Percutaneous Coronary Intervention to Treat Chronic Total Occlusion: Predictors of Technical Success and One-Year Clinical Outcome

We investigated the overall success rate of percutaneous coronary intervention (PCI) as a treatment for coronary chronic total occlusion and sought to determine the predictive factors of technical success and of one-year major adverse cardiac events (MACE). These factors have not been conclusively defined.Using data from our single-center PCI registry, we enrolled 269 consecutive patients (mean age, 56.13 ± 10.72 yr; 66.2% men) who underwent first-time PCI for chronic total occlusion (duration, ≥3 mo) from March 2006 through September 2010. We divided them into 2 groups: procedural success and procedural failure. We compared occurrences of in-hospital sequelae and one-year MACE between the groups, using multivariate models to determine predictors of technical failure and one-year clinical outcome.Successful revascularization was achieved in 221 patients (82.2%). One-year MACE occurred in 13 patients (4.8%), with a predominance of target-vessel revascularization (3.7%). The prevalence of MACE was significantly lower in the procedural-success group (1.8% vs 18.8%; P <0.001). In the multivariate model, technical failure was the only predictor of one-year MACE. The predictors of failed procedures were lesion location, multivessel disease, the occurrence of dissection, a Thrombolysis In Myocardial Infarction flow grade of 0 before PCI, the absence of tapered-stump arterial structure, and an increase in serum creatinine level or lesion length.In our retrospective, observational study, PCI was successful in a high percentage of chronic total occlusion patients and had a low prevalence of complications. This suggests its safety and effectiveness as a therapeutic option.Key words: Angioplasty, balloon, coronary/methods; chronic disease/therapy; coronary occlusion/therapy; disease-free survival; heart diseases/prevention & control; multivariate analysis; myocardial revascularization; patient selection; retrospective studies; treatment outcomeAs a treatment for coronary chronic total occlusion (CTO), percutaneous coronary intervention (PCI) is widely considered to be one of the most complex procedures in interventional cardiology. The low overall success rate of PCI is predominantly attributable to an inability to cross occlusions with an interventional guidewire.^1–1 The overall prevalence of CTO on diagnostic angiograms is 15% to 30%. The results of recent studies show that one third to one half of patients with angiographically significant coronary artery disease have at least one CTO.^6–8 On the basis of the available data, PCI is performed in only 10% to 15% of CTO angioplasty procedures²—most patients with CTO are referred for coronary artery bypass grafting (CABG) or are prescribed medical therapy.New techniques and dedicated devices and improved operator experience have markedly increased the procedural success rate for occlusion recanalization. Investigators conducting large studies in different settings have reported short- and long-term survival advantages associated with successful PCI of chronic occlusions in comparison with failed procedures and have tried to identify clinical and procedural predictors of the success and outcome of PCI.^1,9–12 However, debate continues in regard to whether the benefits of occlusion recanalization outweigh the risks and challenges. The specific factors that might enable the best choice of treatment for patients with CTO (PCI vs CABG or medical therapy) have not been conclusively identified.^3,8,11In the present retrospective study, we investigated the overall success rate of PCI in CTO patients. We sought to determine the in-hospital and one-year outcomes of patients undergoing the procedure, and identify factors that adversely influence the success rate of PCI and the occurrence of one-year major adverse cardiac events (MACE).     

Surgical Removal of an Atrial Septal Occluder Device Embolized to the Main Pulmonary Artery

Percutaneous closure of atrial septal defects in adults has emerged as an alternative to surgery. We report a sequela of such closure in a 16-year-old boy: embolization of the atrial septal defect occluder into the main pulmonary artery when the patient experienced an episode of intense coughing immediately after device deployment. We removed the device surgically and closed the atrial septal defect in a standard manner, with an autologous pericardial patch.Key words: Adolescent, device removal, foreign-body migration, heart septal defects, atrial/therapy, male, prosthesis implantation/adverse effects, pulmonary artery/surgery, septal occluder device/adverse effectsPercutaneous occlusion of atrial septal defect (ASD) in adults has emerged as an alternative to surgery.¹ Percutaneous closure is associated with less surgical morbidity, avoidance of a scar, and shorter hospital stay.¹ However, its increased use has brought recognition of several fairly frequent sequelae. One sequela associated with the procedure is embolization of the device into the pulmonary artery (PA).² We describe the case of a teenager in whom this occurred.     

Median Arcuate Ligament Syndrome Confirmed with the Use of Intravascular Ultrasound

Median arcuate ligament syndrome, a rarely reported condition, is characterized by postprandial abdominal pain, nausea, vomiting, and weight loss. Its cause is unclear. We present the case of a 45-year-old woman who had intermittent chronic positional abdominal pain without weight loss. Magnetic resonance angiograms and computed tomograms revealed stenosis of the celiac artery. Ostial compression was confirmed on catheter angiographic and intravascular ultrasonographic images. Intravascular ultrasound revealed far greater stenosis than did the initial imaging methods and confirmed a diagnosis of median arcuate ligament syndrome. In lieu of surgery, the patient underwent a celiac ganglion block procedure that substantially relieved her symptoms.To our knowledge, this is the first report of the use of intravascular ultrasound in the diagnosis of median arcuate ligament syndrome. We recommend using this imaging method preoperatively in other suspected cases of the syndrome, to better identify patients who might benefit from corrective surgery.Key words: Abdominal pain/etiology, arterial occlusive diseases/diagnosis/pathology/physiopathology, celiac artery/pathology/physiopathology/ultrasonography, constriction, pathologic, diagnostic imaging, ligaments/pathology, mesenteric vascular occlusion/complications/etiology, ultrasonography, intravascularMedian arcuate ligament syndrome (MALS), also called celiac artery compression syndrome, is a rarely reported condition characterized by postprandial abdominal pain, nausea, vomiting, and weight loss. The cause of these symptoms has not been determined, and different anatomic explanations have been formulated.¹ Because the cause of MALS is unclear and symptoms can persist even after surgical intervention, its diagnosis can be controversial.² Advances in imaging techniques and minimally invasive studies have created a niche for MALS in the differential diagnosis of chronic abdominal pain of unclear origin.³We present the case of a woman who had celiac artery compression and stenosis with an atypical clinical presentation and evidence of compression upon expiration.³ The stenosis was initially detected by means of computed tomography (CT) and magnetic resonance angiography (MRA) and was confirmed by means of catheter angiography and intravascular ultrasound (IVUS). Besides the case of the patient, we discuss the usefulness of IVUS in the diagnosis of MALS.     

Systemic Effects of Intracoronary Nitroglycerin during Coronary Angiography in Children after Heart Transplantation

Coronary spasm during coronary angiography for vasculopathy in children can be prevented by the intracoronary administration of nitroglycerin. We reviewed the anesthesia and catheterization reports and charts for pediatric transplant recipients who underwent angiography from 2005 through 2010. Correlation analysis was used to study the relation of post-injection systolic blood pressure (SBP) to nitroglycerin dose. Forty-one angiographic evaluations were performed on 25 patients (13 male and 12 female). Mean age was 9.9 ± 3.2 years (range, 3.3–16.1 yr). The mean total dose of nitroglycerin was 2.93 ± 1.60 µg/kg (range, 1–8 µg/kg).There was a significant drop between the baseline SBP (mean, 106 ± 21.6 mmHg) and the lowest mean SBP before nitroglycerin administration (78 ± 13.2, P <0.0001, paired t test). There was no significant additional change in SBP (mean after nitroglycerin administration, 80.7 ± 13.1 mmHg; P = 0.2). There was a significant drop in lowest heart rate between baseline (109 ± 16.5 beats/min) and before nitroglycerin administration (89 ± 14.3 beats/min; P <0.0001, paired t test). There was no significant additional change in heart rate (mean heart rate after nitroglycerin, 84 ± 17.7 beats/min; P = 0.09). There were 2 interventions for SBP before nitroglycerin and 2 after nitroglycerin. One child experienced a transient ST-T–segment change during angiography after nitroglycerin. In the highest dose range, the additional decrease in SBP was 7.2 mmHg (P=0.03). Routine intracoronary nitroglycerin administration in this dose range produced no significant changes in SBP or heart rate in children.Key words: Child, coronary angiography, coronary vasospasm/etiology, dose-response relationship, drug, heart transplantation/adverse effects, hemodynamics/drug effects, nitroglycerin/administration & dosage/therapeutic use, postoperative complications/therapy, retrospective studies, vasodilation/drug effectsAllograft coronary disease in children occurs with increasing frequency after transplantation, as a function of time. In a multicenter study,¹ the incidence of coronary artery disease in children 5 years post-transplant was 17% of all recipients. Coronary angiography remains the gold standard in the detection of vasculopathy in heart-transplant recipients.² Coronary artery spasm can complicate selective coronary angiography and result in myocardial ischemia. Coronary spasm can simulate the angiographic appearance of graft vasculopathy and cause diagnostic confusion.³ The spasm can arise from manipulation of the arterial wall by the catheter or from intraluminal injection of contrast material. In cardiac transplant recipients, coronary artery spasm has been reported in as many as 4.9% of coronary angiograms.³In adults, intracoronary nitroglycerin is routinely administered during coronary angiography to prevent coronary artery spasm.⁴ In children, however, safety and dosage guidelines for intracoronary nitroglycerin have not yet been firmly established. A dose of 3 µg/kg can be extrapolated by weight from the established adult dose of 200 µg; this dose was used in a study of children after the arterial switch operation and was shown to produce coronary vasodilation—with a small reduction in systolic blood pressure (SBP) and no noteworthy change in heart rate—in a control group of patients.^5,6We previously reported a case of coronary artery spasm during routine coronary angiographic monitoring in a 9-year-old boy who had undergone heart transplantation as an infant.⁷ After left main coronary artery injection of contrast material, the patient''s left anterior descending and left circumflex coronary arteries appeared to be diffusely narrow, and he developed marked ST-segment elevation, hypotension, and ventricular tachycardia. After cardiopulmonary resuscitation, he recovered uneventfully and displayed normal systolic function. Coronary angiography one month later, with the administration of intracoronary nitroglycerin before the injection of contrast material, revealed normal coronary artery diameter and was accomplished without complication.Since 2005, intracoronary nitroglycerin has routinely been used in pediatric transplant patients during biennial selective coronary angiographic monitoring at our institution. The purpose of the study is to report our experience with the routine use of intracoronary nitroglycerin for coronary angiography in children: its effects on blood pressure, on heart rate, and on the occurrence of arrhythmia and ST-segment elevation.     

Evaluation of Coronary Artery–Saphenous Vein Composite Grafts: The Aortic No-Touch Technique

We retrospectively compared the results of conventional coronary artery bypass grafting (CABG) performed on patients who showed no preoperative evidence of serious atherosclerosis of the ascending aorta with the results of the aortic no-touch technique (using coronary artery–saphenous vein composite grafts) on CABG patients who did show such evidence.From 2003 through 2012, 3,152 consecutive patients underwent isolated primary CABG at our hospital. We chose 360 for the current study. The study group (n=120) comprised patients who had undergone operation via the aortic no-touch technique. Propensity-score-matching (1:2) was used to select the control group of 240 patients who had undergone conventional CABG. Early and late survival rates, reintervention-free survival rates, and freedom from cardiac death were compared.Early and late mortality rates were similar in the study and control groups (P=0.19 vs P=0.29, respectively), as were cardiac-related death (2.5% vs 2.1%, respectively; P=0.53) and overall death (8.3% vs 7.9%, respectively; P=0.51). Overall survival rates were 91.7% vs 92.1% and freedom-from-cardiac-death rates were 97.4% vs 97.5% (P=0.71 vs P=0.78, respectively; mean follow-up period, 5.27 ± 2.51 yr). Reintervention-free survival rates were also similar (96.7% vs 98.8%, respectively; P=0.2).As a result of the similar rates of early and late survival, reintervention-free survival, and freedom from cardiac death, we conclude that the aortic no-touch technique with composite grafts might be a reasonable option in patients who have atherosclerotic ascending aorta that cannot be clamped.Key words: Aortic diseases/complications, aortic no-touch technique, calcinosis/complications, coronary artery bypass, graft occlusion, vascular, myocardial revascularization/methods, porcelain aorta, retrospective studies, saphenous vein/transplantation, saphenous vein composite grafts, treatment outcomePorcelain aorta or disseminated atherosclerotic involvement of the entire ascending aorta presents major surgical limitations during coronary artery bypass grafting (CABG). Chief among these is the need to avoid aortic cross-clamping, in order to circumvent neurologic and other sequelae.¹ One alternative to cross-clamping is to bypass the aorta with a composite of one or more saphenous vein (SV) and radial artery grafts anastomosed to the left internal mammary artery (LIMA), which previously has been anastomosed to the left anterior descending coronary artery. These grafts are also known as Y or T composite grafts.Although the safety and efficacy of arterial composite grafts for total arterial revascularization have been proved,^2,3 the safety and efficacy of venous composite grafts are still widely debated. Hwang and colleagues⁴ have reported that the SV composite graft can be used as an alternative to the arterial composite graft. However, Gaudino and associates⁵ have maintained that the patency of SV composite grafts is suboptimal.The objectives of our study were to compare SV-composite-graft results with conventional coronary-artery-graft results in particular regard to reintervention-free survival, freedom from cardiac death, and early and late mortality rates.     

Severe Spinal Cord Ischemic Injury Secondary to Device Embolization after Transcatheter Closure of a Patent Arterial Duct

Percutaneous closure of patent arterial ducts with the Amplatzer Ductal Occluder has become an effective and widely accepted alternative to surgical management. Although rarely, the occluder can be dislodged after an initially successful deployment, and with catastrophic consequences. We describe such a case in a 12-month-old girl who underwent transcatheter closure of a patent arterial duct. After device deployment, the occluder embolized in the patient''s descending thoracic aorta, and severe spinal cord ischemic injury resulted. To our knowledge, ours is the first report of this complication after the deployment of an Amplatzer Ductal Occluder. We discuss pathophysiologic mechanisms that could expose patients to the risk of device dislodgment, and we review the relevant medical literature.Key words: Aorta, thoracic/surgery; device removal/methods; ductus arteriosus, patent/therapy; embolization, therapeutic/instrumentation; foreign-body migration/surgery; spinal cord injuries/etiology/ prevention & controlTranscatheter device closure of patent arterial ducts has become a well-established alternative to surgical management: the procedure is associated with a high success rate and an excellent long-term outcome.¹ Rarely, severe complications can occur, such as device embolization, hemolysis, device-related infective endocarditis, iatrogenic aortic coarctation, and left pulmonary artery stenosis.^1,2 We present the case of an infant in whom an Amplatzer® Ductal Occluder (ADO) (St. Jude Medical, Inc.; St. Paul, Minn) was used to close a patent arterial duct. The device embolized into the patient''s descending thoracic aorta, causing ischemic injury to the spinal cord. We discuss possible reasons and review the relevant medical literature.     

Pitfalls in Diagnosis: Suspected Anomalous Origin of the Right Coronary Artery from the Pulmonary Artery

Anomalous coronary arteries are rare in the general population. We report the case of a term neonate who underwent an echocardiogram to evaluate a possible patent ductus arteriosus. Unexpectedly, an apparent anomalous origin of the right coronary artery from the main pulmonary artery was detected by surface 2-dimensional transthoracic echocardiography and color-flow Doppler imaging. Because ventricular size and function were normal, the patient ultimately underwent cardiac catheterization to verify the anatomy before proposed surgery. Angiograms showed that the right coronary artery arose from the left anterolateral portion of the mid-ascending aorta. The patient did not require surgery. This case report illustrates pitfalls that can occur in the diagnosis of coronary artery anomalies.Key words: Aorta/abnormalities, coronary angiography, coronary vessel anomalies/diagnosis/radiography, echocardiography, transthoracic, heart defects, congenital, infant, maleCoronary arteries that arise from the pulmonary artery (PA) comprise less than 25% of congenital coronary artery anomalies. Anomalous origin of the left coronary artery from the PA is 10 times more common than origin of the right coronary artery (RCA) from the PA.¹ Anomalous origin of the RCA from the PA has been associated with ischemia, syncope, various cardiomyopathies, and sudden death.^2,3 When the condition is discovered, the only treatment is surgical.Correct identification of coronary artery origins remains a challenge. Transthoracic echocardiography (TTE) is the primary screening tool for coronary evaluation in children. We report the case of a term newborn who presented with a murmur and subsequently underwent 3 independent echocardiographic examinations, which raised suspicion of an anomalous RCA, quite possibly arising from the main PA. Ultimately, it was determined that the RCA arose anomalously from a point high on the left side of the anterior ascending aorta, thus eliminating the need for surgical intervention.     

Repair of Bland-White-Garland Syndrome via a Modified Technique

Surgically repairing Bland-White-Garland syndrome (anomalous origin of the left coronary artery from the pulmonary artery) is a challenge if there are variations in the origin of the anomalous artery. We report the successful repair of this congenital abnormality in a 19-year-old woman who presented with an acute anterior myocardial infarction. The anomalous artery originated from the anterior-facing sinus of the pulmonary artery, which precluded typical repair by direct reimplantation or fashioning an intrapulmonary tunnel. We created an extrapulmonary tunnel, using a strip of pulmonary artery anteriorly and an aortic flap posteriorly. Three years postoperatively, the anastomosis was patent and the patient was asymptomatic. Our modified technique might serve as an alternative method during similar surgical circumstances.Key words: Anastomosis, surgical/methods; cardiac surgical procedures/methods; coronary vessel anomalies/surgery; pulmonary artery/abnormalities/surgeryBland-White-Garland syndrome, or anomalous origin of the left coronary artery from the pulmonary artery (ALCAPA), constitutes only 0.5% of congenital cardiac conditions.¹ Without appropriate surgical correction, the condition has a mortality rate as high as 90% in the first year of life.² Symptomatic neonates with ALCAPA typically present either with acute myocardial ischemia that leads to systolic dysfunction and shock, or with congestive heart failure caused by poor left ventricular (LV) function and mitral regurgitation. The usefulness of previously described corrective techniques depends on the specific origin of the anomalous artery.² We present the case of a 19-year-old woman who was diagnosed with a left coronary artery (LCA) that originated from the anterior-facing sinus of the pulmonary artery (PA). We describe how we modified a previously reported surgical technique and thereby overcame the long distance between the patient''s aorta and the anomalous artery.     

A Rare Cause of Pulmonary Hypertension: Congenital Bilateral Atresia of the Superior Pulmonary Arteries and Bilateral Stenosis of the Inferior Pulmonary Arteries

Bilateral absence (atresia) of the superior pulmonary arteries, combined with bilateral stenosis of the inferior pulmonary arteries, has not to our knowledge been reported before now. We report such a case in a 48-year-old woman, together with the medical and percutaneous catheter interventions used to treat her condition.Key words: Adult, echocardiography, heart defects, congenital/diagnosis/therapy, hypertension, pulmonary, pulmonary angiography, pulmonary artery/abnormalitiesThe absence of a main branch of the pulmonary artery (PA) was first described by Fraentzel in 1868.¹ The patient who survives to adulthood with this condition usually presents with an abnormal chest radiograph, but with no concomitant cardiovascular abnormalities, with few symptoms, and with any of a variety of erroneous diagnoses.² When pulmonary hypertension is present in the absence of a PA branch, the patient''s condition can be improved by revascularization of the side with the absent artery. In stenotic PAs, intravascular stents have been used to good effect. We report a case of combined bilateral atresia and stenosis, a condition that to our knowledge has not previously been reported. Further, we describe the medical and percutaneous catheter interventions used to treat the patient, and their effectiveness.     

Inappropriate Implantable Cardioverter-Defibrillator Shocks Attributed to Alternating-Current Leak in a Swimming Pool

Implantable cardioverter-defibrillators (ICDs) are the standard of care for preventing sudden cardiac death in patients who are predisposed to malignant ventricular arrhythmias. Causes of inappropriate ICD shock include equipment malfunction, improper arrhythmia evaluation, misinterpretation of myopotentials, and electromagnetic interference. As the number of implanted ICDs has increased, other contributors to inappropriate therapy have become known, such as minimal electrical current leaks that mimic ventricular fibrillation. We present the case of a 63-year-old man with a biventricular ICD who received 2 inappropriate shocks, probably attributable to alternating-current leaks in a swimming pool. In addition, we discuss ICD sensitivity and offer recommendations to avoid similar occurrences.Key words: Arrhythmias, cardiac/etiology; cardiac pacing, artificial; defibrillators, implantable/adverse effects; electricity/adverse effects; electromagnetic phenomena; electrophysiology; environmental exposure; equipment safety; signal-to-noise ratio; swimming poolsImplantable cardioverter-defibrillators (ICDs) provide primary and secondary prevention of sudden cardiac death in patients who are predisposed to malignant ventricular arrhythmias.^1–3 Despite the clinical efficacy and improved technical specifications of newer ICDs, inappropriate shocks can still affect patients who have implanted devices. We review the case of a patient whose inappropriate ICD shocks were most likely caused by the leakage of small amounts of alternating current in a swimming pool.     

Rituximab-Vincristine Chemotherapy-Induced Acute Anterior Wall Myocardial Infarction with Cardiogenic Shock

We present a case of an elderly man with coronary artery disease who was diagnosed with non-Hodgkin lymphoma. Soon after the administration of chemotherapy, which included rituximab and vincristine, he developed acute myocardial infarction with cardiogenic shock. The condition was managed successfully with primary percutaneous coronary intervention. We briefly discuss the possible pathogenic mechanisms of chemotherapy-induced ischemic syndrome and the management of chemotherapy in patients with high cardiovascular risk.Key words: Acute coronary syndrome/chemically induced, acute myocardial infarction/chemically induced, antineoplastic agents/toxicity, cardiotoxins, endothelium, vascular/drug effects, lymphoma, non-Hodgkin, percutaneous coronary intervention, rituximab/adverse effects, tubulin/metabolism, vincristine/adverse effectsChemotherapy-induced cardiovascular complications include myocardial dysfunction, conduction abnormalities (arrhythmias), hypertension, venous thrombosis, and ischemic syndromes.¹ Chemotherapy-induced left ventricular (LV) dysfunction is often encountered in clinical practice, but chemotherapy-mediated ischemic syndromes are rarely seen. The incidence of acute myocardial infarction (AMI) after chemotherapy varies from 1% to 5%.¹ We describe the case of an elderly man with non-Hodgkin lymphoma (NHL) who developed AMI after the administration of chemotherapeutic agents.     

A Patient with Giant Left Atrium Undergoes Orthotopic Heart Transplantation

We present a novel technique for resolving the problem of radical size mismatch at the time of orthotopic transplantation. A 48-year-old man presented with chronic rheumatic heart disease and a giant left atrium. Twenty-three years before, he had undergone mitral valve replacement with a mechanical prosthesis. At the time of the repeated intervention, the volume of his left atrium was 350 mL.Surgical features of the transplantation included approximation of the pulmonary vein ostia by gathering sutures intentionally, in order to decrease the area of the left atrial posterior wall and thereby enable appropriate coaptation with the donor left atrium. After the operation, left atrial volume had been reduced to 60 mL.Key words: Cardiomyopathy, dilatation, pathologic/complications/surgery, heart atria/pathology, heart disease, rheumatic, heart transplantation/methods, mitral valve, organ size, pulmonary veins/surgeryOrthotopic heart transplantation (OHT) remains the operation of choice in patients with end-stage chronic heart failure. Nowadays, up to 3,800 such operations are performed annually. Only 2.7% of patients undergo transplantation as a consequence of valvular cardiomyopathy.¹ In patients with rheumatic heart disease, the presence of giant left atrium (GLA) makes the technical aspects of transplantation more difficult because of substantial size mismatch between donor and recipient at the point of anastomosis. We present a rare case of OHT in a recipient with GLA.     

Multiple Left Internal Mammary Artery-to-Pulmonary Artery Fistulae 15 Years after Coronary Artery Bypass Grafting

Left internal mammary artery (LIMA)-to-pulmonary artery fistulae rarely develop after coronary artery bypass grafting. Fewer than 30 cases of these fistulae have been reported since 1947. Nevertheless, this entity should be considered as a cause of recurrent angina after bypass surgery, in the absence of other causes. We present the case of a 67-year-old man with cardiac symptoms in whom multiple LIMA-to-pulmonary artery fistulae were found, 15 years after he had undergone coronary artery bypass grafting. The diagnosis was confirmed by means of coronary angiography with selective catheterization of the LIMA and by computed tomographic angiography of the heart. The patient underwent reoperative 2-vessel coronary artery bypass grafting and ligation of multiple fistulae; 16 months postoperatively, he was asymptomatic and doing well. In addition to reporting this case, we discuss relevant diagnostic and treatment considerations.Key words: Arteriovenous malformations/physiopathology, coronary artery bypass/adverse effects, fistula/etiology, internal mammary-coronary artery anastomosis/adverse effects, mammary arteries/surgery, myocardial ischemia/etiology, pulmonary artery/surgery, vascular fistula/complications/etiology/surgeryAs a bypass-graft conduit to the left anterior descending coronary artery (LAD), the left internal mammary artery (LIMA) is the vessel of choice because of its proven longevity and long-term patency. The formation of a LIMA-to-pulmonary artery (PA) fistula after coronary artery bypass grafting (CABG) is a rare complication: fewer than 30 reports have appeared in the medical literature.¹ We report a case of multiple LIMA-to-PA fistulae that we found 15 years after a patient had undergone CABG.     

Case Report: Acute Cerebellar Thrombosis in an Adult Patient with IgM Nephropathy

IgM nephropathy is a relatively rare cause of idiopathic nephrotic syndrome.1 It was initially described by van de Putte,2 then by Cohen and Bhasin in 1978, as a distinctive feature of mesangial proliferative glomerulonephritis.2 It is typically characterized by diffuse IgM deposits on the glomeruli and diffuse mesangial hypercellularity. Little is known about the pathogenesis and treatment of this disease.1,3 We describe a patient who presented with nonspecific symptoms of epigastric pain, nausea, and early satiety. Abdominal imaging and endoscopies were unremarkable. She was found to have significant proteinuria (6.4 g/24 hours), hyperlipidemia, and edema consistent with a diagnosis of nephrotic syndrome. Kidney biopsy was performed and confirmed an IgM nephropathy. Less than 2 weeks after her diagnosis of IgM nephropathy, she presented with an acute cerebellar stroke. Thrombophilia is a well-known complication of nephrotic syndrome, but a review of the literature failed to show an association between IgM nephropathy and acute central nervous system thrombosis.     

Posterobasal Left Ventricular Aneurysms: Surgical Treatment and Long-Term Outcomes

This retrospective study analyzes short- and long-term outcomes in 18 patients who underwent repair of posterobasal left ventricular aneurysm from January 1993 through December 2009. As concomitant procedures, mitral reconstruction was performed in 4 patients, ventricular septal defect repair in 2 patients, and coronary artery bypass grafting in 17 patients. In regard to surgical technique, 10 patients underwent patch repair and 8 underwent closure by linear suture.The in-hospital mortality rate was 11% (2 patients). An intra-aortic balloon pump was placed postoperatively in 1 patient. One patient underwent reoperation for mediastinitis and 2 for bleeding. The 1-, 5-, and 10-year survival rates were 82%, 76%, and 52%, respectively.Posterobasal left ventricular aneurysm repair can be performed with low short-term mortality rates and good long-term outcomes. It must be judged whether a linear repair or patch repair is better, in accordance with aneurysm size and the concomitant operative procedure, if any.Key words: Aneurysm, left ventricular; aneurysmectomy; cardiac surgical procedures/mortality; heart aneurysm/mortality/surgery; heart ventricle/surgery; myocardial infarction; retrospective studiesPosterior left ventricular (LV) aneurysms are less common than anterior aneurysms.^1–3 Their prevalence in large series has usually been reported as less than 10%.^2–4 The posterobasal part of the heart is supplied by the left circumflex coronary artery and by terminal branches of the right coronary artery.⁵ Pathologic states of these branches cause inferoposterior or posterolateral LV aneurysm.³ Posterior aneurysms can be accompanied by various degrees of mitral insufficiency⁶ and by ventricular septal defects (VSD).⁷ A 2004 study reported mitral insufficiency of grade 2/4 or higher in all 13 patients who underwent repair of aneurysm due to posterior myocardial infarction (MI).⁶ Our study investigates operative results among patients who underwent surgery for posterior LV aneurysm. Our surgical approach is discussed in terms of short- and long-term outcomes.     

Colon cancer-associated mutator DNA polymerase δ variant causes expansion of dNTP pools increasing its own infidelity

Defects in DNA polymerases δ (Polδ) and ε (Polε) cause hereditary colorectal cancer and have been implicated in the etiology of some sporadic colorectal and endometrial tumors. We previously reported that the yeast pol3-R696W allele mimicking a human cancer-associated variant, POLD1-R689W, causes a catastrophic increase in spontaneous mutagenesis. Here, we describe the mechanism of this extraordinary mutator effect. We found that the mutation rate increased synergistically when the R696W mutation was combined with defects in Polδ proofreading or mismatch repair, indicating that pathways correcting DNA replication errors are not compromised in pol3-R696W mutants. DNA synthesis by purified Polδ-R696W was error-prone, but not to the extent that could account for the unprecedented mutator phenotype of pol3-R696W strains. In a search for cellular factors that augment the mutagenic potential of Polδ-R696W, we discovered that pol3-R696W causes S-phase checkpoint-dependent elevation of dNTP pools. Abrogating this elevation by strategic mutations in dNTP metabolism genes eliminated the mutator effect of pol3-R696W, whereas restoration of high intracellular dNTP levels restored the mutator phenotype. Further, the use of dNTP concentrations present in pol3-R696W cells for in vitro DNA synthesis greatly decreased the fidelity of Polδ-R696W and produced a mutation spectrum strikingly similar to the spectrum observed in vivo. The results support a model in which (i) faulty synthesis by Polδ-R696W leads to a checkpoint-dependent increase in dNTP levels and (ii) this increase mediates the hypermutator effect of Polδ-R696W by facilitating the extension of mismatched primer termini it creates and by promoting further errors that continue to fuel the mutagenic pathway.When functioning properly, DNA replication is phenomenally accurate, making ∼10⁻¹⁰ mutations per base pair during each replication cycle (1). In respect to human biology, it means that, on average, less than one mutation occurs each time the human genome is replicated. This amazing exactitude is contingent upon the serial action of DNA polymerase selectivity, exonucleolytic proofreading, and DNA mismatch repair (MMR). MMR defects increase spontaneous mutagenesis in numerous model systems (2) and give rise to cancer in mice (3). In humans, inherited mutations in MMR genes predispose to colorectal cancer (CRC) in Lynch syndrome (4, 5). Additionally, MMR genes are inactivated via hypermethylation in ∼15% of sporadic CRC, endometrial cancer (EC), and gastric cancer (6).Like defects in MMR, mutations that decrease the base selectivity or proofreading activity of replicative DNA polymerases elevate spontaneous mutagenesis in eukaryotic cells (7–14) and cancer incidence in mice (15–18). Germline mutations affecting the exonuclease domains of DNA polymerases δ (Polδ) and ε (Polε) cause hereditary CRC (19), and somatic changes in the exonuclease domain of Polε were found in sporadic hypermutated CRC and EC (20–23). Two of these exonuclease domain mutations were modeled in yeast and found to increase mutation rate, supporting their role in the development of hypermutated tumors (19, 24). Because of these discoveries, recent publications emphasized proofreading deficiency as the initiating cause of some human tumors (25–28). The potential role of base selectivity defects in human cancers received much less attention. At the same time, evidence is accumulating that base selectivity defects do occur in tumors and can have dramatic consequences for genome stability. Modeling in yeast of the Polε exonuclease domain mutation most prevalent in CRC and EC produced an increase in the mutation rate far exceeding the increase expected from loss of proofreading, suggesting additional fidelity defects (24). Several studies of colon cancer cell lines and primary tumors reported amino acid changes in Polδ and Polε outside of the exonuclease domain, including some in the conserved DNA polymerase motifs (20, 23, 29). We have previously shown that the yeast analog of one such variant, Polδ-R696W, is an extremely mutagenic DNA polymerase that, notably, retains full exonuclease activity (30). Expression of the pol3-R696W allele was estimated to result in a more than 10,000-fold increase in the mutation rate, which is incompatible with life in both haploid and diploid cells and represents the strongest mutator effect described to date in eukaryotic cells. The corresponding human mutation, POLD1-R689W, was found in two colon cancer cell lines, DLD-1 (29) and HCT15 (31), which were independently derived from the same primary tumor (32), indicating that the R689W change existed in the tumor before the establishment of these cell lines.To understand how a single amino acid change in Polδ could cause such a phenomenal increase in mutagenesis, we first set out to characterize the fidelity of purified Polδ-R696W during in vitro DNA synthesis. Surprisingly, Polδ-R696W was not dramatically less accurate than previously studied Polδ variants that are only moderately mutagenic in vivo. We found, however, that yeast cells producing Polδ-R696W undergo S-phase checkpoint-dependent expansion of dNTP pools. Simulating this dNTP increase in vitro reduced the fidelity of Polδ-R696W to a level that explains its extraordinary mutator effect in vivo. We present evidence that the mutagenesis in pol3-R696W strains results from a combination of a Polδ nucleotide selectivity defect with activation of the signaling pathway that elevates dNTP pools and further increases the rate of Polδ errors. This vicious circle represents a new mechanism through which DNA polymerase alterations can promote the genome instability and which should be taken into consideration when trying to understand the development of hypermutated human cancers.     

Cellular heterogeneity profiling by hyaluronan probes reveals an invasive but slow-growing breast tumor subset

Tumor heterogeneity confounds cancer diagnosis and the outcome of therapy, necessitating analysis of tumor cell subsets within the tumor mass. Elevated expression of hyaluronan (HA) and HA receptors, receptor for HA-mediated motility (RHAMM)/HA-mediated motility receptor and cluster designation 44 (CD44), in breast tumors correlates with poor outcome. We hypothesized that a probe for detecting HA–HA receptor interactions may reveal breast cancer (BCa) cell heterogeneity relevant to tumor progression. A fluorescent HA (F-HA) probe containing a mixture of polymer sizes typical of tumor microenvironments (10–480 kDa), multiplexed profiling, and flow cytometry were used to monitor HA binding to BCa cell lines of different molecular subtypes. Formulae were developed to quantify binding heterogeneity and to measure invasion in vivo. Two subsets exhibiting differential binding (HA^−/low vs. HA^high) were isolated and characterized for morphology, growth, and invasion in culture and as xenografts in vivo. F-HA–binding amounts and degree of heterogeneity varied with BCa subtype, were highest in the malignant basal-like cell lines, and decreased upon reversion to a nonmalignant phenotype. Binding amounts correlated with CD44 and RHAMM displayed but binding heterogeneity appeared to arise from a differential ability of HA receptor-positive subpopulations to interact with F-HA. HA^high subpopulations exhibited significantly higher local invasion and lung micrometastases but, unexpectedly, lower proliferation than either unsorted parental cells or the HA^−/low subpopulation. Querying F-HA binding to aggressive tumor cells reveals a previously undetected form of heterogeneity that predicts invasive/metastatic behavior and that may aid both early identification of cancer patients susceptible to metastasis, and detection/therapy of invasive BCa subpopulations.Breast tumors display substantial heterogeneity driven by genetic and epigenetic mechanisms (1–3). These processes select and support tumor cell subpopulations with distinct phenotypes in proliferation, metastatic/invasive proclivity, and treatment susceptibility that contribute to clinical outcomes. Currently, there is a paucity of biomarkers to identify these subpopulations (3–12). Although detection of genetic heterogeneity may itself be a breast cancer (BCa) prognostic marker (3, 13–15), the phenotypes manifested from this diversity are context-dependent. Therefore, phenotypic markers provide additional powerful tools for biological information required to design diagnostics and therapeutics. Glycomic approaches have enormous potential for revealing tumor cell phenotypic heterogeneity because glycans are themselves highly heterogeneous and their complexity reflects the nutritional, microenvironmental, and genetic dynamics of the tumors (16–18).We used hyaluronan (HA) as a model carbohydrate ligand for probing heterogeneity in glycosaminoglycan–BCa cell receptor interactions. We reasoned this approach would reveal previously undetected cellular and functional heterogeneity linked to malignant progression because the diversity of cell glycosylation patterns, which can occur as covalent and noncovalent modifications of proteins and lipids as well as different sizes of such polysaccharides as HA, is unrivaled (16, 17, 19). In particular, tumor and wound microenvironments contain different sizes of HA polymers that bind differentially to cell receptors to activate signaling pathways regulating cell migration, invasion, survival, and proliferation (19–22).More than other related glycosaminoglycans, HA accumulation within BCa tumor cells and peritumor stroma is a predictor of poor outcome (23) and of the conversion of the preinvasive form of BCa, ductal carcinoma in situ, to an early invasive form of BCa (24). HA is a nonantigenic and large, relatively simple, unbranched polymer, but the manner in which it is metabolized is highly complex (19, 25). There are literally thousands of different HA sizes in remodeling microenvironments, including tumors. HA polymers bind to cells via at least six known receptors (16, 19, 20, 26–32). Two of these, cluster designation 44 (CD44) and receptor for HA-mediated motility/HA-mediated motility receptor (RHAMM/HMMR), form multivalent complexes with different ranges of HA sizes (19, 29, 33), and both receptors are implicated in BCa progression (19–21, 23, 29, 30, 33–36). Elevated CD44 expression in the peritumor stroma is associated with increased relapse (37), and in primary BCa cell subsets may contribute to tumor initiation and progression (38–40). Elevated RHAMM expression in BCa tumor subsets is a prognostic indicator of poor outcome and increased metastasis (22, 33, 41). RHAMM polymorphisms may also be a factor in BCa susceptibility (42, 43).We postulated that multivalent interactions resulting from mixture of a polydisperse population of fluorescent HA (F-HA) sizes, typical of those found in remodeling microenvironments of wounds and tumors (19, 20, 29), with cellular HA receptors would uncover a heterogeneous binding pattern useful for sorting tumor cells into distinct subsets. We interrogated the binding of F-HA to BCa lines of different molecular subtypes, and related binding/uptake patterns to CD44 and RHAMM display, and to tumor cell growth, invasion, and metastasis.     

Cyclic nucleotide-gated channel 18 is an essential Ca2+ channel in pollen tube tips for pollen tube guidance to ovules in Arabidopsis

In flowering plants, pollen tubes are guided into ovules by multiple attractants from female gametophytes to release paired sperm cells for double fertilization. It has been well-established that Ca²⁺ gradients in the pollen tube tips are essential for pollen tube guidance and that plasma membrane Ca²⁺ channels in pollen tube tips are core components that regulate Ca²⁺ gradients by mediating and regulating external Ca²⁺ influx. Therefore, Ca²⁺ channels are the core components for pollen tube guidance. However, there is still no genetic evidence for the identification of the putative Ca²⁺ channels essential for pollen tube guidance. Here, we report that the point mutations R491Q or R578K in cyclic nucleotide-gated channel 18 (CNGC18) resulted in abnormal Ca²⁺ gradients and strong pollen tube guidance defects by impairing the activation of CNGC18 in Arabidopsis. The pollen tube guidance defects of cngc18-17 (R491Q) and of the transfer DNA (T-DNA) insertion mutant cngc18-1 (+/−) were completely rescued by CNGC18. Furthermore, domain-swapping experiments showed that CNGC18’s transmembrane domains are indispensable for pollen tube guidance. Additionally, we found that, among eight Ca²⁺ channels (including six CNGCs and two glutamate receptor-like channels), CNGC18 was the only one essential for pollen tube guidance. Thus, CNGC18 is the long-sought essential Ca²⁺ channel for pollen tube guidance in Arabidopsis.Pollen tubes deliver paired sperm cells into ovules for double fertilization, and signaling communication between pollen tubes and female reproductive tissues is required to ensure the delivery of sperm cells into the ovules (1). Pollen tube guidance is governed by both female sporophytic and gametophytic tissues (2, 3) and can be separated into two categories: preovular guidance and ovular guidance (1). For preovular guidance, diverse signaling molecules from female sporophytic tissues have been identified, including the transmitting tissue-specific (TTS) glycoprotein in tobacco (4), γ-amino butyric acid (GABA) in Arabidopsis (5), and chemocyanin and the lipid transfer protein SCA in Lilium longiflorum (6, 7). For ovular pollen tube guidance, female gametophytes secrete small peptides as attractants, including LUREs in Torenia fournieri (8) and Arabidopsis (9) and ZmEA1 in maize (10, 11). Synergid cells, central cells, egg cells, and egg apparatus are all involved in pollen tube guidance, probably by secreting different attractants (9–15). Additionally, nitric oxide (NO) and phytosulfokine peptides have also been implicated in both preovular and ovular pollen tube guidance (16–18). Thus, pollen tubes could be guided by diverse attractants in a single plant species.Ca²⁺ gradients at pollen tube tips are essential for both tip growth and pollen tube guidance (19–27). Spatial modification of the Ca²⁺ gradients leads to the reorientation of pollen tube growth in vitro (28, 29). The Ca²⁺ gradients were significantly increased in pollen tubes attracted to the micropyles by synergid cells in vivo, compared with those not attracted by ovules (30). Therefore, the Ca²⁺ gradients in pollen tube tips are essential for pollen tube guidance. The Ca²⁺ gradients result from external Ca²⁺ influx, which is mainly mediated by plasma membrane Ca²⁺ channels in pollen tube tips. Thus, the Ca²⁺ channels are the key components for regulating the Ca²⁺ gradients and are consequently essential for pollen tube guidance. Using electrophysiological techniques, inward Ca²⁺ currents were observed in both pollen grain and pollen tube protoplasts (31–36), supporting the presence of plasma membrane Ca²⁺ channels in pollen tube tips. Recently, a number of candidate Ca²⁺ channels were identified in pollen tubes, including six cyclic nucleotide-gated channels (CNGCs) and two glutamate receptor-like channels (GLRs) in Arabidopsis (37–40). Three of these eight channels, namely CNGC18, GLR1.2, and GLR3.7, were characterized as Ca²⁺-permeable channels (40, 41) whereas the ion selectivity of the other five CNGCs has not been characterized. We hypothesized that the Ca²⁺ channel essential for pollen tube guidance could be among these eight channels.In this research, we first characterized the remaining five CNGCs as Ca²⁺ channels. We further found that CNGC18, out of the eight Ca²⁺ channels, was the only one essential for pollen tube guidance in Arabidopsis and that its transmembrane domains were indispensable for pollen tube guidance.