlusion. BACKGROUND: Electrical uncoupling induced by acute ischemia enhances arrhythmogenesis, but it may also protect the heart by limiting intercellular spread of chemical mediators of injury. METHODS: The left anterior descending coronary artery was ligated in wild-type (Cx43(+/+)) mice and Cx43-deficient (Cx43(+/-)) mice that are heterozygous for a null allele in the gene encoding the major gap junction channel protein, connexin43 (Cx43). Ventricular remodeling and infarct size were compared in both groups. RESULTS: Echocardiography at 1 and 10 weeks after infarction showed that left ventricular end-diastolic volume and mass increased and ejection fraction decreased in proportion to infarct size in both Cx43(+/-) and Cx43(+/+) hearts. However, infarct size measured histologically in healing infarcts (eight days after infarction) was 29% smaller in Cx43(+/-) hearts (17 +/- 14% of total left ventricular area, n = 30) than in Cx43(+/+) hearts (24 +/- 15%, n = 23; p = 0.037). Fully healed infarcts were smaller than healing infarcts, owing to resorption of necrotic tissue and maturation of scar, but infarct size at 10 weeks after coronary occlusion was still smaller (by 50%) in Cx43(+/-) hearts (6 +/- 5%, n = 9) compared with Cx43(+/+) hearts (12 +/- 7%, n = 17; p = 0.037). CONCLUSIONS: Cx43-deficient mice develop smaller infarcts than wild-type mice following coronary ligation. New therapies designed to decrease the risk of arrhythmias by enhancing intercellular communication could lead to larger infarcts caused by persistent coronary occlusion.

Echocardiographic evaluation of ventricular remodeling in a mouse model of myocardial infarction.

Gene-targeting in mice is a powerful tool to define molecular mechanisms of ischemic heart disease that determine infarct size, postinfarct left ventricular (LV) remodeling, and arrhythmogenesis. Coronary ligation in mice is becoming a widely used model of myocardial infarction (MI), but the pathophysiologic consequences of MI in mice and its relevance to human MI have not been fully elucidated. To characterize structural and functional changes during evolving MI, we analyzed 2-dimensional-based reconstruction of the left ventricle by noninvasive echocardiography obtained 1 day and 1 week after surgical ligation of the left anterior descending coronary artery in mice. Sequential 2-dimensional short-axis cineloops of the left ventricle were used to measure LV mass, and LV volumes at end-diastole and end-systole. Echocardiographic infarct size was estimated by measuring the volume of akinetic LV segments. Histologic infarct size was measured by planimetry of 9 transverse sections of each heart. There was close correlation between the 2 methods (31% +/- 20% of LV mass and 34% +/- 17% of LV area, respectively; y =.83x + 7.9, r = 0.96, P <.01). LV volumes at end diastole increased significantly between 1 day and 1 week (51 +/- 17 microL vs 78 +/- 46 microL, respectively, P <.05). The relative change in LV volumes at end diastole varied as a function of infarct size (r = 0.93, P <.01). LV mass and the extent of hypertrophy of noninfarcted segments also varied with infarct size (r = 0.92, P <.01; r = 0.90, P <.01, respectively). Thus, echocardiography is an accurate noninvasive tool for determination of infarct size and quantitative characterization of postinfarct remodeling in the mouse model of MI. Alterations in cardiac structure and function after coronary ligation in mice closely resemble pathophysiologic changes in human ischemic heart disease.