Trpc6 Promotes Doxorubicin-Induced Cardiomyopathy in Male Mice With Pleiotropic Differences Between Males and Females.

Background: Doxorubicin is a widely used and effective chemotherapy, but the major limiting side effect is cardiomyopathy which in some patients leads to congestive heart failure. Genetic variants in TRPC6 have been associated with the development of doxorubicin-induced cardiotoxicity, suggesting that TRPC6 may be a therapeutic target for cardioprotection in cancer patients. Methods: Assessment of Trpc6 deficiency to prevent doxorubicin-induced cardiac damage and function was conducted in male and female B6.129 and Trpc6 knock-out mice. Mice were treated with doxorubicin intraperitoneally every other day for a total of 6 injections (4 mg/kg/dose, cumulative dose 24 mg/kg). Cardiac damage was measured in heart sections by quantification of vacuolation and fibrosis, and in heart tissue by gene expression of Tnni3 and Myh7. Cardiac function was determined by echocardiography. Results: When treated with doxorubicin, male Trpc6-deficient mice showed improvement in markers of cardiac damage with significantly reduced vacuolation, fibrosis and Myh7 expression and increased Tnni3 expression in the heart compared to wild-type controls. Similarly, male Trpc6-deficient mice treated with doxorubicin had improved LVEF, fractional shortening, cardiac output and stroke volume. Female mice were less susceptible to doxorubicin-induced cardiac damage and functional changes than males, but Trpc6-deficient females had improved vacuolation with doxorubicin treatment. Sex differences were observed in wild-type and Trpc6-deficient mice in body-weight and expression of Trpc1, Trpc3 and Rcan1 in response to doxorubicin. Conclusions: Trpc6 promotes cardiac damage following treatment with doxorubicin resulting in cardiomyopathy in male mice. Female mice are less susceptible to cardiotoxicity with more robust ability to modulate other Trpc channels and Rcan1 expression.

Relation between body mass index and clinical outcome in acute myocardial infarction.

Obesity has long been identified as a risk factor for coronary artery disease. However, the data evaluating outcomes in patients with acute myocardial infarction (AMI) related to body mass index (BMI) are limited and inconsistent. Patients (n = 284) who were diagnosed with AMI at the Medical College of Georgia from January 1, 2003 to June 25, 2004, were included in this retrospective analysis. BMI, risk for factors for coronary artery disease, AMI characteristics, and outcome variables were obtained from chart records. Logistic and multiple regression techniques were used to model and test hypotheses regarding the effect on outcomes after AMI, adjusting for cardiac risk factors, demographics, and other contextual variables. Compared with normal weight patients, underweight patients had more (65% vs 40%) and morbidly obese patients had fewer (21% vs 40%) ST-elevation AMIs (p = 0.014). Among all patients with AMIs, morbidly obese patients tended to be younger than normal weight subjects. No adverse relations among BMI and mortality, length of stay, readmission rates, or revascularzation in AMI were identified in this analysis. Both diabetes and previous aspirin use were found to increase the odds of in-hosptial mortality during AMI independent of BMI. In conclusion, despite the association between obesity and development of coronary artery disease, obesity does not adversely impact in-hospital outcomes in AMI. However, obesity is associated with AMI at a younger age.

Should coronary artery bypass graft surgery patients with mild or moderate aortic stenosis undergo concomitant aortic valve replacement? A decision analysis approach to the surgical dilemma.

OBJECTIVES: This study utilizes Markov decision analysis to assess the relative benefits of prophylactic aortic valve replacement (AVR) at the time of coronary artery bypass graft surgery (CABG). Multiple sensitivity analyses were also performed to determine the variables that most profoundly affect outcome. BACKGROUND: The decision to perform CABG or concomitant CABG and AVR (CABG/AVR) in asymptomatic patients who need CABG surgery but have mild to moderate aortic stenosis (AS) is not clear-cut. METHODS: We performed Markov decision analysis comparing long-term, quality-adjusted life outcomes of patients with mild to moderate AS undergoing CABG versus CABG/AVR. Age-specific morbidity and mortality risks with CABG, CABG/AVR, and AVR after a prior CABG were based on the Society of Thoracic Surgeons national database (n = 1,344,100). Probabilities of progression to symptomatic AS, valve-related morbidity, and age-adjusted mortality rates were obtained from available published reports. RESULTS: For average AS progression, the decision to replace the aortic valve at the time of elective CABG should be based on patient age and severity of AS measured by echocardiography. For patients under age 70 years, an AVR for mild AS is preferred if the peak valve gradient is >25 to 30 mm Hg. For older patients, the threshold increases by 1 to 2 mm Hg/year, so that an 85-year-old patient undergoing CABG should have AVR only if the gradient exceeds 50 mm Hg. The AS progression rate also influences outcomes. With slow progression (<3 mm Hg/year), CABG is favored for all patients with AS gradients <50 mm Hg; with rapid progression (>10 mm Hg/year), CABG/AVR is favored except for patients >80 years old with a valve gradient <25 mm Hg. CONCLUSIONS: This study provides a decision aid for treating patients with mild to moderate AS requiring CABG surgery. Predictors of AS progression in individual patients need to be better defined.

Usefulness of myocardial viability or ischemia in predicting long-term survival for patients with severe left ventricular dysfunction undergoing revascularization.

In 107 patients with coronary disease and severe left ventricular dysfunction, we examined the prognostic power of viability identified by dobutamine stress echocardiography. At a mean follow-up of 27 months, patients with viable myocardium who underwent revascularization had a significant survival advantage over all other patients (2-year survival 83.5% vs 57.2%, p = 0.0037).

Regional cardiac sympathetic innervation early and late after transmyocardial laser revascularization.

BACKGROUND: Prior experimental and clinical studies have drawn disparate conclusions regarding the effects of transmyocardial laser revascularization (TMR) on regional cardiac innervation in the treated regions. Regional afferent denervation has been proposed as a potential mechanism of action of the procedure, although this as yet remains unproven. The purpose of the present study was to evaluate regional myocardial sympathetic innervation both early (3 days) and late (6 months) after TMR. METHODS: Mini-swine in the early group were randomized to be sacrificed 3 days after holmium:YAG TMR (n = 5) or sham thoractomy (n = 3). In the late group, mini-swine with hibernating myocardium in the left circumflex (LCx) region were randomized to sham redo-thoracotomy (n = 5), TMR of the LCx distribution with a carbon dioxide (n = 5), holmium:YAG (n = 5), or excimer (n = 5) laser. Six months postoperatively the animals were sacrificed. Additional animals in both the early (n = 2) and late (n = 2) groups served as age- and weight-matched normal controls. Immunohistochemistry and Western blot analysis for tyrosine hydroxylase (TYR-OH), a neural-specific enzyme found in sympathetic efferent nerves and a commonly used anatomic marker of regional innervation, were performed on lased and nonlased LCx and septal regions. RESULTS: Immunohistochemical staining for TYR-OH was markedly diminished in the lased myocardial regions 3 days after TMR. This staining was significantly reduced compared to untreated septal regions, sham-operated, and normal LCx myocardium. Quantitative immunoblotting confirmed a significant reduction in TYR-OH (p < 0.05) protein concentration in the lased regions 3 days after TMR. On the contrary, TYR-OH staining was present in LCx myocardium surrounding the laser channels of all animals in all groups 6 months postoperatively. Staining was not different from controls. Similarly, there was no difference in LCx TYR-OH protein concentration between the normal, sham, or 6 months postoperative lased groups (p > 0.2 by one-way ANOVA). CONCLUSIONS: TMR-treated myocardium demonstrates anatomic evidence of regional sympathetic denervation 3 days postoperatively, although myocardium lased with each of the three lasers currently in clinical use is reinnervated by 6 months as evidenced by immunoblotting and immunohistochemistry for TYR-OH. These results suggest that mechanisms other than denervation may account for the long-term reductions in angina seen after TMR.

Therapeutic angiogenesis in chronically ischemic porcine myocardium: comparative effects of bFGF and VEGF.

BACKGROUND: Both vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) have been used in preclinical studies to induce new blood vessel growth in ischemic cardiac muscle with promising results. However, clinical trials have been much less convincing and further work is needed. This study expands on prior work by comparing the long-term proangiogenic effects of direct intramyocardial (IM) injection of bFGF, as well as IM and intravenous (IV) VEGF in a porcine model of chronic hibernating myocardium. METHODS: Mini-swine with proximal 90% left circumflex (LCx) coronary stenosis subtending chronically ischemic, viable (hibernating) myocardium by positron emission tomography (PET) and dobutamine stress echocardiography (DSE) were randomized to IM bFGF (n = 5), IM VEGF(165) (n = 5), IV VEGF(165) (n = 5), IM vehicle (n = 5), or sham redo-thoracotomy (n = 4). The bFGF protein was administered in a total dose of 1.35 microg divided into 30 IM injections. IM VEGF(165) protein was administered in a total dose of 15 microg/kg divided into 30 injections; IV VEGF(165) was given at a dose of 50 ng. kg(-1). min(-1) for 200 minutes at three 72-hour intervals (30 microg/kg total dose). After 3 and 6 months the PET and DSE studies were repeated, and the animals were sacrificed for tissue vascular density and angiogenic protein analysis. RESULTS: Myocardial blood flow (MBF) by PET was significantly improved 3 months posttreatment in the IM bFGF and IM VEGF(165) groups, differences that were sustained at 6 months. There was no significant increase in MBF 3-months posttreatment in the IV VEGF(165) group; however, at 6 months MBF was significantly improved. No change in MBF was seen in the IM vehicle or sham groups. Regional wall motion at rest and peak stress in the LCx region demonstrated small but statistically significant improvements by 6 months in the IM bFGF and IV VEGF(165) groups only; no improvement was seen in the IM VEGF(165), IM vehicle, or sham groups. Quantitative vascular density was significantly increased in the LCx regions of all treatment groups (IM bFGF, IM VEGF(165), IV VEGF(165)) 6-months postoperatively. No significant increase in LCx region myocardial bFGF or VEGF protein levels was seen in the treated animals at 6 months. CONCLUSIONS: The IM bFGF, IM VEGF(165), and IV VEGF(165) all improve regional perfusion and vascular density 6-months posttherapy in the animal model utilized. Functional improvements were less consistent. Both bFGF and VEGF(165) may be useful therapies for improving regional perfusion in chronically ischemic myocardium, although combination therapy with additional growth factors or cellular therapies may be necessary if concomitant improvements in function are to be seen.

Outcome of unroofing procedure for repair of anomalous aortic origin of left or right coronary artery.

BACKGROUND: Anomalous aortic origin of a coronary artery (AAOCA) from an incorrect sinus of Valsalva is a relatively rare congenital defect and is associated with sudden death. Several surgical techniques have been described to address this defect, but functional outcome has never been addressed. In this report we evaluate a consecutive series of patients treated with unroofing techniques using transthoracic echocardiography, graded exercise testing, and stress echocardiography to assess functional repair. METHODS: Nine consecutive patients (range 7 to 65 years) underwent surgical repair of AAOCA from 1995 to 2001. In all patients the intramural segment was at or below the level of the commissure. All patients underwent a modified unroofing procedure to move the coronary artery orifice to the appropriate sinus. In 2 patients, a new orifice was created without significant unroofing and disruption of the commissure. Patients were evaluated prospectively with exercise electrocardiography testing and by resting and stress echocardiography. RESULTS: Of the 9 patients, 8 presented with symptoms suggestive of ischemia (chest pain, dyspnea on exertion, or syncope). Six patients had anomalous left main coronary artery arising from the right sinus of Valsalva, and 3 patients had anomalous right coronary artery from the left sinus of Valsalva. Transthoracic echocardiography and graded exercise testing was performed in all 9 patients (mean 29 months, range 4 to 85 months) after repair. Of the 9 patients, 8 also underwent stress echocardiography. In 8 of 9 patients the newly created coronary artery ostium was visualized by either two-dimensional echocardiography or color flow Doppler. All patients were symptom free at the time of follow-up. Exercise stress echocardiography was negative in all patients. Of the 8 patients, 7 had normal left ventricular shortening. No patients had regional wall motion abnormalities suggestive of ischemia. All patients were intervention free except 1 patient who developed severe aortic insufficiency and underwent a subsequent Ross procedure 44 months after his initial procedure. CONCLUSIONS: Anomalous origin of a coronary artery from an incorrect sinus of Valsalva is known to be associated with increased risk of sudden death. Surgical correction can be carried out with minimal risk and good anatomic and functional results. Manipulation of the commissure can be avoided by creation of a neo-ostia without extensive unroofing of the intramural segment or manipulation of the intercoronary commissure. This may avoid aortic valve malfunction.

A comparison of mechanical and laser transmyocardial revascularization for induction of angiogenesis and arteriogenesis in chronically ischemic myocardium.

OBJECTIVES: The purpose of the present study was to compare the use of a mechanical transmyocardial implant (TMI) device with transmyocardial laser revascularization (TMR) for induction of therapeutic angiogenesis and arteriogenesis in the chronically ischemic heart. BACKGROUND: Prior experimental studies have demonstrated evidence for neovascularization after both mechanical and laser transmyocardial revascularization, although a long-term comparison of the two techniques has not been performed. METHODS: Using an established model of chronic hibernating myocardium, mini-swine underwent 90% proximal left circumflex (LCx) coronary artery stenosis. One month later, baseline positron emission tomography (PET) and dobutamine stress echocardiography (DSE) were performed to quantitate regional myocardial blood flow (MBF) and function. Animals then underwent TMR with a holmium:yttrium-aluminum-garnet (holmium:YAG) laser (n = 5), TMI (n = 5), or sham redo-thoracotomy (n = 5). In the TMR group, the entire LCx region was treated with transmural laser channels at a density of 1/cm(2). Transmyocardial implants were placed transmurally at a similar density in the LCx region of the TMI group. Six months later, the PET and DSE studies were repeated, and the animals were euthanized. RESULTS: Six months after TMR, there was a significant increase over baseline in resting MBF to the lased LCx region (68.9 +/- 4.6% vs. 89.3 +/- 3.0% reference non-ischemic septal segments; p < 0.001). This increased MBF was accompanied by a significant improvement in LCx regional wall motion during peak dobutamine stress (p = 0.04). Compared with baseline, there was no change in LCx region MBF six months after either TMI (72.9 +/- 4.8% vs. 85.7 +/- 3.4%; p = 0.10) or sham redo-thoracotomy (75.6 +/- 4.6% vs. 80.1 +/- 5.0%; p > 0.2). Likewise, there was no significant change in rest or stress wall motion by DSE six months postoperatively in either group. Overall vascular density was increased only in the TMR-treated regions six months postoperatively. The difference between groups was most notable for a twofold increase in the number of small arterioles seen in the lased (4.4 +/- 0.3 arterioles per high power field; p < 0.001 vs. both TMI and sham) compared with TMI (2.2 +/- 0.2) and sham (1.9 +/- 0.2)-treated regions. CONCLUSIONS: Mechanical transmyocardial revascularization with a TMI device does not appear to promote physiologically significant angiogenesis or arteriogenesis in the chronically ischemic porcine heart and cannot be recommended for clinical trials at this time. Infrared laser-mediated injury mechanisms may be important for inducing therapeutic neovascularization with direct myocardial revascularization techniques.