F. Esmailian

Atrial Extracellular Matrix Remodeling and the Maintenance of Atrial Fibrillation

Background—Remodeling occurs in both ventricle and atrium in dilated cardiomyopathy and heart failure. However, the alteration of atrial extracellular matrix components during remodeling and its effect on the electrical remodeling and atrial arrhythmia have never been explored. Methods and Results—Atrial tissue samples of 53 explanted hearts from patients with dilated cardiomyopathy and end-stage heart failure who underwent heart transplantation were examined. Nineteen patients had permanent atrial fibrillation (PmAF), 18 had persistent AF (PsAF), and 16 had no documented AF (NAF). Sixteen donor left atria (LA) were used as controls (CNs). Western Blot analysis revealed a selective downregulation of tissue inhibitor of metalloproteinase (TIMP)-2 in PmAF and PsAF groups compared with the NAF and CN groups and an upregulation of atrial metalloproteinase (MMP)-2 that was most pronounced in the PmAF group followed by the PsAF and NAF groups. Immunofluorescent staining revealed that in the LA, type I collagen volume fraction (CVF-I) increased significantly in the PmAF group followed by the PsAF and NAF groups compared with that in CN. LA CVF-I significantly correlated with LA dimension and TIMP-2 to MMP-2 ratio. In the PsAF group, CVF-I/CVF-III ratio was significantly correlated with AF duration and the frequency of AF recurrence. Conclusions—Atrial extracellular matrix remodeling manifested by the selective downregulation of TIMP-2 along with upregulation of MMP-2 and CVF-I in the atrium is associated with the development of sustained atrial fibrillation in patients with cardiomyopathy and heart failure.

Complications of Extracorporeal Membrane Oxygenation for Treatment of Cardiogenic Shock and Cardiac Arrest: A Meta-Analysis of 1,866 Adult Patients

BACKGROUND Venoarterial extracorporeal membrane oxygenation (ECMO) has been used successfully for treatment of cardiogenic shock or cardiac arrest. The exact complication rate is not well understood, in part because of small study sizes. In the absence of large clinical trials, performance of pooled analysis represents the best method for ascertaining complication rates for ECMO. METHODS A systematic PubMed search was conducted on ECMO for treatment of cardiogenic shock or cardiac arrest in adult patients only, updated to November 2012. Studies with more than 10 patients published in the year 2000 or later that reported complication rates for ECMO were included. Specific complications analyzed included lower extremity ischemia, fasciotomy or compartment syndrome, amputation, stroke, neurologic complications, acute kidney injury, renal replacement therapy, major or significant bleeding, rethoracotomy for bleeding or tamponade, and significant infection. For studies that included overlapping patients, the largest study was included and the others excluded. Cochrans Q and I-squared were calculated. A more conservative random-effects model was chosen for all analyses. RESULTS Twenty studies were included in the analyses encompassing 1,866 patients. Seventeen studies reported survival to hospital discharge, with a cumulative survival rate of 534 of 1,529, and a range of 20.8% to 65.4%. Analyses encompassed 192 to 1,452 patients depending on the specific complication analyzed. The pooled estimate rates of complications with 95% confidence intervals were as follows: lower extremity ischemia, 16.9% (12.5% to 22.6%); fasciotomy or compartment syndrome, 10.3% (7.3% to 14.5%); lower extremity amputation, 4.7% (2.3% to 9.3%); stroke, 5.9% (4.2% to 8.3%); neurologic complications, 13.3% (9.9% to 17.7%); acute kidney injury, 55.6% (35.5% to 74.0%); renal replacement therapy, 46.0% (36.7% to 55.5%); major or significant bleeding, 40.8% (26.8% to 56.6%); rethoracotomy for bleeding or tamponade in postcardiotomy patients, 41.9% (24.3% to 61.8%); and significant infection, 30.4% (19.5% to 44.0%). CONCLUSIONS Although ECMO can improve survival of patients with advanced heart disease, there is significant associated morbidity with performance of this intervention. These findings should be incorporated in the risk-benefit analysis when initiation of ECMO for cardiogenic shock is being considered.

Report from a consensus conference on primary graft dysfunction after cardiac transplantation

Although primary graft dysfunction (PGD) is fairly common early after cardiac transplant, standardized schemes for diagnosis and treatment remain contentious. Most major cardiac transplant centers use different definitions and parameters of cardiac function. Thus, there is difficulty comparing published reports and no agreed protocol for management. A consensus conference was organized to better define, diagnose, and manage PGD. There were 71 participants (transplant cardiologists, surgeons, immunologists and pathologists), with vast clinical and published experience in PGD, representing 42 heart transplant centers worldwide. State-of-the-art PGD presentations occurred with subsequent breakout sessions planned in an attempt to reach consensus on various issues. Graft dysfunction will be classified into primary graft dysfunction (PGD) or secondary graft dysfunction where there is a discernible cause such as hyperacute rejection, pulmonary hypertension, or surgical complications. PGD must be diagnosed within 24 hours of completion of surgery. PGD is divided into PGD-left ventricle and PGD-right ventricle. PGD-left ventricle is categorized into mild, moderate, or severe grades depending on the level of cardiac function and the extent of inotrope and mechanical support required. Agreed risk factors for PGD include donor, recipient, and surgical procedural factors. Recommended management involves minimization of risk factors, gradual increase of inotropes, and use of mechanical circulatory support as needed. Retransplantation may be indicated if risk factors are minimal. With a standardized definition of PGD, there will be more consistent recognition of this phenomenon and treatment modalities will be more comparable. This should lead to better understanding of PGD and prevention/minimization of its adverse outcomes.

Inhaled nitric oxide for pulmonary hypertension after heart transplantation.

Background. Recipient pulmonary hypertension due to chronic congestive heart failure is a major cause of right ventricular (RV) dysfunction after heart transplantation. We hypothesized that inhaled nitric oxide (NO), in the postoperative period, would a) selectively reduce pulmonary vascular resistance and improve RV hemodynamics and b) reduce the incidence of RV dysfunction compared with a matched historical group. Methods. Sixteen consecutive adult heart transplant recipients with lowest mean pulmonary artery (PA) pressures >25 mmHg were prospectively enrolled. Inhaled NO at 20 parts per million (ppm) was initiated before termination of cardiopulmonary bypass (CPB). At 6 and 12 hours after CPB, NO was stopped for 15 minutes and systemic and pulmonary hemodynamics were measured. RV dysfunction was defined as central venous pressure >15 mmHg and consistent echocardiographic findings. The incidence of RV dysfunction and 30-day survival in this group was compared with a historical cohort of 16 patients matched for pulmonary hypertension. Results. Discontinuation of NO for 15 minutes at 6 hours after transplantation resulted in a significant rise in mean PA pressure, pulmonary vascular resistance (PVR), and RV stroke work index. Systemic hemodynamics were not affected by NO therapy. One patient in the NO-treated group, compared with 6 patients in the historical cohort group, developed RV dysfunction (P <.05). The 30-day survival in the NO-treated group and the historical cohort group were 100% and 81%, respectively (P >.05). Conclusion. In heart transplant recipients with pulmonary hypertension, inhaled NO in the postoperative period selectively reduces PVR and enhances RV stroke work. Furthermore, NO reduces the incidence of RV dysfunction in this group of patients when compared with a historical cohort matched for pulmonary hypertension. Inhaled NO is a useful adjunct to the postoperative treatment protocol of heart transplant patients with pulmonary hypertension.

A prospective, randomized, crossover pilot study of inhaled nitric oxide versus inhaled prostacyclin in heart transplant and lung transplant recipients

OBJECTIVE Inhaled nitric oxide has been shown to reduce pulmonary vascular resistance in patients undergoing cardiothoracic surgery, but it is limited by toxicity, the need for special monitoring, and cost. Inhaled prostacyclin also decreases pulmonary artery pressure, is relatively free of toxicity, requires no specific monitoring, and is less expensive. The objective of this study was to compare nitric oxide and prostacyclin in the treatment of pulmonary hypertension, refractory hypoxemia, and right ventricular dysfunction in thoracic transplant recipients in a prospective, randomized, crossover pilot trial. METHODS Heart transplant and lung transplant recipients were randomized to nitric oxide or prostacyclin as initial treatment, followed by a crossover to the other agent after 6 hours. Pulmonary vasodilators were initiated in the operating room for pulmonary hypertension, refractory hypoxemia, or right ventricular dysfunction. Nitric oxide was administered at 20 ppm, and prostacyclin was administered at 20,000 ng/mL. Hemodynamic and oxygenation parameters were recorded before and after initiation of pulmonary vasodilator therapy. At 6 hours, the hemodynamic and oxygenation parameters were recorded again, just before discontinuing the initial agent. Crossover baseline parameters were measured 30 minutes after the initial agent had been stopped. The crossover agent was then started, and the hemodynamic and oxygenation parameters were measured again 30 minutes later. RESULTS Heart transplant and lung transplant recipients (n = 25) were randomized by initial treatment (nitric oxide, n = 14; prostacyclin, n = 11). Nitric oxide and prostacyclin both reduced pulmonary artery pressure and central venous pressure, and improved cardiac index and mixed venous oxygen saturation on initiation of therapy. More importantly, at the 6-hour crossover trial, there were no significant differences between nitric oxide and prostacyclin in the reduction of pulmonary artery pressures or central venous pressure, or in improvement in cardiac index or mixed venous oxygen saturation. Nitric oxide and prostacyclin did not affect the oxygenation index or systemic blood pressure. There were no complications associated with nitric oxide or prostacyclin. CONCLUSION In heart transplant and lung transplant recipients, nitric oxide and prostacyclin similarly reduce pulmonary artery pressures and central venous pressure, and improve cardiac index and mixed venous oxygen saturation. Inhaled prostacyclin may offer an alternative to nitric oxide in the treatment of pulmonary hypertension in thoracic transplantation.

Ex-vivo perfusion of donor hearts for human heart transplantation (PROCEED II): a prospective, open-label, multicentre, randomised non-inferiority trial

BACKGROUND The Organ Care System is the only clinical platform for ex-vivo perfusion of human donor hearts. The system preserves the donor heart in a warm beating state during transport from the donor hospital to the recipient hospital. We aimed to assess the clinical outcomes of the Organ Care System compared with standard cold storage of human donor hearts for transplantation. METHODS We did this prospective, open-label, multicentre, randomised non-inferiority trial at ten heart-transplant centres in the USA and Europe. Eligible heart-transplant candidates (aged >18 years) were randomly assigned (1:1) to receive donor hearts preserved with either the Organ Care System or standard cold storage. Participants, investigators, and medical staff were not masked to group assignment. The primary endpoint was 30 day patient and graft survival, with a 10% non-inferiority margin. We did analyses in the intention-to-treat, as-treated, and per-protocol populations. This trial is registered with ClinicalTrials.gov, number NCT00855712. FINDINGS Between June 29, 2010, and Sept 16, 2013, we randomly assigned 130 patients to the Organ Care System group (n=67) or the standard cold storage group (n=63). 30 day patient and graft survival rates were 94% (n=63) in the Organ Care System group and 97% (n=61) in the standard cold storage group (difference 2·8%, one-sided 95% upper confidence bound 8·8; p=0·45). Eight (13%) patients in the Organ Care System group and nine (14%) patients in the standard cold storage group had cardiac-related serious adverse events. INTERPRETATION Heart transplantation using donor hearts adequately preserved with the Organ Care System or with standard cold storage yield similar short-term clinical outcomes. The metabolic assessment capability of the Organ Care System needs further study. FUNDING TransMedics.

Hybrid procedures for epicardial catheter ablation of ventricular tachycardia: Value of surgical access

BACKGROUND Prior chest surgery limits the ability to obtain epicardial access in patients referred for catheter ablation of ventricular tachycardia (VT). OBJECTIVE The purpose of this study was to describe the utility of different surgical approaches to access the epicardium for VT ablation. METHODS Clinical data of 14 patients with drug-refractory VT who underwent hybrid surgical epicardial access for catheter mapping and ablation in the electrophysiology lab were reviewed. Baseline patient and procedural characteristics including access, exposure, mapping techniques, and ablation were analyzed. RESULTS Of a total of 14 patients (age 63.2 ± 10.3 years), 11 had a subxiphoid window performed, and three patients underwent limited anterior thoracotomy to access the epicardium. The indication for surgical access was prior cardiac surgery (n = 12), previous failed epicardial access (n = 1), and ablation in close proximity to the coronary arteries and phrenic nerve (n = 1). Mapping in patients with subxiphoid surgical access was limited to the inferior and diaphragmatic surface of the heart extending posteriorly to the basal lateral wall. With limited anterior thoracotomy, access to the apex, anterior, and mid to apical anterolateral walls was obtained. In these regions, adhesions were more severe and repeat entry into the epicardial region at a different intercostal level was needed in two of three patients. CONCLUSION Surgical access with subxiphoid window and limited anterior thoracotomy in the electrophysiology lab is feasible and safe. The surgical approach can be tailored to the region of interest in the ventricle to be mapped and ablated.

Heart transplant recipients supported with extracorporeal membrane oxygenation: Outcomes from a single-center experience

BACKGROUND Extracorporeal membrane oxygenation (ECMO) provides hemodynamic support in refractory cardiogenic shock and may be used after heart transplantation for primary graft dysfunction or rejection. We hypothesized that survival after ECMO support is contingent upon patient selection. METHODS We examined consecutive adult heart transplant recipients at a single center who underwent transplantation between 1997 and 2009 and required ECMO support. Patients were divided by clinical presentation: pre-emptive therapy, escalating inotropic requirements despite support by intra-aortic balloon pump (IABP); and salvage therapy, cardiac arrest undergoing cardiopulmonary resuscitation with chest compressions. RESULTS Between 1997 and 2009, there were 37 instances of ECMO use in 32 patients: 23 episodes (19 patients) for pre-emptive therapy and 14 episodes (14 patients) for salvage therapy; 1 patient had both pre-emptive and salvage therapy. Patients did not differ in age, gender or ischemic time. ECMO support was for a median 6 days in both groups, and the incidence of serious vascular complications was comparable (35% and 36%). In the pre-emptive therapy group, 15 episodes (79%) were associated with survival to hospital discharge and 5 patients (26%) were alive at 1 year. In the salvage therapy group, 2 episodes (14%) were associated with survival to hospital discharge and 1 patient (7%) was alive at 1 year. CONCLUSIONS ECMO support is a viable option for adult heart transplant recipients with severe rejection and refractory cardiogenic shock. To maximize the benefit of this aggressive approach in heart transplant recipients requires early intervention, with a heightened awareness of this option to facilitate expedited use.

Recent Trends in Early Outcome of Adult Patients after Heart Transplantation: A Single‐institution Review of 251 Transplants Using Standard Donor Organs1

Older age, prior transplantation, pulmonary hypertension, and mechanical support are commonly seen in current potential cardiac transplant recipients. Transplants in 436 consecutive adult patients from 1994 to 1999 were reviewed. There were 251 using standard donors in 243 patients (age range 18–69 years). To emphasize recipient risk, 185 patients who received a nonstandard donor were excluded from analysis. The indications for transplant were ischemic heart disease (n = 123, 47%), dilated cardiomyopathy (n = 82, 32%), and others (n = 56, 21%). One hundred and forty‐nine (57%) recipients were listed as status I; 5 and 6% were supported with an intra‐aortic balloon and an assist device, respectively. The 30‐d survival and survival to discharge were 94.7 and 92.7%, respectively; 1‐year survival was 89.1%. Causes of early death were graft failure (n = 6), infection (n = 4), stroke (n = 4), multiorgan failure (n = 3) and rejection (n = 2). Predictors were balloon pump use alone (OR = 11.4, p = 0.002), pulmonary vascular resistance > 4 Wood units (OR = 5.7, p = 0.007), pretransplant creatinine > 2.0 mg/dL (OR = 6.9, p = 0.004) and female donor (OR = 8.3, p = 0.002). Recipient age and previous surgery did not affect short‐term survival. Heart transplantation in the current era consistently offers excellent early and 1‐year survival for well‐selected recipients receiving standard donors. Early mortality tends to reflect graft failure while hospital mortality may be more indicative of recipient selection.

Seventeen-year experience with 1,083 heart transplants at a single institution

BACKGROUND Heart transplantation is the most accepted treatment for end-stage heart disease. A review of 1,083 consecutive transplants (1984 to 2001) was undertaken. METHODS Adult recipients were divided into quartiles. The last 540 transplants were combined. Three eras were created from these, 1984 to 1991, 1991 to 1995, and 1995 to 2001, with three age groups: 0 to 18 years, 19 to 61 years, and 62 to 74 years. All patients have at least 1 year of follow-up time. End points were survival, rejection, and graft coronary artery disease. RESULTS There were 1,012 patients. Donor age, graft ischemic time, and the proportion of elderly recipients and nonstandard donor hearts have increased in the current era. Actuarial 60-month survivals of recipients after 1995 were 80.7% (0 to 18 years); 75.3% (19 to 61 years); and 76.2% (>62 years). The current era children and younger adult groups demonstrated improved results when compared with previous eras (p = 0.003 and p = 0.05). Rejection episodes equal to or greater than ISHLT grade 3A per person per year improved to 0.15 in the current era (p < 0.001). During the three eras, older recipients (>62 years) demonstrated fewer episodes of rejection when compared with other adults (0.13 versus 0.58, p = 0.03). Deaths attributed to graft coronary artery disease decreased from 11% to 5% from era 2 to era 3. Regression analysis revealed a mild effect of donor age on survival and graft coronary artery disease (hazard ratio = 1.02, p = 0.001; hazard ratio = 1.039, p < 0.001, respectively). Recipient predictors of graft coronary artery disease were diagnosis of ischemic cardiomyopathy (hazard ratio = 1.6, p = 0.014) and congenital heart disease (hazard ratio = 3.41, p = 0.02). CONCLUSIONS Improved survival in the current era may be attributed to better organ preservation, improved immunosuppression and control of infection, and less life-threatening graft coronary artery disease.