Anomalous Aortic Origin of Right Coronary Artery: Outcomes of Surgical and Nonsurgical Treatment.

BACKGROUND: Anomalous aortic origin of right coronary artery (AAORCA) is a congenital heart lesion that may be associated with coronary ischemia and sudden death; however, the management of these patients remains controversial. The aim of this study was to analyze all patients with AAORCA managed at our center. METHODS: The medical records of patients with an isolated diagnosis of AAOCA were retrospectively reviewed, irrespective of symptoms, from 2007 to 2020. Follow-up was obtained by medical record review. AAORCA was diagnosed by echocardiogram and computed tomographic or magnetic resonance imaging studies in all patients. Treatment was based on anatomic, morphologic, and symptomatic features for patients older than 10 years with AAORCA. RESULTS: The review identified 86 patients with a median age of 16 years; of these, 26 (30%) were managed surgically and 60 (70%) are monitored nonsurgically. Surgical intervention included a "classic" unroofing in 10 (39%), neo-ostial creation in 7 (27%), modified unroofing with neo-ostial creation in 6 (23%), a "classic" unroofing with reimplantation in 2 (7%), and reimplantation only in 1 (4%). Surgical patients were significantly older (P = .01), described more chest pain symptoms (P = .004), had the presence of slitlike ostia (P = .03), and longer length of coronary artery narrowing (P = .0002). At follow-up (median, 3 years; range, 0-13 years), 100% of surgical patients underwent functional testing and had no evidence of ischemia. Postoperative evaluation included one or more of echocardiography, computed tomographic angiogram, magnetic resonance imaging, and exercise stress test. CONCLUSIONS: Our program uses a systematic approach for patients with AAORCA. With this paradigm, outcomes are excellent in the midterm, as validated with anatomic- and function-based testing.

Dilatable Pulmonary Artery Banding Palliation in Congenital Heart Disease.

BACKGROUND: Surgical pulmonary artery banding (PAB) has been limited in practice because of later requirement for surgical removal or adjustment. The aim of this study is to describe our experience creating a dilatable PAB via transcatheter balloon dilation (TCBD) in congenital heart disease (CHD) patients. METHODS: Retrospective chart review of adjustable PAB-outline anatomical variants palliated and patient outcomes. RESULTS: Sixteen patients underwent dilatable PAB-median age 52 days (range 4-215) and weight 3.12 kg (1.65-5.8). Seven (44%) of the patients were premature, 11 (69%) had ventricular septal defect(s) with pulmonary over-circulation, four (25%) atrioventricular septal defects, and four (25%) single ventricle physiology. Subsequent to the index procedure: five patients have undergone intracardiac complete repair, six patients remain well palliated with no additional intervention, and four single ventricles await their next palliation. One patient died from necrotizing enterocolitis (unrelated to PAB) and one patient required a pericardiocentesis postoperatively. Five patients underwent TCBD of the PAB without complication-Two had one TCBD, two had two TCBD, and another had three TCBD. The median change in saturation was 14% (complete range 6-22) and PAB diameter 1.7 mm (complete range 1.1-5.2). Median time from PAB to most recent outpatient follow-up was 868 days (interquartile range 190-1,079). CONCLUSIONS: Our institution has standardized a PAB technique that allows for transcatheter incremental increases in pulmonary blood flow over time. This methodology has proven safe and effective enough to supplant other institutional techniques of limiting pulmonary blood flow in most patients-allowing for interval growth or even serving as the definitive palliation.

Scavenging right atrial Bretschneider histidine-tryptophan-ketoglutarate cardioplegia: Impact on hyponatremia and seizures in pediatric cardiac surgery patients.

OBJECTIVE: Custodiol-HTK cardioplegia (Custodiol-HTK Koheler Chemie, GmbH, Bensheim, Germany) causes fluctuations in serum sodium levels, hyponatremia, and is associated with postoperative seizures. We investigated the influence of scavenging right atrial effluent during delivery on intraoperative serum sodium levels and postoperative seizure incidence in pediatric cardiac surgery patients. METHODS: A total of 204 patients younger than age 18 years undergoing congenital heart surgery between January 2016 and March 2018 were analyzed retrospectively. Serum sodium levels after administration of Custodiol-HTK cardioplegia were compared between the scavenge and nonscavenge groups and then in the propensity score-matched cohort (n = 96). Postoperative seizures were documented clinically and with electroencephalogram findings. Logistic regression models were used to identify the independent predictors of serum sodium level after aortic crossclamp. RESULTS: Of 204 patients, 156 (76.5%) were in the nonscavenge, and 48 (23.5%) in the scavenge groups. A serum sodium level <130 mEq/L after crossclamp and administration of Custodiol-HTK cardioplegia in the nonscavenge group were 70% versus 21% in the scavenge group (odds ratio, 8.8; 95% confidence interval, 4.1-18.3; P < .0001) in the entire cohort, and 77% versus 21% (odds ratio, 12.8; 95% confidence interval, 4.8-33.1; P < .0001) in the propensity score-matched cohort. Of 16 patients experiencing a postoperative seizure, 14 (87.5%) had a sodium level <130 mEq/L and 2 (12.5%) had a sodium level ≥130 mEq/L (odds ratio, 5.1; 95% confidence interval, 1.3-22.8; P = .021) after crossclamp. Postoperative seizures occurred in the nonscavenge group but not the scavenge group in the entire cohort (P = .02) and in the propensity score-matched patients (P = .041). Multivariable analysis of the entire cohort showed that scavenge intervention was an independent factor associated with significantly decreased risk of sodium level <130 mEq/L (odds ratio, 0.17; 95% confidence interval, 0.08-0.36; P = .000). CONCLUSIONS: Right atrial effluent scavenging was protective against fluctuations in serum sodium levels after crossclamp and Custodiol-HTK cardioplegia administration independently in both entire and matched cohort, and was also associated with decreased incidence of postoperative seizures.

Anomalous aortic origin of a coronary artery: preoperative diagnosis and surgical planning.

BACKGROUND: Anomalous aortic origin of a coronary artery (AAOCA), the anomalous coronary artery arises from an inappropriate coronary sinus and travels between the aorta and pulmonary artery. Proper surgical management depends upon correct diagnosis and accurate characterization of the origin and course of the coronary artery. Transthoracic echocardiography (TTE) has been the mainstay for diagnosis, but magnetic resonance imaging (MRI) and computed tomographic angiography (CTA) have been increasingly utilized. In this study, we report the largest series of surgically repaired AAOCA and accuracy of preoperative diagnostic studies. METHODS: A review of 53 consecutive patients (mean age 13.9 years, range 4-65 years) undergoing repair of an AAOCA from 1995 to 2009 was performed. In all, 40 patients were identified with an anomalous right coronary artery (ARCA) from the left sinus of Valsalva, 13 patients had an anomalous left coronary artery (ALCA) arising from the opposite sinus. Symptoms of angina or syncope were present in 58% and 46% of cases with ARCA and ALCA, respectively. RESULTS of preoperative diagnostic testing were compared to actual surgical findings to determine the accuracy of the tests. RESULTS: Lack of an intramural course was observed intraoperatively in 7 cases (5 ARCA and 2 ALCA). Preoperative TTE accurately predicted whether the AAOCA was intramural or extramural in 49 (92.5%) of 53 cases. Magnetic resonance imaging was predictive in 5 (83.3%) of 6 patients and CTA in 11 (64.7%) of 17. Survival was 100%. Complications occurred in 4 (7.5%) of 53 patients (mean follow-up 29 months). Patency was confirmed in 97.7% with TTE, and 23 (95.8%) of 24 patients had a negative postoperative functional study. CONCLUSIONS: Transthoracic echocardiography was found to be very accurate at defining the presence or absence of an intramural course in AAOCA. Both MRI and CTA can provide additional information but may not be as accurate as TTE.

Chronic administration of membrane sealant prevents severe cardiac injury and ventricular dilatation in dystrophic dogs.

Duchenne muscular dystrophy (DMD) is a fatal disease of striated muscle deterioration caused by lack of the cytoskeletal protein dystrophin. Dystrophin deficiency causes muscle membrane instability, skeletal muscle wasting, cardiomyopathy, and heart failure. Advances in palliative respiratory care have increased the incidence of heart disease in DMD patients, for which there is no cure or effective therapy. Here we have shown that chronic infusion of membrane-sealing poloxamer to severely affected dystrophic dogs reduced myocardial fibrosis, blocked increased serum cardiac troponin I (cTnI) and brain type natriuretic peptide (BNP), and fully prevented left-ventricular remodeling. Mechanistically, we observed a markedly greater primary defect of reduced cell compliance in dystrophic canine myocytes than in the mildly affected mdx mouse myocytes, and this was associated with a lack of utrophin upregulation in the dystrophic canine cardiac myocytes. Interestingly, after chronic poloxamer treatment, the poor compliance of isolated canine myocytes remained evident, but this could be restored to normal upon direct application of poloxamer. Collectively, these findings indicate that dystrophin and utrophin are critical to membrane stability-dependent cardiac myocyte mechanical compliance and that poloxamer confers a highly effective membrane-stabilizing chemical surrogate in dystrophin/utrophin deficiency. We propose that membrane sealant therapy is a potential treatment modality for DMD heart disease and possibly other disorders with membrane defect etiologies.

Ca2+-independent positive molecular inotropy for failing rabbit and human cardiac muscle by alpha-myosin motor gene transfer.

Current inotropic therapies used to increase cardiac contractility of the failing heart center on increasing the amount of calcium available for contraction, but their long-term use is associated with increased mortality due to fatal arrhythmias. Thus, there is a need to develop and explore novel inotropic therapies that can act via calcium-independent mechanisms. The purpose of this study was to determine whether fast alpha-myosin molecular motor gene transfer can confer calcium-independent positive inotropy in slow beta-myosin-dominant rabbit and human failing ventricular myocytes. To this end, we generated a recombinant adenovirus (AdMYH6) to deliver the full-length human alpha-myosin gene to adult rabbit and human cardiac myocytes in vitro. Fast alpha-myosin motor expression was determined by Western blotting and immunocytochemical analysis and confocal imaging. In experiments using electrically stimulated myocytes from ischemic failing hearts, AdMYH6 increased the contractile amplitude of failing human [23.9+/-7.8 nm (n=10) vs. AdMYH6 amplitude 78.4+/-16.5 nm (n=6)] and rabbit myocytes. The intracellular calcium transient amplitude was not altered. Control experiments included the use of a green fluorescent protein or a beta-myosin heavy chain adenovirus. Our data provide evidence for a novel form of calcium-independent positive inotropy in failing cardiac myocytes by fast alpha-myosin motor protein gene transfer.

Double oxygen-sensing vector system for robust hypoxia/ischemia-regulated gene induction in cardiac muscle in vitro and in vivo.

High-fidelity genetically encoded bio-sensors that respond to changes in cellular environmental milieu in disease offer great potential in a range of patho-physiological settings. Here a unique hypoxia-regulated vector-based system with double oxygen-sensing transcriptional elements was developed for rapid and robust hypoxia-regulated gene expression in the heart. Hypoxia-responsive cis elements were used in tandem with a single proline-modified oxygen-dependent degradation (ODD) domain of hypoxia-inducible factor-1alpha to form a double oxygen-sensing vector system (DOSVS). In adult cardiac myocytes in vitro, the DOSVS demonstrated a low background expression not different from baseline control in normoxia, and with 100% efficiency, robust, 1,000-fold induction upon hypoxia. In the heart in vivo, hypoxic and ischemic challenges elicited rapid 700-fold induction in living animals, exceeding that obtained by a high-fidelity constitutive cytomegalovirus (CMV) viral promoter. DOSVS also showed high temporal resolution in the heart in response to cyclical bouts of hypoxia in vivo. We propose that DOSVS will be valuable for a range of applications, including bio-sensing and therapeutic gene expression in the heart and other organ systems that are confronted by chronic or episodic hypoxic/ischemic stresses in vivo.

Treatment of metronidazole-refractory Clostridium difficile enteritis with vancomycin.

BACKGROUND: Clostridium difficile infection of the colon is a common and well-described clinical entity. Clostridium difficile enteritis of the small bowel is believed to be less common and has been described sparsely in the literature. METHODS: Case report and literature review. RESULTS: We describe a patient who had undergone total proctocolectomy with ileal pouch-anal anastomosis who was treated with broad-spectrum antibiotics and contracted C. difficile refractory to metronidazole. The enteritis resolved quickly after initiation of combined oral vancomycin and metronidazole. A literature review found that eight of the fifteen previously reported cases of C. difficile-associated small-bowel enteritis resulted in death. CONCLUSIONS: It is important for physicians who treat acolonic patients to be aware of C. difficile enteritis of the small bowel so that it can be suspected, diagnosed, and treated.

Cardiac-directed parvalbumin transgene expression in mice shows marked heart rate dependence of delayed Ca2+ buffering action.

Relaxation abnormalities are prevalent in heart failure and contribute to clinical outcomes. Disruption of Ca2+ homeostasis in heart failure delays relaxation by prolonging the intracellular Ca2+ transient. We sought to speed cardiac relaxation in vivo by cardiac-directed transgene expression of parvalbumin (Parv), a cytosolic Ca2+ buffer normally expressed in fast-twitch skeletal muscle. A key feature of Parv's function resides in its Ca2+/Mg2+ binding affinities that account for delayed Ca2+ buffering in response to the intracellular Ca2+ transient. Cardiac Parv expression decreased sarcoplasmic reticulum Ca2+ content without otherwise altering intracellular Ca2+ homeostasis. At high physiological mouse heart rates in vivo, Parv modestly accelerated relaxation without affecting cardiac morphology or systolic function. Ex vivo pacing of the isolated heart revealed a marked heart rate dependence of Parv's delayed Ca2+ buffering effects on myocardial performance. As the pacing frequency was lowered (7 to 2.5 Hz), the relaxation rates increased in Parv hearts. However, as pacing rates approached the dynamic range in humans, Parv hearts demonstrated decreased contractility, consistent with Parv buffering systolic Ca2+. Mathematical modeling and in vitro studies provide the underlying mechanism responsible for the frequency-dependent fractional Ca2+ buffering action of Parv. Future studies directed toward refining the dose and frequency-response relationships of Parv in the heart or engineering novel Parv-based Ca2+ buffers with modified Mg2+ and Ca2+ affinities to limit systolic Ca2+ buffering may hold promise for the development of new therapies to remediate relaxation abnormalities in heart failure.

Molecular cardiology in translation: gene, cell and chemical-based experimental therapeutics for the failing heart.

Acquired and inherited diseases of the heart represent a major health care issue in this country and throughout the World. Clinical medicine has made important advancements in the past quarter century to enable several effective treatment regimes for cardiac patients. Nevertheless, it is apparent that even with the best care, current treatment strategies and therapeutics are inadequate for treating heart disease, leaving it arguably the most pressing health issue today. In this context it is important to seek new approaches to redress the functional deficits in failing myocardium. This review focuses on several recent gene, cell and chemical-based experimental therapeutics currently being developed in the laboratory for potential translation to patient care. For example, new advances in bio-sensing inducible gene expression systems offer the potential for designer cardio-protective proteins to be expressed only during hypoxia/ischemia in the heart. Stem cells continue to offer the promise of cardiac repair, and some recent advances are discussed here. In addition, discovery and applications of synthetic polymers are presented as a chemical-based strategy for acute and chronic treatment of diseased and failing cardiac tissue. Collectively, these approaches serve as the front lines in basic biomedical research, with an eye toward translation of these findings to clinically meaningful applications in cardiac disease.

The balance of thrombosis and hemorrhage in surgery.

Postoperative hemorrhage and thrombosis is a significant problem during the perioperative period. Understanding the complex and dynamic interplay of factors, proteins, and enzymes during coagulation is imperative to maintain balance between hemostasis and thrombosis. To improve patient outcome, each patient should be risk stratified for bleeding or thrombosis during the preoperative examination. Additional research focused on improvement in screening tools, monitoring, and therapeutic regimens for surgical patients with a coagulopathy are warranted.

Impact of neoadjuvant therapy on postoperative complications in patients undergoing resection for rectal adenocarcinoma.

Surgical resection continues to be the mainstay of treatment for rectal cancer. Neoadjuvant therapy (chemotherapy and radiation) has also been shown to be efficacious. The impact of preoperative chemotherapy and radiation on postoperative complications is unclear. The purpose of this study is to evaluate the relationship of neoadjuvant therapy on postoperative complications in patients undergoing a resection of rectal cancer. A total of 325 patients who underwent curative resection for rectal cancer from 1984 to 2001 were retrospectively reviewed. Only cases with complete data sets who had undergone surgery at this institution were evaluable (257). The patients were divided into groups based on the operative procedure performed; abdominoperineal resection (APR) versus sphincter-sparing (SS) procedures (LAR/Transanal) and whether or not preoperative chemotherapy or radiation was administered. There was no significant difference between complication rates for APR and SS with 19 per cent and 14 per cent, respectively. The preoperative therapy had no effect on complications after APR. However, the SS group showed 21 per cent of the patients who received radiation had complications compared to 11 per cent in those who did not (P = 0.087). Complications in the SS group included leaks, wound infections, abscess, embolism, cardiac dysrhythmias, and myocardial infarctions. The 30-day mortality was 1.9 per cent for the entire cohort with no clear difference between groups. There was no significant difference in complication rate between APR and SS. In the APR group, neoadjuvant therapy had no impact on the incidence of complications. However, the SS group did show a trend between preoperative chemotherapy and radiation and complication rate. However, this may not outweigh the advantages of preoperative therapy in this setting.

Chloride increases adrenergic receptor-mediated platelet and vascular responses.

BACKGROUND: We postulated that increasing intracellular chloride concentration ([Cl-]i) in human platelets would potentiate alpha2 adrenergic receptor (A2AR)-mediated platelet aggregation, and that vascular reactivity would also be increased by raising [Cl-]i in blood vessels. We further hypothesized that ligands binding to the A2AR would increase [Cl-]i by stimulating carbonic anhydrase-dependent chloride/bicarbonate exchange. Because diuretics are potent inhibitors of carbonic anhydrase, we speculated that these agents inhibit platelet aggregation and vascular contractility through inhibition of chloride influx by decreasing carbonic anhydrase activity, and subsequently, chloride/bicarbonate exchange. The aim of this study was to test these hypotheses. METHODS: Platelet aggregation was measured by determining changes in optical density of platelet-rich plasma. Contractile responses to A2AR agonists were recorded in isolated vascular smooth muscle. The substances [Cl-]i and intracellular pH (pHi) were measured using microfluorometric methods. Carbonic anhydrase activity and chloride/bicarbonate exchange were determined by an in vitro assay based on the Stewart cycle. RESULTS: Increasing [Cl-]i potentiated platelet aggregation and vascular contractility, and epinephrine raised [Cl-]i by stimulating carbonic anhydrase-dependent chloride/bicarbonate exchange. Furthermore, diuretic-dependent inhibition of carbonic anhydrase activity decreased chloride/bicarbonate exchange. CONCLUSIONS: Our data support the concept that diuretics inhibit carbonic anhydrase activity and chloride/bicarbonate exchange in platelets and vascular smooth muscle. The ensuing reduction in [Cl-]i that is induced by diuretics in these tissues could play a role in reducing the effect of catecholamines on precipitating thrombotic stroke or myocardial infarction.