Phillip C. Camp

Thin Filament-Based Modulation of Contractile Performance in Human Heart Failure

Background—The contribution of the sarcomere’s thin filament to the contractile dysfunction of human cardiomyopathy is not well understood. Methods and Results—We have developed techniques to isolate and functionally characterize intact (native) thin filaments obtained from failing and nonfailing human ventricular tissue. By use of in vitro motility and force assays, native thin filaments from failing ventricular tissue exhibited a 19% increase in maximal velocity but a 27% decrease in maximal contractile force compared with nonfailing myocardium. Native thin filaments isolated from human myocardium after left ventricular assist device support demonstrated a 37% increase in contractile force. Dephosphorylation of failing native thin filaments resulted in a near-normalization of thin-filament function, implying a phosphorylation-mediated mechanism. Tissue expression of the protein kinase C isoforms &agr;, &bgr;1, and &bgr;2 was increased in failing human myocardium and reduced after left ventricular assist device support. Conclusions—These novel findings demonstrate that (1) the thin filament is a key modulator of contractile performance in the failing human heart, (2) thin-filament function is restored to near normal levels after LVAD support, and (3) the alteration of thin-filament function in failing human myocardium is mediated through phosphorylation, most likely through activation of protein kinase C.

Atrial Arrhythmias After Lung Transplantation: Epidemiology, Mechanisms at Electrophysiology Study, and Outcomes

Background—Atrial arrhythmias (AAs) including atrial fibrillation (AF) and atrial tachycardia (AT) are often observed after cardiothoracic surgery. Our aim was to evaluate the prevalence and mechanism of AAs after lung transplantation. Methods and Results—All patients (n=127) after bilateral sequential lung transplantation followed at our institution over 20 years were included. All patients received postoperative rhythm monitoring and clinic visits with ECG at 1, 3, 6, and 12 months, or as needed. AAs occurred in 40 of 127 (31.5%) patients over 4.2±4.1 years. AA prevalence at postoperation and 1, 3, 6, 12, and >12 months was 24%, 11%, 3%, 2%, 4%, and 11%, respectively. Early AAs were predominantly AF, whereas all AAs >12 months were AT. Time to first AF versus AT was 11±9 versus 1485±2462 days (P=0.09). Male sex, age, and preoperative AA predicted any early (<3 months) AA but did not predict late AA. Early AA did not predict late AT. In 4 patients with drug-resistant AT, electrophysiology studies found AT involving the pulmonary vein/left atrium anastomoses in 3 patients, including donor-to-recipient conduction in 1, border zone macroreentry in 2, and cavotricuspid isthmus dependent flutter in 1; all patients were successfully treated with ablation. Conclusions—AAs after lung transplantation are common. Although AF is common early, AF is rare after healing of left atrial incisions, which probably result in surgical pulmonary vein isolation with rare exception. This raises the question of whether additional surgical or ablation lines at the time of lung transplantation would prevent late AA.Background— Atrial arrhythmias (AAs) including atrial fibrillation (AF) and atrial tachycardia (AT) are often observed after cardiothoracic surgery. Our aim was to evaluate the prevalence and mechanism of AAs after lung transplantation. Methods and Results— All patients (n=127) after bilateral sequential lung transplantation followed at our institution over 20 years were included. All patients received postoperative rhythm monitoring and clinic visits with ECG at 1, 3, 6, and 12 months, or as needed. AAs occurred in 40 of 127 (31.5%) patients over 4.2±4.1 years. AA prevalence at postoperation and 1, 3, 6, 12, and >12 months was 24%, 11%, 3%, 2%, 4%, and 11%, respectively. Early AAs were predominantly AF, whereas all AAs >12 months were AT. Time to first AF versus AT was 11±9 versus 1485±2462 days ( P =0.09). Male sex, age, and preoperative AA predicted any early (<3 months) AA but did not predict late AA. Early AA did not predict late AT. In 4 patients with drug-resistant AT, electrophysiology studies found AT involving the pulmonary vein/left atrium anastomoses in 3 patients, including donor-to-recipient conduction in 1, border zone macroreentry in 2, and cavotricuspid isthmus dependent flutter in 1; all patients were successfully treated with ablation. Conclusions— AAs after lung transplantation are common. Although AF is common early, AF is rare after healing of left atrial incisions, which probably result in surgical pulmonary vein isolation with rare exception. This raises the question of whether additional surgical or ablation lines at the time of lung transplantation would prevent late AA. Received March 24, 2009; accepted August 5, 2009. # CLINICAL PERSPECTIVE {#article-title-2}

Impact of Pretransplant Anti-HLA Antibodies on Outcomes in Lung Transplant Candidates

RATIONALE The prevalence of anti-HLA antibodies in lung transplant candidates and their impact on waitlist and transplant outcomes is not known. OBJECTIVES We examined the prevalence of pretransplant anti-HLA antibodies at varying thresholds and evaluated their impact on outcomes before and after lung transplantation. METHODS We performed a single-center retrospective cohort study including all patients listed for lung transplantation between January 2008 and August 2012. Per protocol, transplant candidates were assessed by solid phase LABscreen mixed Class I and II and LABscreen Single Antigen assays. MEASUREMENTS AND MAIN RESULTS Among 224 patients, 34% had anti-HLA antibodies at mean fluorescent intensity (MFI) greater than or equal to 3,000 (group III), and 24% had antibodies at MFI 1,000 to 3,000 (group II). Ninety percent of the patients with pretransplant anti-HLA antibodies had class I antibodies, whereas only seven patients developed class II alone. Patients in group III were less likely to receive transplants than patients without any anti-HLA antibodies (group I) (45.5 vs. 67.7%, P = 0.005). Wait time to transplant was longer in group III than group I, although this difference did not meet statistical significance, and waitlist mortality was similar. Among transplant recipients, antibody-mediated rejection (AMR) was more frequent in group III than in group II (20% vs. 0%, P = 0.01) or group I (6.3%, P = 0.05). CONCLUSIONS The presence of anti-HLA antibodies at the high MFI threshold (>3,000) was associated with lower transplant rate and higher rates of AMR. Screening for anti-HLA antibodies using the 3,000 MFI threshold may be important in managing transplant candidates and recipients.

A targeted peritransplant antifungal strategy for the prevention of invasive fungal disease after lung transplantation: a sequential cohort analysis.

Background Lung transplant recipients are at high risk of invasive fungal disease (IFD), particularly invasive aspergillosis and candidiasis. The antifungal strategy that optimally balances effective reduction of IFD with a minimum of toxicity remains undefined; universal triazole prophylaxis is common at lung transplantation (LT) centers, despite the well-known toxicities and costs of this approach. Methods We implemented an antifungal strategy in March 2007 targeted at LT recipients at highest risk for IFD based on our institutional epidemiology. All patients received inhaled amphotericin B during their initial LT hospitalization, bilateral lung transplant recipients received 7 to 10 days of micafungin, and only patients with growth of yeast or mold in their day-of-transplant cultures received further oral antifungal therapy tailored to their fungal isolate. Results IFD events were assessed in sequential cohorts composed of 82 lung transplant recipients before and 83 patients after the implementation of this targeted antifungal strategy. We observed a sharp decline in IFD; in the second cohort, 87%, 91%, and 96% of patients were free of IFD, invasive candidiasis, and invasive aspergillosis at 1 year. Only 19% of patients in the second cohort received systemic antifungal therapy beyond the initial LT hospitalization, and no patients experienced antifungal drug-related toxicity or IFD-associated mortality. Conclusions The targeted antifungal strategy studied seems to be a reasonable approach to reducing post-LT IFD events while limiting treatment-related toxicities and costs.

Extracorporeal Membrane Oxygenation in Adults With Cardiogenic Shock

A 28-year-old previously healthy woman was brought to the hospital after out-of-hospital resuscitated cardiac arrest attributable to ventricular fibrillation. On the evening of presentation, she was found unconscious at home by family members. Bystander cardiopulmonary resuscitation (CPR) was immediately initiated. The patient was defibrillated in the field by emergency medical response providers with return of spontaneous circulation. She aspirated during intubation in the field, and arrived to the hospital in shock, with blood pressure 88/71 mm Hg on norepinephrine 20 μg/min and vasopressin 0.04 U/min. She did not have purposeful movements, and therapeutic hypothermia was initiated in the Emergency Department. She had a metabolic acidosis and concomitant type I acute respiratory failure, with PaO2 66 mm Hg on volume-cycled assist/control mode with tidal volumes of 400 cc, FiO2 1.0, positive end-expiratory pressure 10 cm H2O, and a respiratory rate of 26 breaths/min. Her ECG did not demonstrate stigmata of ischemia or infarction. However, a type I Brugada pattern was noted in leads V1 and V2 before cooling. Over the ensuing several hours, vasopressor requirements escalated. A Swan-Ganz catheter demonstrated severely depressed cardiac index and elevated pulmonary capillary wedge pressure. She remained severely hypoxic despite maximal ventilator support. Chest x-ray showed diffuse bilateral pulmonary infiltrates, consistent with severe aspiration pneumonitis. PaO2 decreased to 49 mm Hg despite increased positive end-expiratory pressure and chemical paralysis, meeting Berlin criteria for severe acute respiratory distress syndrome.1 Options for percutaneous hemodynamic support were considered (including extracorporeal membrane oxygenation [ECMO] or percutaneous ventricular assist device [VAD], such as Impella and TandemHeart), and the patient was placed on veno-arterial ECMO (VA ECMO) for both hemodynamic and respiratory rescue 6 hours after presentation. Cardiopulmonary bypass was first developed in 1954 to facilitate open-heart surgery and used successfully 1 year later.2,3 …

Cytomegalovirus disease in lung transplantation: impact of recipient seropositivity and duration of antiviral prophylaxis

A recent randomized trial demonstrated that 1 year of antiviral prophylaxis for cytomegalovirus (CMV) after lung transplantation is superior to 3 months of treatment for prevention of CMV disease. However, it is uncertain if a shorter duration of prophylaxis might result in a similar rate of CMV disease among select lung transplant (LT) recipients who are at lower risk for CMV disease, based on baseline donor (D) and recipient (R) CMV serologies.

Short Telomeres, Telomeropathy, and Subclinical Extrapulmonary Organ Damage in Patients With Interstitial Lung Disease

BACKGROUND Human telomere disease consists of a wide spectrum of disorders, including pulmonary, hepatic, and bone marrow abnormalities. The extent of bone marrow and liver abnormalities in patients with interstitial lung disease (ILD) and short telomeres is unknown. METHODS The lung transplant clinic established a prospective protocol to identify short telomeres in patients with ILD not related to connective tissue disease or sarcoidosis. Patients with short telomeres underwent bone marrow biopsies, liver biopsies, or both as part of the evaluation for transplant candidacy. RESULTS One hundred twenty-seven patients met ILD categorization for inclusion. Thirty were suspected to have short telomeres, and 15 had the diagnosis confirmed. Eight of 13 (53%) patients had bone marrow abnormalities. Four patients had hypocellular marrow associated with macrocytosis and relatively normal blood counts, which resulted in changes to planned immunosuppression at the time of transplant. Four patients with more severe hematologic abnormalities were not listed because of myelodysplastic syndrome (two); monoclonal gammopathy of unclear significance (one); and hypocellular marrow, decreased megakaryocyte lineage associated with thrombocytopenia (one). Seven patients underwent liver biopsies, and six had abnormal liver pathology. These abnormalities did not affect listing for lung transplant, and liver biopsies are no longer routinely obtained. CONCLUSIONS Subclinical bone marrow and liver abnormalities can be seen in patients with ILD and short telomeres, in some cases in the absence of clinically significant abnormalities in peripheral blood counts and liver function tests. A larger study examining the implication of these findings on the outcome of patients with ILD and short telomeres is needed.

The association between mood, anxiety and adjustment disorders and hospitalization following lung transplantation ☆ ☆☆

OBJECTIVES Psychiatric comorbidities such as mood, anxiety and adjustment disorders are common among individuals seeking lung transplantation. The objective of this study is to describe the association between these disorders and length of initial hospitalization and number of hospitalizations in the first year following transplantation. METHODS This was a retrospective cohort study of all lung transplantation patients between January 1, 2008 and July 1, 2014 at a large academic center. We evaluated whether pretransplantation mood, anxiety or adjustment disorders were associated with length and number of hospitalizations after transplant, adjusting for age, sex, native disease, forced expiratory volume in 1 s prior to transplantation, wait list time and lung allocation score. RESULTS There were 185 patients who underwent transplantation during the 7.5-year study period of whom 125 (67.6%) had a mood, anxiety or adjustment disorder. Patients with an adjustment disorder had decreased length of initial hospitalization [B coefficient=-5.76; 95% confidence interval (CI)=-11.40 to -0.13; P=.04]. Patients with anxiety disorders had an increased number of hospitalizations in the first year following transplantation (rate ratio=1.41; 95% CI=1.06-1.88; P=.02). There was no association between mood disorders and length or number of hospitalizations. Mood, adjustment and anxiety disorders were not associated with time to initial rehospitalization. CONCLUSIONS Among the three most common pretransplantation psychiatric disorders, only anxiety disorders are associated with increased hospitalization in the first year following lung transplant. Interventions designed to better control pretransplantation and posttransplantation anxiety may be associated with less frequent hospitalization.

The Presence of Pretransplant HLA Antibodies Does Not Impact the Development of Chronic Lung Allograft Dysfunction or CLAD Related Death.

Background Development of donor-specific antibodies (DSA) after lung transplantation is associated with antibody mediated rejection, acute cellular rejection, and bronchiolitis obliterans syndrome; however, the significance of circulating antibodies before transplant remains unclear. Methods We performed a retrospective cohort study including recipients of primary lung transplants between 2008 and 2012. We assessed the impact of circulating HLA and noncytotoxic DSA detected before transplant on development of Chronic Lung Allograft Dysfunction (CLAD) or CLAD-related death. Results 30% of subjects had circulating class I antibodies alone, 4% Class II, and 14.4% class I and class II at mean fluorescent intensity greater than 1000. Nine percent of the subjects had DSA class I, 9% class II, and 2.4% both DSA classes 1 and 2. Neither the presence of circulating antibodies (adjusted hazard ratio, 0.87; 95% confidence interval, 0.50-1.54) nor the presence of DSA (adjusted hazard ratio, 1.56; 95% confidence interval, 0.77-3.18) before transplant at mean fluorescent intensity greater than 1000 was associated with the development of CLAD or CLAD-related death. Conclusions Although in previous studies we have shown an increased incidence of antibody-mediated rejection in patients with pretransplant DSA, neither the presence of HLA antibodies nor DSA translated to an increased risk of allograft dysfunction or death if prospective crossmatch testing was negative. Prospective studies are needed to define the impact of pretransplant sensitization on lung transplant recipients.

Aminocaproic acid for the management of bleeding in patients on extracorporeal membrane oxygenation: Four adult case reports and a review of the literature.

BACKGROUND Extracorporeal membrane oxygenation (ECMO) is associated with a significant risk of bleeding and thrombosis. Despite high rates of bleeding and bleeding-related mortality in patients on ECMO, there is little evidence available to guide clinicians in the management of ECMO-associated bleeding. METHODS We report the use of aminocaproic acid in four patients with bleeding on ECMO and a review of the literature. RESULTS High D-dimer levels and low fibrinogen levels suggested that an antifibrinolytic agent may be effective as an adjunct to control bleeding. After aminocaproic acid administration, bleeding was controlled in each patient as evidenced by clinical and laboratory parameters. One patient suffered a cardiac arrest and care was withdrawn. CONCLUSIONS In patients on ECMO with evidence of fibrinolysis, aminocaproic acid may be an effective option to control bleeding and to stabilize clot formation.