Novel approach to the treatment of distal malperfusion secondary to ascending aortic dissection.

Acute Type A dissection is a surgical emergency. The presence of visceral and extremity malperfusion syndromes increases perioperative mortality twofold. On occasion, significant malperfusion may best be addressed in a staged fashion with preliminary attention to specific vascular beds with delayed repair of the dissection itself. We present a subacute Type A dissection associated with malperfusion of multiple vascular beds (mesenteric, renal, and iliofemoral) managed with a complication-specific approach utilizing endovascular thoracoabdominal aortic repair prior to ascending repair.

Pannus-related prosthetic valve dysfunction and life-threatening aortic regurgitation.

Prosthetic valve dysfunction is a rare but life-threatening condition. A 66-year-old woman presented with shock 15 years after aortic valve replacement with a tilting-disc valve. Imaging demonstrated severe aortic insufficiency and a fixed-open prosthetic valve. Reoperation revealed pannus ingrowth from the aortic aspect, resulting in immobility of the occluder. A bioprosthetic valve was installed and the patient recovered uneventfully. The diagnosis and surgical management of this problem are discussed.

A novel protective effect of erythropoietin in the infarcted heart.

Erythropoietin (EPO) has been shown to protect neurons from ischemic stroke, but can also increase thrombotic events and mortality rates in patients with ischemic heart disease. We reasoned that benefits of EPO might be offset by increases in hematocrit and evaluated the direct effects of EPO in the ischemic heart. We show that preconditioning with EPO protects H9c2 myoblasts in vitro and cardiomyocytes in vivo against ischemic injury. EPO treatment leads to significantly improved cardiac function following myocardial infarction. This protection is associated with mitigation of myocyte apoptosis, translating into more viable myocardium and less ventricular dysfunction. EPO-mediated myocyte survival appears to involve Akt activation. Importantly, cardioprotective effects of EPO were seen without an increase in hematocrit (eliminating oxygen delivery as an etiologic factor in myocyte survival and function), demonstrating that EPO can directly protect the ischemic and infarcted heart.

Gene delivery to aortocoronary saphenous vein grafts in a large animal model of intimal hyperplasia.

OBJECTIVE: More than 50% of aortocoronary saphenous vein grafts are occluded 10 years after surgery. Intimal hyperplasia is an initial, critical step in the progression toward occlusion. To date, no clinically relevant large animal models of aortocoronary saphenous vein graft intimal hyperplasia have been fully characterized. Gene therapy holds promise as a novel treatment for aortocoronary saphenous vein graft intimal hyperplasia. The 2 objectives of this study are to characterize a canine model of aortocoronary saphenous vein graft intimal hyperplasia and to demonstrate that ex vivo gene delivery is possible in these grafts using adenoviral vectors. METHODS: Ten dogs underwent aortocoronary bypass grafting using saphenous veins. Six dogs underwent serial arteriograms to monitor graft patency. On postoperative day 90, the dogs were killed and their grafted and nongrafted saphenous veins were studied histologically. Four dogs underwent the same procedure, but their saphenous veins were treated with 1 x 10(12) total viral particles of a replication-deficient, recombinant adenovirus containing beta-galactosidase (n = 2) or the beta-adrenergic receptor kinase carboxyl terminus (n = 2). These animals were killed on postoperative day 7 for determination of transgene expression. RESULTS: All grafts were demonstrated patent by arteriogram before the animals were killed. The mean intimal area of the saphenous vein grafts was increased when compared with that of the nongrafted saphenous veins (2.83 mm(2) vs 0.09 mm(2), P <.0008). Adenoviral-treated saphenous vein grafts demonstrated positive transgene expression either by X-gal staining (beta-galactosidase) or Northern analysis (beta-adrenergic receptor kinase carboxyl terminus). CONCLUSION: This study characterizes a clinically relevant canine model of aortocoronary saphenous vein graft intimal hyperplasia. In addition, it demonstrates that adenoviral vectors can be delivered ex vivo to the saphenous vein graft vessel wall at subphysiologic distension pressures. This model may be used in future studies to manipulate molecular targets critical in aortocoronary saphenous vein graft intimal hyperplasia.

Fluid and electrolytes in the aged.

OBJECTIVE: To review the physiological changes in fluid and electrolytes that occur in aging. DATA SOURCES: Data collected for this review were identified from a MEDLINE database search of the English-language literature. The indexing terms were fluids, intravenous fluids, fluid resuscitation, fluid management, perioperative, electrolytes, aged, elderly, hemodynamics, hyponatremia, hypernatremia, hypocalcemia, hypercalcemia, hypomagnesemia, hypermagnesemia, hypophosphatemia, hypokalemia, and hyperkalemia. Relevant references from articles obtained by means of the above search terms were also used. STUDY SELECTION: All pertinent studies were included. Only articles that were case presentations or did not specifically address the topic were excluded. DATA SYNTHESIS: The fastest-growing segment of the population in the United States is individuals 65 years or older. It is imperative that health care professionals review the physiological changes that manifest during the aging process. Fluids and electrolytes are important perioperative factors that undergo age-related changes. These changes include impaired thirst perception; decreased glomerular filtration rate; alterations in hormone levels, including antidiuretic hormone, atrial natriuretic peptide, and aldosterone; decreased urinary concentrating ability; and limitations in excretion of water, sodium, potassium, and acid. CONCLUSIONS: There are age-related alterations in the homeostatic mechanisms used to maintain electrolyte and water balance. Health care providers must familiarize themselves with these alterations to guide treatment of this growing population.

Gene interventions in the beta-adrenergic system for treating heart failure.

Cardiovascular disease accounts for nearly 40% of all deaths annually in this country. Prevention management and advances in medical treatments have dramatically reduced the overall mortality rate due to heart disease. However, death due to chronic heart failure (HF) continues to rise, and effective therapy, particularly for end-stage HF, has been elusive. The myocardial beta-adrenergic receptor (betaAR) system is critical not only in chronic HF but also in acute settings where cardiac function is compromised. Adding to its importance is the fact that drugs that act by altering betaAR signal transduction are at the forefront of conventional HF therapeutic strategies. Accordingly, the ability to genetically manipulate betaAR signaling in the heart is of great interest since it may provide unique inotropic support and improve existing therapeutic strategies for HF.

Twenty-five-year outcomes after multiple internal thoracic artery bypass.

OBJECTIVE: Coronary artery bypass grafting with multiple internal thoracic artery grafts is currently controversial. This study assessed single institutional outcomes with multiple internal thoracic artery grafting for guidance with future clinical decisions. METHODS: In 19,482 patients undergoing multivessel coronary artery bypass grafting (1984-2009), baseline characteristics were recorded in a prospective databank, and follow-up was obtained by questionnaires, phone contact, or National Death Index. Outcomes examined were subsequent myocardial infarction, percutaneous coronary intervention, reoperative coronary artery bypass grafting, all-cause death, and a composite of the 4. Three groups were defined: (1) no internal thoracic artery graft (1874/19,482 or 9%); (2) single internal thoracic artery grafts and adjunctive venous conduits (single internal thoracic artery; 16,881/19,482 or 87%); and (3) multiple internal thoracic artery grafts (728/19,482 or 4%). Multivariable Cox modeling adjusted for differences in baseline characteristics, and comparisons were performed using area under the curve analysis. RESULTS: Differences in baseline characteristics for the no internal thoracic artery graft, single internal thoracic artery, and multiple internal thoracic artery groups were as follows: median age 66, 64, and 59 years, respectively; congestive heart failure 22%, 18%, and 13%, respectively; ejection fraction 0.50, 0.52, and 0.51, respectively; reoperation 10%, 3%, and 7%, respectively; diabetes 27%, 30%, and 15%, respectively; and female gender 33%, 28%, and 20%, respectively. No differences existed in the median number of diseased vessels (3, 3, and 3, respectively) or number of grafts per patient (3, 3, and 3, respectively). Composite outcome improved with increasing internal thoracic artery grafts, whether assessing unadjusted or risk-adjusted data. Compared with no internal thoracic artery graft, the adjusted hazard ratio was 0.79 (confidence interval, 0.74-0.83) for single internal thoracic artery grafting and 0.70 (confidence interval, 0.62-0.80) for multiple internal thoracic artery grafting (both P < .001), reducing risk by 21% and 30%, respectively. CONCLUSIONS: This study confirms improved patient outcomes with multiple internal thoracic artery grafting, achieving half again as much benefit as single internal thoracic artery grafting alone. The data suggest that increasing application of multiple internal thoracic artery grafting should be encouraged to mitigate the inherent risks and costs of long-term cardiac events.

Midterm results with thoracic endovascular aortic repair for chronic type B aortic dissection with associated aneurysm.

OBJECTIVE: Thoracic endovascular aortic repair for chronic type B aortic dissection with associated descending thoracic aneurysm remains controversial. Concerns include potential ischemic complications due to branch vessel origin from the chronic false lumen and continued retrograde false lumen/aneurysm sac pressurization via fenestrations distal to implanted endografts. The present study examines midterm results with thoracic endovascular aortic repair for chronic (>2 weeks) type B aortic dissection with associated aneurysm to better understand the potential role of thoracic endovascular aortic repair for this condition. METHODS: Between March 2005 and December 2009, 51 thoracic endovascular aortic repair procedures were performed at a single institution for management of chronic type B dissection. The indication for thoracic endovascular aortic repair was aneurysm in all cases. A subset of 7 patients (14%) underwent placement of the EndoSure wireless pressure measurement system (CardioMEMS, Inc, Atlanta, Ga) in the false lumen adjacent to the primary tear for monitoring aneurysm sac/false lumen pulse pressure after thoracic endovascular aortic repair. RESULTS: Mean patient age was 57±12 years (range, 30-82 years); 14 patients (28%) were female. Mean aortic diameter was 6.2±1.4 cm. There were no in-hospital/30-day deaths, strokes, or permanent paraplegia/paresis. There were no complications related to compromise of downstream branch vessels arising from the false lumen. Two patients (3.9%) who had preexisting ascending aortic dilation had retrograde acute type A aortic dissection; both were repaired successfully. Median postoperative length of stay was 4 days. Mean follow-up is 27.0±16.5 months (range, 2-60 months). Actuarial overall survival is 77.7% at 60 months with an actuarial aorta-specific survival of 98% over this same time period. Actuarial freedom from reintervention is 77.3% at 60 months. All patients with the EndoSure wireless pressure measurement system exhibited a decrease in aneurysm sac/false lumen pulse pressure indicating a depressurized false lumen. The aneurysm sac/false lumen pulse pressure ratio decreased from 52%±27% at the predischarge measurement to 14%±5% at the latest follow-up reading (P=.029). CONCLUSIONS: Thoracic endovascular aortic repair for chronic type B dissection with associated aneurysm is safe and effective at midterm follow-up. Aneurysm sac/false lumen pulse pressure measurements demonstrate a significant reduction in false lumen endotension, thus ruling out clinically significant persistent retrograde false lumen perfusion and provide proof of concept for a thoracic endovascular aortic repair-based approach. Longer-term follow-up is needed to determine the durability of thoracic endovascular aortic repair for this aortic pathology.

Midterm results for endovascular repair of complicated acute and chronic type B aortic dissection.

BACKGROUND: Thoracic endovascular aortic repair (TEVAR) for the management of type B aortic dissections has become more commonplace despite some controversy. Results of endovascular management of complicated acute (<2 weeks from symptom onset) and chronic (>2 weeks) type B aortic dissection with a view towards determining safety, efficacy, and requirement for secondary procedures are reviewed. METHODS: Between June 2005 and November 2008, 55 patients (41 men) with a mean age of 59 +/- 12 years (range, 31 to 77 years) underwent TEVAR for the management of complicated acute (n = 22) or chronic (n = 33) type B dissection. Indications in acute dissection included impending or frank rupture in 11 and malperfusion syndromes in 11; the indication in chronic dissections was aneurysmal degeneration in 33. RESULTS: Primary technical success was 100%. In-hospital and 30-day rates of death, stroke, and permanent paraplegia/paresis were 2% (n = 1), 0%, and 2% (n = 1), respectively. Median follow-up was 7.1 months (range, 1 to 38 months). Overall actuarial midterm survival was 63% at 38 months, with an aorta-specific actuarial survival of 94%. Two patients (4%) required late conversion to open repair. Postoperative type I or III endoleak occurred in 3 (6%) and type II endoleak in 7 (15%). Two patients underwent subsequent endovascular occlusion. The composite reintervention rate in follow-up was 23.4% (n = 13). CONCLUSIONS: Endovascular repair for complicated acute and chronic type B dissection is safe and effective at early midterm follow-up. TEVAR for type B dissection requires more secondary interventions and imaging surveillance than conventional open reconstruction. Longer-term follow-up is needed to determine the durability of this approach.

Utility of remote wireless pressure sensing for endovascular leak detection after endovascular thoracic aneurysm repair.

BACKGROUND: The goal of thoracic endovascular aneurysm repair (TEVAR) is to exclude and depressurize the aneurysm sac. Type I and III endovascular leaks (EL) transmit systemic pressure and represent treatment failures. The significance of type II EL is more controversial. Remote pressure sensing is a novel nonradiographic technology for EL detection and monitoring. However, little experience exists with regard to use in the thoracic aorta. We present our experience with the EndoSure wireless pressure measurement system (CardioMEMS, Atlanta, GA) for monitoring aneurysm sac pulse pressure (ASP) after TEVAR. METHODS: Beginning May 2006, the EndoSure system was routinely implanted in TEVAR patients with suitable anatomy (36 aneurysm patients; 7 chronic dissection patients). The ASP measurements were taken predischarge and at scheduled follow-up visits. Computed tomography angiograms were performed at scheduled follow-up appointments. Data were prospectively maintained in an institutional aortic database. RESULTS: Through June 2008, 43 patients (34% of TEVARs performed during this interval) underwent implantation. In 10 patients (23%), the device was suboptimally positioned between the endovascular graft and the aortic wall, rather than in an area of thrombus-free lumen, with subsequent transmission of systemic pressure despite no radiographic evidence of EL. In patients with well-positioned sensors, predischarge ASP averaged 43% +/- 22% of systemic. In 2 patients, systemic ASP measurements before discharge prompted imaging, confirming type I EL; both patients were treated successfully with cuff extension. One patient exhibited reduced ASP before discharge but exhibited increased ASP (70% systemic) at 1 month; computed tomography scan confirmed a type I EL. Additional TEVAR sealed the EL and reduced ASP to 39% systemic. For all patients at midterm follow-up, ASP decreased further, averaging 19% +/- 12% systemic (p = 0.019); this correlates with computed tomography imaging demonstrating a 5 mm or greater reduction in aortic diameter in 76% of patients (25 of 33) with follow-up of 6 months or longer. No patients manifested a recurrent type I or type III EL at latest follow-up. The device has also been used to follow 8 patients with type II EL with low ASP. CONCLUSIONS: Implantation of a wireless ASP sensor provides useful information regarding type I and type III EL after TEVAR and permits serial observation of type II EL. This information may guide clinical therapy and improve outcomes. Longer term follow-up will define sensor reliability in postoperative surveillance.

A previously unreported complication of apicoaortic conduit for severe aortic stenosis.

Given the aging population, use of an apicoaortic conduit serves as an alternative method to treat severe aortic stenosis, especially in patients with a heavily calcified ascending aorta or prior cardiac surgery. Although an apicoaortic conduit fractionates systemic blood flow, it does so without significant deleterious effects. However, we report a novel complication with thrombosis of the aortic root and subsequent coronary insufficiency that likely resulted from a preponderance of cardiac output though the apicoaortic conduit with stagnation of native antegrade blood flow. Given increasing use of the apicoaortic conduit procedure, surgeons considering this approach should be familiar with this potential complication.

A Gbetagamma inhibitor reduces intimal hyperplasia in aortocoronary saphenous vein grafts.

OBJECTIVE: Approximately 50% of aortocoronary saphenous vein grafts are occluded 10 years after coronary revascularization surgery. Intimal hyperplasia, a critical component in saphenous vein graft failure, is defined by vascular smooth muscle cell proliferation, which is mediated in part by betagamma subunits of heterotrimeric G proteins (G(betagamma)) and downstream effectors such as mitogen-activated protein kinases. A peptide consisting of the carboxyl-terminus of the beta-adrenergic receptor kinase (betaARKct) binds G(betagamma), thereby inhibiting G(betagamma) signaling. Utilizing a recombinant adenovirus containing the coding sequence for the betaARKct peptide (AdbetaARKct), this study investigates whether treatment of the vein graft with AdbetaARKct reduces intimal hyperplasia in a large animal model of aortocoronary saphenous vein graft intimal hyperplasia. METHODS: Twenty-seven dogs (27-32 kg) underwent aortocoronary bypass grafting to the left anterior descending artery using autologous saphenous vein. Vein grafts were treated with saline (n = 8), an empty adenovirus (n = 8), or AdbetaARKct (n = 8). A subset of dogs (n = 3) were sacrificed on postoperative day 7 and betaARKct expression confirmed by Northern blotting. RESULTS: Arteriograms performed on postoperative day 90 confirmed that saphenous vein grafts were patent. At postoperative day 90, AdbetaARKct-treated grafts demonstrated reduced intimal area compared to empty virus and saline treated animals (P < .05). Additionally, AdbetaARKct treatment of isolated vascular smooth muscle cells in vitro inhibited mitogen-activated protein kinase activation and decreased overall vascular smooth muscle cell proliferation. CONCLUSION: This study demonstrates that betaARKct expression in aortocoronary saphenous vein grafts reduces intimal hyperplasia and decreases vascular smooth muscle cell proliferation in vitro via inhibition of G(betagamma)-mediated mitogen-activated protein kinase activation. Modulation of G(betagamma) via betaARKct may represent a novel therapy to reduce intimal hyperplasia and saphenous vein graft failure.

Catheter-mediated subselective intracoronary gene delivery to the rabbit heart: introduction of a novel method.

BACKGROUND: Recent studies suggest that gene therapy using replication-deficient adenoviruses will benefit treatment of cardiovascular diseases including heart failure. A persistent hurdle is the effective and reproducible delivery of a transgene to the myocardium with minimal iatrogenic morbidity. In this study, we sought to design a relatively non-invasive percutaneous gene delivery system that would maximize cardiac transgene expression and minimize mortality after intracoronary adenovirus injection. METHODS: Adult rabbits received a left circumflex coronary artery (LCx) infusion of 5x10(11) total viral particles of an adenovirus containing the marker transgene beta-galactosidase (Adeno-betaGal) via either a continuous infusion method utilizing an oxygenated, normothermic, physiologic pH Krebs solution driven by a Langendorff apparatus (n=12) or a timed bolus and set concentration at a constant infusion rate to the LCx (n=12). Six rabbits underwent global transgene delivery via an invasive method involving intraventricular delivery and aortic root cross-clamping. The efficacy of transgene expression via these three distinct delivery methods was determined in the left ventricle at 5 days by histological staining and colorimetric quantification assay. RESULTS: While the open-chest, aortic cross-clamping method provides the highest level of gene expression throughout the heart, the morbidity of this procedure is clinically prohibitive. Percutaneous LCx delivery of Adeno-betaGal using the Langendorff apparatus was associated with the lowest morbidity and mortality while still supporting significant myocardial gene expression. CONCLUSIONS: Percutaneous delivery of an adenovirus solution using a continuous infusion of oxygenated Krebs solution via a Langendorff apparatus appears to be a gene delivery modality offering the best compromise of gene expression and clinical utility to maximize any potential therapeutic outcome.

Cardioprotective effects of erythropoietin in the reperfused ischemic heart: a potential role for cardiac fibroblasts.

Erythropoietin has recently been shown to have effects beyond hematopoiesis such as prevention of neuronal and cardiac apoptosis secondary to ischemia. In this study, we evaluated the in vivo protective potential of erythropoietin in the reperfused rabbit heart following ventricular ischemia. We show that "preconditioning" with erythropoietin activates cell survival pathways in myocardial tissue in vivo and adult rabbit cardiac fibroblasts in vitro. These pathways, activated by erythropoietin in both whole hearts and cardiac fibroblasts, are also activated acutely by ischemia/reperfusion injury. Moreover, in vivo studies indicate that erythropoietin treatment either prior to or during ischemia significantly enhances cardiac function and recovery, including left ventricular contractility, following myocardial ischemia/reperfusion. Our data indicate that a contributing in vivo cellular mechanism of this protection is mitigation of myocardial cell apoptosis. This results in decreased infarct size as evidenced by area at risk studies following in vivo ischemia/reperfusion injury, translating into more viable myocardium and less ventricular dysfunction. Therefore, erythropoietin treatment may offer novel protection against ischemic heart disease and may act, at least in part, by direct action on cardiac fibroblasts and myocytes to alter survival and ventricular remodeling.

Video-assisted thoracoscopic transplantation of myoblasts into the heart.

PURPOSE: Currently, cells are transplanted into injured myocardium either through thoracotomy for open surgical delivery or through catheterization for endoventricular or intracoronary delivery; both methods have limitations. Open surgical delivery limits the potential patient population, whereas catheter-based delivery limits the ability to visualize the injection site and confirm delivery of the cells to the appropriate region. In this study, we examine the feasibility of cell transplantation into myocardium using a minimally invasive thoracoscopic approach. DESCRIPTION: Seven swine underwent thoracoscopic cell transplantation. Using a prototype injection device, approximately 10 million myoblasts were injected into the anterior, lateral, posterior, and apical regions of myocardium. Animals were recovered up to 7 days, and after euthanasia, hearts were explanted for histology. EVALUATION: All seven swine had successful delivery of myoblasts into the defined injection sites, as confirmed by analysis of an operative video, magnetic resonance imaging of iron-oxide-labeled cells, and histologic examination. CONCLUSIONS: Thoracoscopic cellular cardiomyoplasty is feasible and allows the surgeon the benefits of direct visualization of the cell injection while minimizing morbidity associated with open cell delivery.

Vascular rarefaction in peripheral skeletal muscle after experimental heart failure.

A decrease in vascular density in peripheral skeletal muscle has been associated with exercise intolerance in humans with congestive heart failure (CHF). The purpose of this study was to determine whether CHF results in a reduction in vascular density in peripheral skeletal muscle. In this established model, CHF was induced by coronary artery ligation in New Zealand White rabbits and sham rabbits that underwent an identical surgical procedure without ligation of the coronary artery. At study termination, rabbits underwent hemodynamic testing and skeletal muscle analysis. The first series of rabbits was divided into sham (n = 6) and CHF (n = 6) 21 days postoperatively. Ten CHF rabbits were then examined 3 (n = 3), 7 (n = 3), and 14 days (n = 4) postoperatively. Vascular density in sham tibialis anterior muscle was 347 +/- 41 capillaries/mm2 or 1.20 +/- 0.11 capillaries/muscle fiber. In 21-day CHF rabbits, the capillary density was significantly lower, 236 +/- 14 capillaries/mm2 or 0.84 +/- 0.04 capillaries/muscle fiber (both P < 0.00001 vs. sham); PECAM protein was 2-fold lower (P < 0.0001) in muscle protein lysates; the fraction of apoptotic cells was greater, 3.8 +/- 2.2 vs. 0.69 +/- 0.56 (P < 0.02 vs. sham) with many TdT-mediated dUTP-biotin nick-end labeling-positive endothelial cells; and Bax protein was 2.8-fold greater (P < 0.0001). By regression analysis, vascular density tended to decrease over time (r2 = 0.572, P < 0.0001). Vascular rarefaction and endothelial apoptosis develop after experimental CHF and may contribute to the skeletal muscle abnormalities in this disease. Modulating vascular density may provide new approaches to treat exercise intolerance in CHF.