PKA phosphorylation activates the calcium release channel (ryanodine receptor) in skeletal muscle: defective regulation in heart failure.

The type 1 ryanodine receptor (RyR1) on the sarcoplasmic reticulum (SR) is the major calcium (Ca2+) release channel required for skeletal muscle excitation-contraction (EC) coupling. RyR1 function is modulated by proteins that bind to its large cytoplasmic scaffold domain, including the FK506 binding protein (FKBP12) and PKA. PKA is activated during sympathetic nervous system (SNS) stimulation. We show that PKA phosphorylation of RyR1 at Ser2843 activates the channel by releasing FKBP12. When FKB12 is bound to RyR1, it inhibits the channel by stabilizing its closed state. RyR1 in skeletal muscle from animals with heart failure (HF), a chronic hyperadrenergic state, were PKA hyperphosphorylated, depleted of FKBP12, and exhibited increased activity, suggesting that the channels are "leaky." RyR1 PKA hyperphosphorylation correlated with impaired SR Ca2+ release and early fatigue in HF skeletal muscle. These findings identify a novel mechanism that regulates RyR1 function via PKA phosphorylation in response to SNS stimulation. PKA hyperphosphorylation of RyR1 may contribute to impaired skeletal muscle function in HF, suggesting that a generalized EC coupling myopathy may play a role in HF.

Thoracoscopic resection of an apical extralobar pulmonary sequestration in an infant.

Pulmonary sequestration is a form of bronchopulmonary-foregut malformation that is treated with surgical resection, either via a thoracotomy or the thoracoscopic approach. Apical extralobar pulmonary sequestrations are rare. We report a case of an apical pulmonary sequestration in an infant that was amenable to thoracoscopic resection. An 8-month-old girl, weighing 10.3 kg, with a left apical extralobar pulmonary sequestration underwent thoracoscopic resection. The pulmonary sequestration was identified and dissected free from surrounding tissue. The vascular peduncle was secured with an endo-GIA loaded with 2-mm vascular staples. The infant was discharged on postoperative day two without complications. In spite of the patient's small size and the apical nature of the sequestration, the operation was easily performed via a thoracoscopic approach. Thoracoscopic resection of an apical extrapulmonary sequestration in a small infant is feasible and may minimize the morbidity of this procedure.

Off-pump epicardial atrial fibrillation surgery utilizing a novel bipolar radiofrequency system.

BACKGROUND: Over the past several years, pulmonary vein isolation for the treatment of atrial fibrillation has gained significant popularity. This study was undertaken to evaluate a novel radiofrequency (RF)-enabled clamp system designed to create transmural lesions epicardially on the beating heart using bipolar RF. METHODS: A set of differently shaped clamps modified to deliver bipolar RF energy were used to create a series of lesions in a beating heart canine model. The pulmonary veins and atrial appendages of 6 dogs were electrically isolated using bipolar RF energy. The right and left atrial appendages served as controls for the right and left pulmonary veins, respectively. Temperature-controlled RF energy was delivered to maintain a tissue temperature of 80 degrees C for 15 seconds. Electrical isolation was assessed acutely and after 4 weeks by a bipolar pacing protocol. RESULTS: A total of 24 circumferential lesions were created. By pacing analysis, 100% (24/24) of these lesions were electrically isolated acutely and 95% (19/20) were still isolated 4 weeks later. At 4 weeks, 92% (22/24) of lesions were transmural by histologic analysis, and 96% (23/24) demonstrated endocardial continuity. One animal experienced a fatal cardiac arrhythmia during initiation of the post-survival procedure, prior to electrophysiologic evaluation, accounting for the reduced number of potential electrically isolated lesions. CONCLUSION: Bipolar RF ablation utilizing a novel bipolar RF clamp device results in electrical isolation and histologic transmurality in an off-pump epicardial model.

Direct left ventricle to great cardiac vein retroperfusion: a novel alternative to myocardial revascularization.

BACKGROUND: As the number of patients with diffuse coronary artery disease continues to grow, there is renewed interest in alternative methods of perfusing the ischemic myocardium. We tested the feasibility of myocardial retroperfusion via a direct left ventricle-to-great cardiac vein (LV-GCV) conduit to support regional contractility in this setting. METHODS: LV-GCV flow was established using an extracorporeal circuit in 5 dogs. Left ventricle (LV) pressure, aortic pressure, regional myocardial segment length, and circuit blood flow were measured prior to left anterior descending coronary artery (LAD) ligation, following LAD ligation, and after LV-GCV circuit placement. To eliminate backward flow during diastole, an in-line flow regulator was placed. Regional myocardial function was quantified by pressure-segment length loop area divided by end-diastolic segment length (PSLA/EDSL). RESULTS: LAD ligation reduced PSLA/EDSL from 10.0 +/- 1.2 mm Hg mm to 1.6 +/- 0.3 mm Hg mm (P < .05). With LV-GCV retroperfusion, mean peak systolic flow was +152 +/- 14 mL/min, mean peak diastolic flow was -39 +/- 11 mL/min, and net mean flow was +36 +/- 13 mL/min. Regional function recovered to approximately 39% of baseline (3.9 +/- 0.4 mm Hg mm, P < .05). Upon elimination of backflow, mean flow increased to +41 +/- 12 mL/min and regional function recovered even further to approximately 47% of baseline (4.6 +/- 0.7 mm Hg mm, P < .05). CONCLUSIONS: A LV-GCV circuit can significantly restore regional function to the acutely ischemic myocardium. An inline valve that eliminates backward diastolic flow improves regional function even further. This approach may provide an effective therapy for diffuse coronary disease not amenable to traditional revascularization strategies.

Does a pre-left ventricular assist device screening score predict long-term transplantation success? A 2-center analysis.

BACKGROUND: A risk factor summation score was previously validated to successfully predict survival after insertion of a left ventricular assist device (LVAD). We investigated whether this scoring system also predicts clinical outcomes after eventual heart transplantation in LVAD recipients. METHODS: A retrospective review was performed on 153 consecutive patients who received an LVAD as a bridge to transplantation at 2 large-volume centers from 1996 to 2003. The scoring system was used to designate low- and high-scoring groups. RESULTS: Thirty-day mortality and 5-year survival after transplantation were equivalent between groups (4.46% versus 7.32% and 76% versus 70%, respectively). No difference was seen in length of posttransplantation ventilator dependence (2.83 +/- 0.49 versus 3.3 +/- 0.72 days) or intensive care unit monitoring (6.38 +/- 0.77 versus 6.97 +/- 1.1 days). However, low-scoring patients had a significantly decreased duration of inotrope support (5.57 +/- 0.45 versus 7.74 +/- 1.0 days, P = .035). CONCLUSION: A risk factor summation score may predict which LVAD patients will require prolonged inotropic support following heart transplantation. However, survival in high-risk (elevated score) LVAD patients following heart transplantation is comparable to low-risk groups, favoring the continued practice of LVAD implantation as a bridge to transplantation even in high-risk patients.

Prolonged donor ischemic time does not adversely affect long-term survival in adult patients undergoing cardiac transplantation.

OBJECTIVE: With liberalization of donor eligibility criteria, organs are being harvested from remote locations, increasing donor ischemic times. Although several studies have evaluated the effects of prolonged donor ischemic times on short-term survival and graft function, few have addressed concerns regarding long-term survival. METHODS: Over the last 11 years, 819 consecutive adults underwent cardiac transplantation at Columbia Presbyterian Medical Center. Recipients were separated into the following 4 groups based on donor ischemic time: <150 minutes, 150 to 200 minutes, 200 to 250 minutes, and >250 minutes. Statistical analysis included Kaplan-Meier survival and Cox proportional hazard models to identify predictors of long-term survival. RESULTS: Donor ischemic time was 120.1 +/- 21.1 minutes for group 1 (n = 321), 174.1 +/- 14.7 minutes for group 2 (n = 264), 221.7 +/- 14.6 minutes for group 3 (n = 154), and 295.5 +/- 37.1 minutes for group 4 (n = 80) (P <.001). There were no significant differences in recipient age, donor age, etiology of heart failure, United Network for Organ Sharing status, or history of previous cardiac surgery among the groups (P = NS). Prolonged donor ischemic time did not adversely affect long-term survival, with actuarial survival at 1, 5, and 10 years of 86.9%, 75.2%, and 56.4% for group 1; 86.2%, 76.9%, and 50.9% for group 2; 86.4%, 71.0%, and 43.7% for group 3; and 86.7%, 70.1%, and 50.9% for group 4 (P =.867). There was no significant difference in freedom from transplant coronary artery disease among the 4 groups (P =.474). CONCLUSIONS: Prolonged donor ischemic time is not a risk factor for decreased long-term survival. Procurement of hearts with prolonged donor ischemic time is justified in the setting of an increasing recipient pool with a fixed donor population.

How to improve organ donation: results of the ISHLT/FACT poll.

BACKGROUND: Worldwide organ shortages remain a long-standing problem. Efforts to address this have ranged from attempts to improve public awareness to modified mandated choice systems; most have been unsuccessful. In the face of this intractable problem, increased consideration has been given to direct and indirect compensation, and in certain countries, black markets for organs have developed. To examine the attitudes of the transplant medical community regarding these issues, we surveyed members of the International Society for Heart and Lung Transplantation (ISHLT) in conjunction with the Foundation for the Advancement of Cardiac Therapies (FACT). METHODS/RESULTS: We asked for opinions about how to improve organ donation. Of 739 respondents, 75% supported presumed consent, and 39% identified it as the single best way to increase donation; improved public education was a distant second (18%). Seventy percent supported indirect compensation (e.g., payment of funeral expenses, donation to a charity of the family's choice), and 66% opposed direct compensation (e.g., tax credit, life insurance benefit). When asked whether next of kin should be consulted regarding organ donation, and 84.2% responded affirmatively. However, of these individuals, 77.2% did not think that consultation should be required if the potential donor already had signed a donor card. MEMBERSHIP: Our membership dramatically favors indirect over direct compensation as a way of increasing organ donation. The majority also favors the wishes of the individual over the family in determining donor status. However, presumed consent is the single best way to significantly improve organ donation, according to the majority of our respondents. More effort should be directed toward policy in these areas as opposed to improving public education, which has failed to yield satisfactory results.

Robotic techniques improve quality of life in patients undergoing atrial septal defect repair.

BACKGROUND: Minimally invasive cardiac surgery has emerged as an alternative to conventional, open surgery. Although most studies of robotically assisted cardiac surgery have reported morbidity and mortality, few have addressed outcome measures, such as pain and quality of life, which was the aim of this study. METHODS: Eleven patients with atrial septal defects (ASD), and five patients with patent foramen ovale, underwent repair using the Da Vinci system (Intuitive Surgical, Mountain View, CA). The Medical Outcomes Study Short Form Survey (SF-36), along with two additional questions, were administered to these patients on postoperative day 30, along with a similar number of patients who underwent ASD repair by mini-thoracotomy or sternotomy. Quality of life endpoints included bodily pain, vitality, mental health, general health, physical function, and social function. RESULTS: Robotic patients demonstrated significantly higher scores in 6 of the eight variables (p < 0.05). There was no significant difference in intensive care unit or overall hospital stay among the groups (p = NS). Robotic patients returned to work after 40.2 +/- 30.2 days, mini-thoracotomy patients after 45.6 +/- 27.9 days, and sternotomy patients after 51.7 +/- 40.2 days (p = 0.767). There were no significant differences in SF-36 scores between patients who underwent mini-thoracotomy and sternotomy approaches. CONCLUSIONS: Closure of an ASD can be performed safely and effectively via an endoscopic approach. Robotic technology minimized the degree of invasiveness, hastened postoperative recovery, and improved quality of life, although length of hospital stay was unchanged.

Off-pump right atrial thrombectomy for heparin-induced thrombocytopenia with thrombosis.

This report describes a 72-year-old woman with atrial fibrillation who presented with lower extremity ischemia secondary to thromboembolism. After lower extremity thrombectomy, the patient developed heparin-induced thrombocytopenia with thrombosis (HITT). Her postoperative course was complicated by recurrent supraventricular and ventricular tachycardia, secondary to a mobile thrombus in the right atrium extending into the right ventricle. Because administration of heparin was contraindicated, the patient underwent off-pump right atrial thrombectomy during a brief period of inflow occlusion. Postoperatively, she was placed on lepirudin. Her platelet count normalized without any further thrombotic episodes, and she was discharged on warfarin.

Long-term results of cardiac transplantation in patients 65 years of age and older: a comparative analysis.

BACKGROUND: Advanced age is viewed by some transplant centers as a contraindication for heart transplantation secondary to concerns regarding decreased survival. METHODS: Between January 1992 and June 2002, 63 of 881 (7.2%) orthotopic heart transplants were performed in patients above 65 years. These patients were compared to 63 recipients below age 65 who were matched for sex, etiology of heart failure, United Network for Organ Sharing status, and immunosuppression therapy era. RESULTS: Mean age was 67.1 +/- 2.3 years (range, 65.0 to 74.8) for the older group and 48.1 +/- 14.5 years (range, 18.3 to 64.4) for the younger group (p < 0.001). There was no significant difference in the incidence of diabetes, hypertension, chronic obstructive pulmonary disease, or peripheral vascular disease between the groups (p = not significant) although there were more patients with prior myocardial infarctions in the older group (p < 0.001). There was no significant difference in overall survival between the groups, with 1-, 3-, 5-, and 10-year actuarial survival of 85.8%, 80.3%, 73.1%, and 49.9% for the older group; and 86.9%, 83.4%, 75.0%, and 57.0% for the younger group (p = 0.597). Postoperative intensive care unit stay and overall hospital stay were similar for the two groups (p = not significant). There was no significant difference between the groups in freedom from infection or rejection at 1, 3, or 5 years after transplant (p = not significant) although the incidence of transplant coronary artery disease was higher in the older group (p = 0.025). CONCLUSIONS: These data demonstrate similar short-term and long-term results for elderly and young recipients undergoing cardiac transplantation. This supports proceeding with transplantation in carefully selected elderly patients.

Nontransplant surgical options for congestive heart failure.

A wide array of surgical options are currently available for the treatment of congestive heart failure ranging from traditional coronary artery bypass grafting to total artificial heart implantation. The indications for each procedure depend on the severity of disease and the individual patients desires. Some surgical options are indicated for patients with moderate disease and prevent worsening heart failure, whereas other procedures are limited to patients who will only survive with high-risk surgery. Ongoing technologic advances are increasing the number of patients that benefit from the reparative surgical treatment of congestive heart failure.

Ventricular assistance to bridge to transplantation.

In 2001, 2202 heart transplants were performed in the United States, leaving 4137 patients waiting who suffer from 30% annual mortality. Status I, Class IV heart failure patients have a 66% 1-year mortality rate and a survival approximating our worst cancers. Left ventricular assist devices (LVADs) first successfully bridged a patient to transplantation in 1978. LVADs have since functioned primarily thus, minimizing end-organ damage and providing rehabilitation potential for individuals awaiting transplantation. In this role, their effectiveness is well-established: they gain time for patients awaiting donors, preserve end-organ function, and provide potential for a high quality of life in and out of the hospital. This success has been the result of numerous advances in VAD technology, which this article discusses.

Magnetic resonance imaging to detect acute cerebral events in on-pump and hybrid-pump patients.

BACKGROUND: Conventional cardiopulmonary bypass results in cerebral ischemic sequelae that may be reduced with hybrid pump technologies, such as the CardioVention system (CardioVention, Santa Clara, CA, USA). CardioVention differs from conventional bypass in that it has a novel air elimination module and reduced membrane surface area and priming volume. This preliminary study tested whether this pump confers neurological safety advantages over conventional bypass. METHODS: Ten patients were studied, with 6 assigned to on-pump coronary artery bypass grafting and 4 to the CardioVention system. No patients had any stroke history. Within 72 hours postsurgery, each underwent diffusion-weighted magnetic resonance imaging, a sensitive test for cerebral ischemic events. RESULTS: Two on-pump patients (33%) had postoperative findings on imaging, but none of the CardioVention patients demonstrated comparable changes ( P =.47). No patients had symptoms of acute stroke. CONCLUSION: Postoperative magnetic resonance imaging showed a trend toward a greater rate of ischemic events in patients undergoing traditional on-pump surgery. These preliminary findings suggest that hybrid pump technologies, such as the CardioVention system, may attenuate the risk of short-term neurological complications. Future studies are indicated to confirm these subclinical ischemic changes and to correlate them with long-term neurocognitive changes.

beta(2)-Adrenergic stimulation attenuates left ventricular remodeling, decreases apoptosis, and improves calcium homeostasis in a rodent model of ischemic cardiomyopathy.

The benefit of the beta(2)-adrenergic agonist, clenbuterol, in left ventricular assist device patients with dilated cardiomyopathy has been reported, but its effect on ischemic heart failure (HF) is unknown. We investigated whether clenbuterol improves left ventricular remodeling, myocardial apoptosis and has synergy with a beta(1) antagonist, metoprolol, in a model of ischemic HF. Rats were randomized to: 1) HF only; 2) HF + clenbuterol; 3) HF + metoprolol; 4) HF + clenbuterol + metoprolol; and 5) rats with sham surgery. HF was induced by left anterior descending artery (LAD) artery ligation and confirmed by decreased left ventricular fractional shortening, decreased maximum left ventricular dP/dt (dP/dt(max)), and elevated left ventricular end-diastolic pressure (LVEDP) compared with sham rats (p < 0.01). After 9 weeks of oral therapy, echocardiographic, hemodynamic, and ex vivo end-diastolic pressure-volume relationship (EDPVR) measurements were obtained. Immunohistochemistry was performed for myocardial apoptosis and DNA damage markers. Levels of calcium-handling proteins were assessed by Western blot analysis. Clenbuterol-treated HF rats had increased weight gain and heart weights versus HF rats (p < 0.05). EDPVR curves revealed a leftward shift in clenbuterol rats versus metoprolol and HF rats (p < 0.05). The metoprolol-treated group had a lower LVEDP and higher dP/dt(max) versus the HF group (p < 0.05). Clenbuterol and metoprolol groups had decreased myocardial apoptosis and DNA damage markers and increased DNA repair markers versus HF rats (all p < 0.01). Protein levels of the ryanodine receptor and sarcoplasmic reticulum calcium-ATPase were improved in clenbuterol-, metoprolol-, and clenbuterol+metoprolol-treated groups versus HF rats. However, as a combination therapy, there were no synergistic effects of clenbuterol+metoprolol treatment. We conclude that clenbuterol ameliorates EDPVR, apoptosis, and calcium homeostasis but does not have synergy with metoprolol in our model of ischemic HF.

Alternate waiting list strategies for heart transplantation maximize donor organ utilization.

BACKGROUND: Alternate waiting list strategies have been promoted as a means to offer the benefit of heart transplantation to a greater number of candidates. We undertook the current study to evaluate our experience with transplantation in alternate list (AL) candidates. METHODS: Adults undergoing heart transplantation from January 1, 2001, through April 15, 2004, were evaluated. Selected patients who did not meet criteria for standard listing for heart transplantation were offered alternate listing. Primary posttransplant outcomes included 30-day, 90-day, and more than 90-day mortality, and determinants of perioperative morbidity. RESULTS: Thirty-seven patients (14.3%) met alternate list criteria. Among these alternate list patients, contraindications to standard listing included age greater than 65 years, amyloidosis, severe diabetes mellitus and peripheral vascular disease, human immunodeficiency virus, and high-risk retransplant. The average age of alternate list donors was 41.2 +/- 13.9 years. Survival analysis revealed no posttransplant survival advantage for standard list recipients However, mean ventilatory support time was significantly (p < 0.001) longer in the alternate list group (5.7 +/- 9.3 days) compared with the standard group (2.3 +/- 4.2 days), and significantly more sternal wound infections (p = 0.03) were observed in the alternate list group (6 [16.2%]) compared with the standard group (13 [5.9%]). CONCLUSIONS: The alternate list patients demonstrated comparable survival with standard list patients, but did exhibit more ventilatory dependence and sternal wound infections. More than half of alternate list donor organs in the future could be considered for standard list candidates as well. Use of the alternate list reinforces the assertion that, even today, our donor criteria remain too stringent.

Ventricular assist devices as a bridge to transplant or recovery.

Ventricular assist devices have emerged as the standard of care in treating end-stage heart failure. Their success in bridging patients to transplantation is well documented. The data supporting their ability to bridge patients to recovery is sparser. However, as technology continues to advance, these devices will offer a high quality of life both in and out of the hospital setting, making them options for a broader spectrum of heart failure patients.

Macrophage inhibitor, semapimod, reduces tumor necrosis factor-alpha in myocardium in a rat model of ischemic heart failure.

Pharmaceutical agents aimed at reducing tumor necrosis factor-alpha (TNF-alpha) levels appeared to be attractive possibilities in the medical management of heart failure, as heart failure was shown to be associated with high TNF-alpha levels. However, therapies specifically targeting TNF-alpha failed to show any survival benefit. We examined whether a broad inhibition of inflammatory cytokine production secondary to macrophage inhibition would be more effective at improving cardiac function in the setting of heart failure. To this end, we studied Semapimod (formerly known as CNI-1493), a synthetic guanylhydrazone that inhibits macrophage activation and the production of several inflammatory cytokines. Left anterior descending coronary ligation surgery was performed on each animal to induce a myocardial infarction. After confirming heart failure by echocardiography, the animals were randomly assigned to one of four groups: (1) rats with myocardial infarct receiving high-dose Semapimod, 10 mg/kg/d (MI-H, N = 13); (2) rats with myocardial infarct receiving low-dose Semapimod, 3 mg/kg/d (MI-L, N = 9); (3) rats with myocardial infarct receiving vehicle treatment, 2.5% mannitol in water (MI-0, N = 9); and (4) control rats with sham operation and vehicle treatment (Sham, N = 10). Both Semapimod and vehicle treatments were administered by daily tail vein injections over a course of five days. Echoes were repeated at 2, 5, and 9 weeks following treatment. At 9 weeks, hemodynamic data were collected and the animals were euthanized. Trichrome staining was done to assess infarct, and immunohistochemistry was performed to assess TNF-alpha levels. Prior to drug administration, serum was taken from 5 random rats. No detectable level of TNF-alpha was seen (lower limit of detection for the assay used = 12.5 pg/mL). Also prior to any treatment, echocardiography confirmed significant cardiac impairment of rats undergoing LAD ligation as compared with sham. Over the course of the 9 weeks, there were 4 deaths, all in the MI-H group. There was no difference between Semapimod-treated animals and vehicle-treated MI animals in any echocardiographic or hemodynamic parameter. TNF-alpha staining in the noninfarcted region was evident only in the MI groups, not the sham group. When blindly compared on a semiquantitative scale (ie, 0 = no visible staining to 3 = marked staining), a significant difference in staining was observed between MI-0 versus MI-H (1.19 +/- 0.32 versus 0.33 +/- 0.14; P = 0.03) and between MI-0 and MI-L (1.19 +/- 0.32 versus 0.39 +/- 0.22; P = 0.05). In this setting, despite the fact that Semapimod treatment decreased tissue TNF-alpha levels, it did not improve cardiac function, and at high doses it was associated with higher mortality. These results in a rodent model confirm the results of clinical trials with etanercept and infliximab (ie, that decreasing TNF levels in plasma or tissues does not improve cardiac function and may actually increase mortality).