Mitral valve repair for ischemic mitral regurgitation: review of current techniques.

INTRODUCTION: Ischemic mitral regurgitation can be defined as moderate to severe mitral leak precipitated by acute myocardial infarction. Valve repair is now the procedure of choice, but some cases can pose difficult anatomy. This review will illustrate current techniques for repairing complex ischemic mitral regurgitation. METHODS: Most patients with ischemic mitral regurgitation have predominant annular dilatation at the posterior commissure and require only ring annuloplasty. Full rigid rings are used preferentially. With leaflet tethering, adjunctive autologous pericardial patches are effective in restoring leaflet coaptation. If papillary muscle elongation or rupture occurs, Gore-Tex artificial chordal replacement performs well. With ischemic mitral regurgitation accompanying posterior ventricular aneurysms, standard trans-atrial mitral repair provides the best results, with associated aneurysms being repaired concurrently. RESULTS: Surgical approaches and technical outcomes of mitral repair in ischemic mitral regurgitation are illustrated in 5 patients using operative images and echocardiograms. Each method is illustrated, including ring annuloplasty, pericardial leaflet augmentation, artificial chordal replacement, and ventricular aneurysm repair. Using these techniques, virtually all ischemic mitral regurgitation can be repaired, with consequential patient benefits, even in the most complex anatomy. CONCLUSIONS: Ischemic mitral regurgitation has been shown to have better outcomes when managed with valve repair. Using combinations of annular, leaflet, and chordal procedures, even complex ischemic mitral regurgitation can undergo autologous reconstruction with excellent long-term results.

Institutional response to FDA warning on aprotinin and impact on outcomes.

INTRODUCTION: New evidence of potential risks of aprotinin in 2006 generated public concern about a previously approved drug that was routinely used. In response, we assembled a team of experts within the institution to form guidelines for the appropriate use of aprotinin in cardiac surgery. We report the basis for the guidelines, their implementation, follow-up and resulting patterns of change in aprotinin use. METHODS: We proposed a three-tier system for aprotinin use, according to risk of bleeding and transfusion, and evidence of benefit of aprotinin. Specific recommendations were made with regard to discussion with the patient and documentation regarding aprotinin use and options for patients who refuse the drug. Guidelines were disseminated and accessible on all anesthesia workstations. Aprotinin use was compared before and after institution of guidelines in equivalent categories.  RESULTS: Aprotinin was used in 58.5% (469/802) of cases from March 2005 to January 2006. Following institution of guidelines from March 2006 to January 2007, aprotinin was used in 19.7% (151/767) cases representing a 67.8% reduction in usage. In the subset of groups with large reductions in aprotinin use (pre- 82%, n=239; post-guidelines 17%, n=241) there was a significant decrease in acute kidney injury (%?Cr 43.8 vs. 31.7%, p=0.05). CONCLUSIONS: In response to new data and regulatory guidelines, we formulated guidelines based on expert review of data. We reduced aprotinin use, but more importantly, introduced an evidence-based approach to the use of aprotinin, consistent with regulatory guidelines. This model of guideline implementation can be useful in similar scenarios.

Inflammatory gene polymorphisms and risk of postoperative myocardial infarction after cardiac surgery.

BACKGROUND: The inflammatory response triggered by cardiac surgery with cardiopulmonary bypass (CPB) is a primary mechanism in the pathogenesis of postoperative myocardial infarction (PMI), a multifactorial disorder with significant inter-patient variability poorly predicted by clinical and procedural factors. We tested the hypothesis that candidate gene polymorphisms in inflammatory pathways contribute to risk of PMI after cardiac surgery. METHODS AND RESULTS: We genotyped 48 polymorphisms from 23 candidate genes in a prospective cohort of 434 patients undergoing elective cardiac surgery with CPB. PMI was defined as creatine kinase-MB isoenzyme level > or = 10x upper limit of normal at 24 hours postoperatively. A 2-step analysis strategy was used: marker selection, followed by model building. To minimize false-positive associations, we adjusted for multiple testing by permutation analysis, Bonferroni correction, and controlling the false discovery rate; 52 patients (12%) experienced PMI. After adjusting for multiple comparisons and clinical risk factors, 3 polymorphisms were found to be independent predictors of PMI (adjusted P<0.05; false discovery rate <10%). These gene variants encode the proinflammatory cytokine interleukin 6 (IL6 -572G>C; odds ratio [OR], 2.47), and 2 adhesion molecules: intercellular adhesion molecule-1 (ICAM1 Lys469Glu; OR, 1.88), and E-selectin (SELE 98G>T; OR, 0.16). The inclusion of genotypic information from these polymorphisms improved prediction models for PMI based on traditional risk factors alone (C-statistic 0.764 versus 0.703). CONCLUSIONS: Functional genetic variants in cytokine and leukocyte-endothelial interaction pathways are independently associated with severity of myonecrosis after cardiac surgery. This may aid in preoperative identification of high-risk cardiac surgical patients and development of novel cardioprotective strategies.

Adenoviral gene transfer to the heart during cardiopulmonary bypass: effect of myocardial protection technique on transgene expression.

OBJECTIVE: Adenoviral gene transfer to the arrested heart during cardiopulmonary bypass (CPB) is a novel method of allowing prolonged vector contact with the myocardium. In this model we investigated the importance of temperature, duration of arrest and cardioplegia on transgene expression. METHODS: First-generation adenoviral vector (1 x 10(12) total viral particles) containing the transgene for the human beta2-adrenoceptor (Adeno-beta(2)AR) or beta-galactosidase (Adeno-beta(gal)) was delivered to neonatal piglets via the proximal aorta, during simulated cardiac surgery, and allowed to dwell for the cross-clamp duration. Four treatment groups received Adeno-beta(2)AR. Groups A (n=4) and B (n=6) underwent cold crystalloid cardioplegia arrest for 10 and 30 min, respectively, Group C (n=5) underwent warm crystalloid cardioplegia arrest for 10 min, and Group D (n=5) underwent warm fibrillatory arrest for 10 min. Group E (n=6) received Adeno-beta(gal) and underwent cold crystalloid cardioplegia arrest (30 min). Animals were weaned off CPB and recovered for 2 days. Receptor density was assessed in membrane fractions using radioligand binding and compared using the Mann-Whitney U-test. RESULTS: Left ventricular transgene overexpression, as evidenced by elevated betaAR density, following Adeno-beta(2)AR treatment was greatest with cold cardioplegia (Group A 588+/-288.8 fmol/mg; P=0.002 and Group B 520+/-250.9 fmol/mg; P=0.01) versus control (Group E 109+/-8.4 fmol/mg). Overexpression also occurred with warm cardioplegia (Group C 274+/-69.5 fmol/mg; P=0.05) and ventricular fibrillation (Group D 215+/-48.4 fmol/mg; P=0.02) versus control. Comparison of the combined cold cardioplegia groups versus those treated with warm conditions showed a trend towards increased expression with cold conditions (P=0.1). Receptor density was also significantly increased in the right ventricle of animals in Group B (165+/-18.1 fmol/mg; P=0.03) and Group D (181+/-23.4 fmol/mg; P=0.02) versus control (Group E 118+/-5.8 fmol/mg). CONCLUSIONS: Cold crystalloid cardioplegia is not detrimental to gene transfer in vivo. In fact, there was a trend towards increased left ventricular transgene expression when the adenoviral vector was delivered following cold versus warm cardioplegia. Shorter periods of contact with the vector may reduce transgene overexpression. Therefore, gene transfer is possible during cardiac surgery with clinically used myocardial protection techniques.

Cardiac gene delivery with cardiopulmonary bypass.

BACKGROUND: Cardiac gene therapy offers the possibility of enhancing myocardial performance in the compromised heart. However, current gene delivery techniques have limited myocardial transgene expression and pose the risk of extracardiac expression. Isolation of the coronary circulation during cardiac surgery may allow for more efficient and cardiac-selective gene delivery in a clinically relevant model. Methods and Results-- Neonatal piglets (3 kg) underwent a median sternotomy and cardiopulmonary bypass, followed by aortic cross-clamping with 30 minutes of cardioplegic arrest. Adenoviral vectors containing transgenes for either beta-galactosidase (adeno-beta-gal, n=11) or the human beta(2)-adrenergic receptor (adeno-beta(2)-AR, n=15) were administered through the cardioplegia cannula immediately after arrest and were allowed to dwell in the coronary circulation during the cross-clamp period. After 1 week, the animals were killed, and their heart, lungs, and liver were excised and examined for gene expression. Analysis of beta-galactosidase staining revealed transmural myocardial gene expression among animals receiving adeno-beta-gal. No marker gene expression was detected in liver or lung tissue. beta-AR density in the left ventricle after adeno-beta(2)-AR delivery was 396+/-85% of levels in control animals (P<0.01). Animals receiving adeno-beta(2)-AR and control animals demonstrated similar beta-AR density in both the liver (114+/-8% versus 100+/-9%, P=NS) and lung (114+/-7% versus 100+/-9%, P=NS). There was no evidence of cardiac inflammation. CONCLUSIONS: By using cardiopulmonary bypass and cardioplegic arrest, intracoronary delivery of adenoviral vectors resulted in efficient myocardial uptake and expression. Undetectable transgene expression in liver or lung tissue suggests cardiac-selective expression.

Evaluation of early postoperative results after bicaval versus standard cardiac transplantation and review of the literature.

OBJECTIVE: Previous studies have been inconsistent in defining a clinical benefit to the bicaval cardiac transplantation technique relative to the standard technique, and many major centers have not adopted this newer approach. The purpose of this study was to determine whether clinically significant benefits support utilization of the bicaval technique. METHODS: Sixty-eight consecutive adult patients undergoing a standard cardiac transplant were compared with 75 consecutive patients who underwent the bicaval technique during the period from 1991 to 1999. Etiology, recipient sex, recipient age, donor age, and pulmonary vascular resistance were similar between the two groups. RESULTS: Cardiac index at 24 hours after operation was increased for the bicaval group relative to the standard group (3.15 +/- 0.7 vs 2.7 +/- 0.5 L/min/m(2), P <. 05). Inotropic requirements were significantly less, and there was significantly less tricuspid regurgitation in the bicaval group relative to the standard group. In addition, the bicaval group more frequently had a nonpaced normal sinus rhythm at 24 hours after operation (73.9% vs 50.7% [standard group], P =.025) and had fewer postoperative arrhythmias (29.3% vs 47.7% [standard group], P <.01). Finally, although mortality was similar for the two groups, length of postoperative hospitalization was longer for the standard group relative to the bicaval group (12.1 +/- 11 vs 20.4 +/- 12 days, P <. 001). Review of the literature identified reduced tricuspid regurgitation and improved rhythm as consistent benefits of the bicaval technique. CONCLUSION: This review demonstrates a clinical benefit during the early postoperative period with bicaval cardiac transplantation (relative to standard) and encourages further utilization of this technique.

Adverse effects of constitutively active alpha(1B)-adrenergic receptors after pressure overload in mouse hearts.

Cardiac hypertrophy and function were studied 6 wk after constriction of the thoracic aorta (TAC) in transgenic (TG) mice expressing constitutively active mutant alpha(1B)-adrenergic receptors (ARs) in the heart. Hearts from sham-operated TG animals and nontransgenic littermates (WT) were similar in size, but hearts from TAC/TG mice were larger than those from TAC/WT mice, and atrial natriuretic peptide mRNA expression was also higher. Lung weight was markedly increased in TAC/TG animals, and the incidence of left atrial thrombus formation was significantly higher. Ventricular contractility in anesthetized animals, although it was increased in TAC/WT hearts, was unchanged in TAC/TG hearts, implying cardiac decompensation and progression to failure in TG mice. There was no increase in alpha(1A)-AR mRNA expression in TAC/WT hearts, and expression was significantly reduced in TAC/TG hearts. These findings show that cardiac expression of constitutively actively mutant alpha(1B)-ARs is detrimental in terms of hypertrophy and cardiac function after pressure overload and that increased alpha(1A)-AR mRNA expression is not a feature of the hypertrophic response in this murine model.

Anomalous origin of the right coronary artery from the left coronary sinus: case report and review of surgical treatments.

An anomalous right coronary artery arising from the left sinus of Valsalva is a rare but potentially lethal abnormality. We present a case report and literature review of this anomaly as well as its surgical management in the face of unobstructed distal coronary arteries. Furthermore we report the use of intraoperative transesophageal stress echocardiography to evaluate adequacy of graft flow.

Comparison of omental and pectoralis flaps for poststernotomy mediastinitis.

BACKGROUND: Pectoralis flaps are frequently used to treat poststernotomy mediastinitis. We compared the outcomes of omental transfer, an alternative treatment for mediastinitis, with those of pectoralis flaps. METHODS: Patients treated for poststernotomy mediastinitis with isolated omental flaps (n = 21) were compared with a group of consecutive patients treated with pectoralis flaps (n = 38). Baseline characteristics were equivalent for the two groups, and both early and late outcomes were compared. RESULTS: Length of procedure and length of postoperative hospitalization were reduced significantly and there were significantly fewer early complications in the group treated with omental flaps. Furthermore, there were no early or late flap failures or abscesses in the omental flap group. CONCLUSIONS: This study found that omental flaps had improved early outcomes and are a more effective therapy relative to pectoralis flaps for poststernotomy mediastinitis. Technical considerations for omental transfer that could optimize results are given.

Thoracic organ transplantation at Papworth Hospital.

More than 1,200 patients have now undergone thoracic transplantation at Papworth Hospital and about 90 transplants are performed annually. Papworth remains one of the largest transplant units in the UK. Unique activities include a very large heart-lung transplant program: 247 patients have now undergone heart-lung transplants and 73 domino heart transplants have been performed. The 5-year survival rates are 71% for heart transplants, 48% for heart-lung and 41% for lung transplants, respectively. Chronic obliterative bronchiolitis remains an important limitation for heart-lung and lung transplant survival.

Transgenic mice with cardiac overexpression of alpha1B-adrenergic receptors. In vivo alpha1-adrenergic receptor-mediated regulation of beta-adrenergic signaling.

Transgenic mice were generated with cardiac-specific overexpression of the wild-type (WT) alpha1B-adrenergic receptor (AR) using the murine alpha-myosin heavy chain gene promoter. Previously, we described transgenic mice with alpha-myosin heavy chain-directed expression of a constitutively active mutant alpha1B-AR that had a phenotype of myocardial hypertrophy (Milano, C. A., Dolber, P. C., Rockman, H. A., Bond, R. A., Venable M. E., Allen, L. F., and Lefkowitz, R. J. (1994) Proc. Natl. Acad. Sci. U. S. A. 91, 10109-10113). In animals with >40-fold WT alpha1-AR overexpression, basal myocardial diacylglycerol content was significantly increased, indicating enhanced alpha1-adrenergic signaling and phospholipase C activity. In contrast to the mice overexpressing constitutively active mutant alpha1B-ARs, the hearts of these mice did not develop cardiac hypertrophy despite an 8-fold increase in ventricular mRNA for atrial natriuretic factor. In vivo physiology was studied in anesthetized intact animals and showed left ventricular contractility in response to the beta-agonist isoproterenol to be significantly depressed in animals overexpressing WT alpha1B-ARs. Membranes purified from the hearts of WT alpha1BAR-overexpressing mice demonstrated significantly attenuated adenylyl cyclase activity basally and after stimulation with isoproterenol, norepinephrine, or phenylephrine. Interestingly, these in vitro changes in signaling were reversed after treating the mice with pertussis toxin, suggesting that the extraordinarily high levels of WT alpha1B-ARs can lead to coupling to pertussis toxin-sensitive G proteins. Another potential contributor to the observed decreased myocardial signaling and function could be enhanced beta-AR desensitization as beta-adrenergic receptor kinase (betaARK1) activity was found to be significantly elevated (>3-fold) in myocardial extracts isolated from WT alpha1B-AR-overexpressing mice. This type of altered signal transduction may become critical in disease conditions such as heart failure where betaARK1 levels are elevated and beta-ARs are down-regulated, leading to a higher percentage of cardiac alpha1-ARs. Thus, these mice serve as a unique experimental model to study the in vivo interactions between alpha- and beta-ARs in the heart.

Force-frequency relations in the failing rabbit heart and responses to adrenergic stimulation.

BACKGROUND: Recent experiments have documented the importance of beta-adrenergic regulation of the force-frequency relation (FFR) in the normal and failing heart. As in isolated human cardiac muscle, a descending limb of the FFR occurs at high frequencies in the intact rabbit heart, and therefore a new model of atrial pacing-induced heart failure was developed in the rabbit. Responses of the FFR to beta-adrenergic stimulation were then assessed in the conscious state before and after the induction of heart failure. METHODS AND RESULTS: Rapid atrial pacing for an average of 19.5 days in instrumented rabbits produced severe left ventricular dilation with reduced cardiac output (echocardiography) and depressed myocardial contractility and relaxation rate (left ventricular dP/dt, catheter-tip micromanometer), associated with reductions in beta-adrenergic receptor density and adenylyl cyclase activity. Before heart failure, heart rate was slowed in the conscious animal from 280 +/- 30 (SD) to about 225 beats/min using a sinus node inhibitor (zatebradine), and heart rate was then increased in steps by atrial pacing from 250 to 450 beats/min; the heart rate-versus-left ventricular dP/dtmax (FFR) response showed an ascending response (increasing contractility), with a descending limb at rates greater than 375 beats/min, and dobutamine infusion amplified the ascending limb of the FFR (increased slope) and attenuated the descending limb. In heart failure the basal FFR was severely depressed with a descending limb over 350 beats/min; dobutamine shifted the FFR upward somewhat without change in the slope of the ascending limb, whereas dobutamine prevented the descending limb of the FFR. Similar responses were observed in the relations between heart rate and cardiac output. CONCLUSIONS: A new model of heart failure in the conscious rabbit was developed using rapid atrial pacing and applied to study force-frequency effects. In heart failure, normal beta-adrenergic amplification of the ascending limb of the FFR by dobutamine was absent, but a marked descending limb of the FFR at higher heart rates was prevented by dobutamine. Observed reductions in components of the beta-adrenergic receptor system likely were responsible for impaired beta-adrenergic FFR amplification, but the mechanism(s) for the descending limb and its correction by dobutamine are not yet established. These responses of the FFR may influence importantly the ability of the failing heart to respond to exercise and stress.

Functional analysis of myocardial performance in murine hearts overexpressing the human beta 2-adrenergic receptor.

Transgenic mice overexpressing the human beta 2-adrenergic receptor gene were compared with wild mice type in terms of cardiac function, using a modified work-performing isolated murine heart preparation and on-line computer analysis. A preload-dependent experiment was performed, in which venous return was gradually increased in 5 mmHg increments from 5 mmHg to 25 mmHg. At each preload, aortic flow, left atrial pressure and aortic pressure were measured in all hearts, and from these parameters stroke volume, contractility, and cardiac index (cardiac output divided by body weight in g) were calculated and compared between groups. At increasing preload levels, the heart rates ranged from 322 beats/min (+/-29) to 369 beats/min (+/-39) in control mice and from 469 beats/min (+/-36) to 540 beats/min (+/-39) in transgenic mice. Cardiac index increased from 138 microliters/min/g (+/-13) and 48 microliters/min/g (+/-5) for transgenic and control mice, respectively at 5 mmHg preload to 262 microliters/min/g (+/-51) and 167 microliters/min/g (+/-15), respectively at 20 mmHg preload. The contractility in the transgenic mice were significantly increased at lower preload levels compared to control mice (1420 mmHg/s +/- 204 v 1187 mmHg/s +/- 127). An increase in myocardial adrenergic receptor density (100-200 fold) leads to significantly higher indices of cardiac function in transgenic mice compared to control mice. The increased heart rate leading to a positive inotropic effect in the hearts of transgenic mice is, at least in part, due to the overexpression of adrenergic receptors. These findings suggest a possible alternative method of establishing a positive chronotropic and inotropic state without the use of pharmacological agents.

Ligand-induced overexpression of a constitutively active beta2-adrenergic receptor: pharmacological creation of a phenotype in transgenic mice.

Transgenic overexpression (40- to 100-fold) of the wild-type human beta2-adrenergic receptor in the hearts of mice leads to a marked increase in cardiac contractility, which is apparently due to the low level of spontaneous (i.e., agonist-independent) activity inherent in the receptor. Here we report that transgenic mice expressing a mutated constitutively active form of the receptor (CAM) show no such phenotype, owing to its modest expression (3-fold above endogenous cardiac beta-adrenergic receptor levels). Surprisingly, treatment of the animals with a variety of beta-adrenergic receptor ligands leads to a 50-fold increase in CAM beta2-adrenergic receptor expression, by stabilizing the CAM beta2-adrenergic receptor protein. Receptor up-regulation leads in turn to marked increases in adenylate cyclase activity, atrial tension determined in vitro, and indices of cardiac contractility determined in vivo. These results illustrate a novel mechanism for regulating physiological responses, i.e., ligand-induced stabilization of a constitutively active but inherently unstable protein.

Myocardial beta-adrenergic receptor signaling in vivo: insights from transgenic mice.

Heart failure is a problem of increasing importance in cardiovascular medicine. An important characteristic of heart failure is reduced agonist-stimulated adenylyl cyclase activity (receptor desensitization) due to both diminished receptor number (receptor downregulation) and impaired receptor function (receptor uncoupling). These changes in the section-adrenergic receptor (section-AR) system may in part account for some of the abnormalities of contractile function in this disease. Myocardial contraction is closely regulated by G protein coupled beta-adrenergic receptors through the action of the second messenger cAMP. The beta-adrenergic receptors themselves are regulated by a set of specific kinases, termed the G-protein-coupled receptor kinases. The study of this complex system in vivo has recently been advanced by the development of transgenic and gene targeted ("knockout") mouse models. Combining transgenic technology with sophisticated physiological measurements of cardiac hemodynamics is an extremely powerful strategy to study the regulation of myocardial contractility in the normal and failing heart.

Response to cardiac sympathetic activation in transgenic mice overexpressing beta 2-adrenergic receptor.

Transgenic mice have been created with 200-fold overexpression of beta 2-adrenergic receptors specifically in the heart. Cardiac function was studied in these transgenic mice and their controls at baseline and during isoproterenol perfusion or sympathetic nerve stimulation. The model used was an in situ buffer-perfused, innervated heart, and the left ventricle maximal derivative of pressure over time (dP/dtmax) and heart rate (HR) were measured. Basal HR and dP/dtmax were 30-40% higher in hearts from transgenic mice than controls. Electrical stimulation of sympathetic nerves (2, 4, and 8 Hz) or infusion of isoproterenol markedly increased HR and dP/dtmax in control hearts. Hearts from transgenic mice did not respond to isoproterenol. However, hearts from transgenic mice retained the HR response to nerve stimulation, and a small increase in dP/dtmax was also detected. Atenolol inhibited the response to nerve stimulation in control hearts but not that in hearts from transgenic mice. ICI-118551 inhibited the response in transgenic hearts. Basal HR and dP/dtmax were decreased by ICI-118551 only in transgenic hearts. Thus overexpression of cardiac beta 2-receptors modifies beta-adrenergic activity, but the responses to endogenous and exogenous adrenergic stimulation are affected differently.