Regression of Tricuspid Valve Regurgitation After Lung Transplant: A Single-Center Experience.

BACKGROUND: Although tricuspid regurgitation (TR) is common in candidates for lung transplant, no data or established guidelines exist regarding the need for surgical repair at the time of transplant. We aimed to evaluate the natural course of TR by assessing the incidence and extent of TR regression among patients who did not undergo tricuspid valve repair (TVR) concomitantly with lung transplant. METHODS: We retrospectively identified adult patients who underwent lung transplant without TVR at our institution from 2001 through 2017. Pretransplant and posttransplant echocardiograms were reviewed to assess severity of TR, tricuspid annular plane systolic excursion, central venous pressure, mean pulmonary arterial pressure, and right ventricular size and function. RESULTS: Among 553 included patients, 324 (58.7%) were men, the mean (SD) age was 61.9 years (12.7), and 417 (75.4%) had a double lung transplant. TR before transplant was reported as trivial in 265 patients (47.9%), mild in 235 (42.5%), moderate in 40 (7.2%), and severe in 13 (2.4%). After transplant, TR improved significantly overall (P < .001). TR improved in 193 patients: 158 patients (81.9%) by 1 grade and 35 patients (18.1%) by 2 or more grades. Additionally, of 53 patients with pretransplant moderate or severe TR, 44 (83%) had improvement to mild, trivial, or no TR. After transplant, 12 patients (2.2%) had no remaining TR. CONCLUSION: The severity of TR improved or showed no change in most patients after lung transplant, which obviates the need for TVR among most lung transplant recipients.

Sex Differences in the Impact of Aortic Valve Calcium Score on Mortality After Transcatheter Aortic Valve Replacement.

BACKGROUND: Transcatheter aortic valve replacement (TAVR) is now an approved alternative to surgical aortic valve replacement for the treatment of severe aortic stenosis. As the clinical adoption of TAVR expands, it remains important to identify predictors of mortality after TAVR. We aimed to evaluate the impact of sex differences in aortic valve calcium score (AVCS) on long-term mortality following TAVR in a large patient sample. METHODS: We included consecutive patients who successfully underwent TAVR for treatment of severe native aortic valve stenosis from June 2010 to May 2021 across all US Mayo Clinic sites with follow-up through July 2021. AVCS values were obtained from preoperative computed tomography of the chest. Additional clinical data were abstracted from medical records. Kaplan-Meier curves and Cox-proportional hazard regression models were employed to evaluate the effect of AVCS on long-term mortality. RESULTS: A total of 2543 patients were evaluated in the final analysis. Forty-one percent were women, median age was 82 years (Q1: 76, Q3: 86), 18.4% received a permanent pacemaker following TAVR, and 88.5% received a balloon expandable valve. We demonstrate an increase in mortality risk with higher AVCS after multivariable adjustment (P<0.001). When stratified by sex, every 500-unit increase in AVCS was associated with a 7% increase in mortality risk among women (adjusted hazard ratio, 1.07 [95% CI, 1.02-1.12]) but not in men. CONCLUSIONS: We demonstrate a notable sex difference in the association between AVCS and long-term mortality in a large TAVR patient sample. This study highlights the potential value of AVCS in preprocedural risk stratification, specifically among women undergoing TAVR. Additional studies are needed to validate this finding.

Characteristics and Outcomes After Transcatheter Aortic Valve Implantation in Immunocompromised Patients.

Immunocompromised (IC) patients are at greater risk of adverse outcomes from cardiac surgery, and less invasive options for treating severe aortic stenosis among IC patients are often sought. However, despite greater preference for transcatheter aortic valve implantation (TAVI) in this population, there are limited data on outcomes in IC patients. Between January 2015 and December 2019, we studied patients with severe aortic stenosis who underwent TAVI. We defined IC status by the presence of active malignancy and receipt of oncologic treatment, post-organ transplantation-associated immunosuppression, human immunodeficiency virus, chronic steroid use (>5 mg/day), or active autoimmune disorder, and compared characteristics and outcomes of IC patients with those of non-IC patients. Of 173 patients who underwent TAVI, 56 (32%) were IC, 30 (54%) had active malignancy and underwent active treatment, 19 (34%) were IC without malignancy, and 7 (13%) were both IC and had active malignancy. IC patients, compared with non-IC patients, had similar baseline demographics, Society of Thoracic Surgeons risk scores (median 4.3% vs 4.4%), and overall complications (29% vs 26%). There were 37 deaths (16 IC and 21 non-IC) over a median follow-up of 17 months (95% confidence interval [CI] 14 to 20 months), and 1-year survival after TAVI was 84.0% for IC patients and 89.0% for non-IC patients (p = 0.51 by log-rank). After adjusting for Society of Thoracic Surgeons risk scores, IC patients had a nonsignificant trend toward greater risk of death compared with non-IC patients (adjusted hazard ratio 1.48, 95% CI 0.77 to 2.84). IC patients had a significantly smaller risk of cardiac-related death (adjusted hazard ratio 0.21, 95% CI 0.05 to 0.98) but a greater risk of noncardiac-related death (adjusted hazard ratio 4.14, 95% CI 1.71 to 10.0) than non-IC patients. In conclusion, IC patients who underwent TAVI have similar complication rates as non-IC patients, with a nonsignificant trend toward greater mortality, specifically related to noncardiac causes.

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.

Clinical Outcomes following Left Atrial Appendage Occlusion: A Single-Center Experience.

INTRODUCTION: Percutaneous left atrial appendage closure is an established alternative to anticoagulation therapy for stroke prophylaxis among patients with nonvalvular atrial fibrillation. There are currently no guidelines on the choice of antithrombotic therapy following placement of the Watchman® device, the optimal time to discontinue anticoagulation or the duration of follow-up imaging after device deployment. Our main objective was to evaluate clinical outcomes among these patients. METHODS: We conducted a retrospective review of patients who received a Watchman® device at Mayo Clinic sites between January 2010 and December 2018. We constructed Cox-proportional hazard models to evaluate the effect of specific variables on clinical outcomes. RESULTS: 231 patients were identified (33% female), median age was 77 years, CHA2DS2-VASc score was 5 and HASBLED score was 4. We found no difference in clinically significant bleeding based on initial antithrombotic choice. However, patients with prior gastrointestinal bleeding were more likely to have a bleeding event in the first 6 weeks following Watchman® implantation (HR 9.40, 95% CI 2.15-41.09). Device sizes of 24-27 mm were significantly associated with a decreased risk of thromboembolic events (HR 0.15, 95% CI 0.04-0.55) compared to 21-mm devices. Peridevice leak (PDL) sizes appeared to either remain the same or increase on follow-up imaging. DISCUSSION/CONCLUSIONS: This observational study showed no statistically significant difference in bleeding risk related to initial antithrombotic choice. Smaller device sizes were associated with thromboembolic events, and longitudinal PDL assessment using transesophageal echocardiography showed these frequently do not decrease in size. Larger studies are needed.

Association of Genetic Variants at TRPC6 With Chemotherapy-Related Heart Failure.

Background: Our previous GWAS identified genetic variants at six novel loci that were associated with a decline in left ventricular ejection fraction (LVEF), p < 1 × 10-5 in 1,191 early breast cancer patients from the N9831 clinical trial of chemotherapy plus trastuzumab. In this study we sought replication of these loci. Methods: We tested the top loci from the GWAS for association with chemotherapy-related heart failure (CRHF) using 26 CRHF cases from N9831 and 984 patients from the Mayo Clinic Biobank which included CRHF cases (N = 12) and control groups of patients treated with anthracycline +/- trastuzumab without HF (N = 282) and patients with HF that were never treated with anthracycline or trastuzumab (N = 690). We further examined associated loci in the context of gene expression and rare coding variants using a TWAS approach in heart left ventricle and Sanger sequencing, respectively. Doxorubicin-induced apoptosis and cardiomyopathy was modeled in human iPSC-derived cardiomyocytes and endothelial cells and a mouse model, respectively, that were pre-treated with GsMTx-4, an inhibitor of TRPC6. Results: TRPC6 5' flanking variant rs57242572-T was significantly more frequent in cases compared to controls, p = 0.031, and rs61918162-T showed a trend for association, p = 0.065. The rs61918162 T-allele was associated with higher TRPC6 expression in the heart left ventricle. We identified a single TRPC6 rare missense variant (rs767086724, N338S, prevalence 0.0025% in GnomAD) in one of 38 patients (2.6%) with CRHF. Pre-treatment of cardiomyocytes and endothelial cells with GsMTx4 significantly reduced doxorubicin-induced apoptosis. Similarly, mice treated with GsMTx4 had significantly improved doxorubicin-induced cardiac dysfunction. Conclusions: Genetic variants that are associated with increased TRPC6 expression in the heart and rare TRPC6 missense variants may be clinically useful as risk factors for CRHF. GsMTx-4 may be a cardioprotective agent in patients with TRPC6 risk variants. Replication of the genetic associations in larger well-characterized samples and functional studies are required.

Subaortic Membrane Papillary Fibroelastoma.

A 61-year-old male presented for an annual exam and received a transthoracic echocardiogram (TTE) which revealed a mobile mass arising from a subaortic membrane. Further investigations with a transesophageal echocardiogram (TEE) and cardiac computerized tomography angiography (CTA) confirmed the presence of a mobile 9 mm × 3 mm mass on a subaortic membrane. Cardiothoracic surgery was performed with an open operation removing the mass and subaortic membrane. Upon visual inspection, the mass was likened to a sea anemone and immunohistochemical staining performed pathologically confirmed the diagnosis of cardiac papillary fibroelastoma. This case represents the first reported example of a cardiac papillary fibroelastoma (PFE) arising from a subaortic membrane. Although PFEs are benign cardiac tumors, proper identification and consideration for excision of these lesions may be indicated to prevent thromboembolic complications.

Extracorporeal membrane oxygenation as a salvage therapy for patients with severe primary graft dysfunction after heart transplant.

BACKGROUND: Severe primary graft dysfunction (PGD) is the leading cause of early death after heart transplant. AIM: To examine the outcomes of heart transplant recipients who received venoarterial extracorporeal membrane oxygenation (VA-ECMO) for severe PGD. METHODS: We reviewed electronic health records of adult patients who underwent heart transplant from November 2005 through June 2015. We defined severe PGD according to International Society for Heart and Lung Transplantation consensus statements. RESULTS: Of 1030 heart transplant patients, 31 (3%) had severe PGD and required VA-ECMO. The mean (range) age was 59 (43-69) years. Fifteen patients (48%) underwent prior sternotomy and 10 (32%) received a left ventricular assist device as a bridge to transplant. Severe PGD manifested as failure to wean from cardiopulmonary bypass in 20 patients (65%) and as severe hemodynamic instability in the immediate postoperative period in 10 (32%), including cardiac arrest in 3 (10%). Twenty-five patients (81%) were successfully weaned from VA-ECMO, and 19 (61%) were discharged; the other 12 (39%) died. CONCLUSIONS: Although VA-ECMO is a common method for providing mechanical circulatory support to patients with PGD, multicenter studies are needed to assess factors associated with successful outcomes and improved survival of these patients.

Reprint of: Promoting Physical Activity and Exercise: JACC Health Promotion Series.

Physical inactivity is one of the leading modifiable risk factors for global mortality, with an estimated 20% to 30% increased risk of death compared with those who are physically active. The "behavior" of physical activity (PA) is multifactorial, including social, environmental, psychological, and genetic factors. Abundant scientific evidence has demonstrated that physically active people of all age groups and ethnicities have higher levels of cardiorespiratory fitness, health, and wellness, and a lower risk for developing several chronic medical illnesses, including cardiovascular disease, compared with those who are physically inactive. Although more intense and longer durations of PA correlate directly with improved outcomes, even small amounts of PA provide protective health benefits. In this state-of-the-art review, the authors focus on "healthy PA" with the emphasis on the pathophysiological effects of physical inactivity and PA on the cardiovascular system, mechanistic/triggering factors, the role of preventive actions through personal, education/environment, and societal/authoritative factors, as well as factors to provide guidance for caregivers of health promotion regarding PA. Sustainable and comprehensive programs to increase PA among all individuals need to be developed and implemented at local, regional, national, and international levels to effect positive changes and improve global health, especially the reduction of cardiovascular disease.

Promoting Physical Activity and Exercise: JACC Health Promotion Series.

Physical inactivity is one of the leading modifiable risk factors for global mortality, with an estimated 20% to 30% increased risk of death compared with those who are physically active. The "behavior" of physical activity (PA) is multifactorial, including social, environmental, psychological, and genetic factors. Abundant scientific evidence has demonstrated that physically active people of all age groups and ethnicities have higher levels of cardiorespiratory fitness, health, and wellness, and a lower risk for developing several chronic medical illnesses, including cardiovascular disease, compared with those who are physically inactive. Although more intense and longer durations of PA correlate directly with improved outcomes, even small amounts of PA provide protective health benefits. In this state-of-the-art review, the authors focus on "healthy PA" with the emphasis on the pathophysiological effects of physical inactivity and PA on the cardiovascular system, mechanistic/triggering factors, the role of preventive actions through personal, education/environment, and societal/authoritative factors, as well as factors to provide guidance for caregivers of health promotion regarding PA. Sustainable and comprehensive programs to increase PA among all individuals need to be developed and implemented at local, regional, national, and international levels to effect positive changes and improve global health, especially the reduction of cardiovascular disease.

Noninvasive assessment of right heart function and hemodynamics during exercise in patients with pulmonary arterial hypertension.

OBJECTIVES: Noninvasive assessment of right heart function and hemodynamics in patients with pulmonary arterial hypertension (PAH) is most often performed at rest, whereas the symptoms, in general, present with exertion. Assessment during exertion is limited to symptom assessment and the 6-minute walk distance. We investigated the feasibility of obtaining echocardiographic data that could accurately reflect pulmonary artery pressures (PAP), particularly mean PAP and right ventricular function during exercise in patients with PAH. METHODS: We investigated right ventricular function and hemodynamics using echocardiography during symptom-limited exercise in 10 consecutive patients undergoing right heart catheterization (RHC) as part of their clinical evaluation for PAH. We further assessed these measurements for correlation with known predictors of outcome in PAH in an exploratory analysis. RESULTS: We were able to successfully obtain complete right heart measurements by echocardiography, including mean PAP, in the majority (9 of 10) of the subjects. One patient had an incomplete tricuspid regurgitation jet at rest and with exercise. Echocardiographic pulmonary vascular resistance correlated with RHC cardiac output and brain natriuretic peptide level, whereas tricuspid annular plane systolic excursion during exercise correlated with right atrial pressure on RHC, brain natriuretic peptide, and 6-minute walk distance. Tricuspid regurgitation velocity and mean PAP with exercise correlated moderately with mean PAP and cardiac output by RHC. CONCLUSIONS: Exercise echocardiography can provide meaningful data in patients with PAH, including measuring mean PAP. The presence of correlations in this small number of patients indicates promising targets for future investigation.

Inferior vena cava diameter (IVCD) measured with transesophageal echocardiography (TEE) can be used to derive the central venous pressure (CVP) in anesthetized mechanically ventilated patients.

BACKGROUND: Estimation of right atrial pressure (RAP) from variations in the diameter of the inferior vena cava (IVC) during the respiratory cycle using transthoracic echocardiography (TTE) is used routinely to calculate pulmonary artery systolic pressure, adding to right ventricular systolic pressure (RVSP) from the jet velocity of tricuspid regurgitation. Using transesophageal echocardiography (TEE) we sought to determine if the inferior vena cava diameter (IVCD) could be used to derive the central venous pressure (CVP) in anesthetized, mechanically ventilated patients. METHODS: The IVCD was measured in its long axis (bicaval view) at the cavo-atrial junction using TEE and ECG synchronization (to coincide with the end of the T-wave) in 95 anesthetized, mechanically ventilated patients undergoing elective cardiac surgery. Each patient received a pulmonary artery catheter (PAC) that allowed for continuous monitoring of the CVP. Three independent readers were assigned to document the IVCD and the CVP. Statistical analysis was performed using bivariate correlation, variance (ANOVA), linear regression, Bland-Altman and Passing-Bablock analysis of agreement. RESULTS: The IVCD measured in millimeters at the cavo-atrial junction showed a positive correlation with the CVP (n = 95, r = 0.860, P < 0.0001, r(2)= 0.737, P < 0.0001). The linear regression equation [CVPc = (IVCD-4.004/0.751] was prospectively tested in a cohort of 12 anesthetized, mechanically ventilated patients under various hemodynamic conditions with a good correlation between the mean CVP (CVPm) and the calculated CVP (CVPc) (r = 0.923, P < 0.0001, r(2)= 0.851, P < 0.0001). CONCLUSION: The TEE measured IVCD at the cavo-atrial junction showed a statistically significant correlation with the mean CVP. Using an equation derived from linear regression analysis, a reliable CVP can be estimated from the IVCD.

A novel approach to the diagnosis of left atrial appendage thrombus using contrast echocardiography and power Doppler imaging.

BACKGROUND: Transesophageal echocardiography is performed routinely among patients with atrial fibrillation (AF) in order to exclude left atrial appendage (LAA) thrombus prior to cardioversion. Because assessment for LAA thrombus is dependent upon the experience of the operator and is therefore subjective, there remains a subset of patients in whom the diagnosis may not be definitive. The purpose of this report is to present a novel technique which may aid in the confirmation and/or exclusion of LAA thrombus using contrast echocardiography (CE) and power Doppler (PD) imaging. METHODS: TEE imaging of the LAA appendage was performed in 3 patients. By visual inspection, the presence of the thrombus was absent (patient one), equivocal (patient two) and definite (patient three). Contrast echocardiography with Definity and power Doppler imaging was performed to aid in the confirmation and/or exclusion of thrombus in these 3 patients. RESULTS: CE alone was useful in confirming the absence and presence of LA thrombus determined by visual inspection in patients one and three, respectively. CE in conjunction with PD imaging was useful in identifying the presence of LAA thrombus (by showing a filling defect and the absence of flow in the tip) in the patient with equivocal results by visual inspection CONCLUSION: Contrast echocardiography alone may be useful in confirming and/or excluding the presence of LAA thrombus among patients with AF. CE with PD imaging provides incremental information in aiding in the diagnosis when the conventional images are equivocal.

Derivation and validation of a diagnostic model for the evaluation of left ventricular filling pressures and diastolic function using mitral annulus tissue Doppler imaging.

BACKGROUND: Several modalities to diagnose diastolic dysfunction by transthoracic echocardiography (TTE) exist. We compared the ratio of early mitral filling velocity (E) to early diastolic velocity by tissue Doppler imaging at the medial (E/E'm) and the lateral (E/E'l) mitral annulus and developed a model to diagnose elevated left ventricular end-diastolic pressure (LVEDP). METHODS: Sixty patients underwent same-day cardiac catheterization and TTE. Left ventricular end-diastolic pressure was recorded in addition to TTE data, including left atrial area (LAA), E/E'm, and E/E'l. An LVEDP >15 mm Hg was considered to be elevated and diagnostic of diastolic dysfunction. RESULTS: E/E'm had a significantly higher correlation (r = 0.68, P < .001) than did E/E'l (r = 0.46, P < .001). By univariate analysis, LAA >18.75 cm(2), E/E'l >11.2, and E/E'm >15.75 were found to be significant predictors of high LV filling pressure. By multivariate binary logistic regression model analysis, only E/E'm and LAA were independent predictors of LVEDP >15 mm Hg. The presence of 1 variable had a sensitivity of 95% and a specificity of 43.4%, whereas the presence of 2 variables had a sensitivity of 76.2% and a specificity of 100%. CONCLUSIONS: Use of a diagnostic model based on easily derived measurements such as E/E'm and LAA was a powerful noninvasive diagnostic modality for elevated LVEDP. Measurement of the mitral annulus velocity by tissue Doppler imaging at the medial aspect of the mitral valve appeared to be superior to that at the lateral aspect.

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.