Daniel G. Tang

KCNE2 protein is expressed in ventricles of different species, and changes in its expression contribute to electrical remodeling in diseased hearts.

Background—Mutations in KCNE2 have been linked to long-QT syndrome (LQT6), yet KCNE2 protein expression in the ventricle and its functional role in native channels are not clear. Methods and Results—We detected KCNE2 protein in human, dog, and rat ventricles in Western blot experiments. Immunocytochemistry confirmed KCNE2 protein expression in ventricular myocytes. To explore the functional role of KCNE2, we studied how its expression was altered in 2 models of cardiac pathology and whether these alterations could help explain observed changes in the function of native channels, for which KCNE2 is a putative auxiliary (β) subunit. In canine ventricle injured by coronary microembolizations, the rapid delayed rectifier current (IKr) density was increased. Although the protein level of ERG (IKr pore-forming, &agr;, subunit) was not altered, the KCNE2 protein level was markedly reduced. These data are consistent with the effect of heterologously expressed KCNE2 on ERG and suggest that in canine ventricle, KCNE2 may associate with ERG and suppress its current amplitude. In aging rat ventricle, the pacemaker current (If) density was increased. There was a significant increase in the KCNE2 protein level, whereas changes in the &agr;-subunit (HCN2) were not significant. These data are consistent with the effect of heterologously expressed KCNE2 on HCN2 and suggest that in aging rat ventricle, KCNE2 may associate with HCN2 and enhance its current amplitude. Conclusions—KCNE2 protein is expressed in ventricles, and it can play diverse roles in ventricular electrical activity under (patho)physiological conditions.

Exercise blood pressure response during assisted circulatory support: Comparison of the total artifical heart with a left ventricular assist device during rehabilitation

BACKGROUND The total artificial heart (TAH) consists of two implantable pneumatic pumps that replace the heart and operate at a fixed ejection rate and ejection pressure. We evaluated the blood pressure (BP) response to exercise and exercise performance in patients with a TAH compared to those with a with a continuous-flow left ventricular assist device (LVAD). METHODS We conducted a single-center, retrospective study of 37 patients who received a TAH and 12 patients implanted with an LVAD. We measured the BP response during exercise, exercise duration and change in tolerated exercise workload over an 8-week period. RESULTS In patients with a TAH, baseline BP was 120/69 ± 13/13, exercise BP was 118/72 ± 15/10 and post-exercise BP was 120/72 ± 14/12. Mean arterial BP did not change with exercise in patients with a TAH (88 ± 10 vs 88 ± 11; p = 0.8), but increased in those with an LVAD (87 ± 8 vs 95 ± 13; p < 0.001). Although the mean arterial BP (MAP) was negatively correlated with metabolic equivalents (METs) achieved during exercise, the association was not statistically significant (β = -0.1, p = 0.4). MAP correlated positively with METs achieved in patients with LVADs (MAP: β = 0.26, p = 0.04). Despite the abnormal response to exercise, patients with a TAH participated in physical therapy (median: 5 days; interquartile range [IQR] 4 to 7 days) and treadmill exercise (19 days; IQR: 13 to 35 days) early after device implantation, with increased exercise intensity and duration over time. CONCLUSIONS During circulatory support with a TAH, the BP response to exercise was blunted. However, aerobic exercise training early after device implantation was found to be safe and feasible in a supervised setting.

Implantable Mechanical Circulatory Support: Demystifying Patients With Ventricular Assist Devices and Artificial Hearts

Engineering advancements have expanded the role for mechanical circulatory support devices in the patient with heart failure. More patients with mechanical circulatory support are being discharged from the implanting institution and will be seen by clinicians outside the immediate surgical or heart‐failure team. This review provides a practical understanding of device design and physiology, general troubleshooting, and limitations and complications for implantable left ventricular assist devices (pulsatile‐flow and continuous‐flow pumps) and the total artificial heart.

Impact of low-dose B-type natriuretic peptide infusion on urine output after total artificial heart implantation.

The total artificial heart (TAH) orthotopically replaces a recipient’s native ventricles and all four cardiac valves, interrupting neural and hormonal signaling pathways that are dependent upon the intact ventricular myocardium. Btype natriuretic peptide (BNP) is a cardiac neurohormone primarily secreted from ventricular cardiomyocytes in response to cardiac stretch. In healthy individuals, BNP decreases vascular tone, increases renal blood flow, promotes natriuresis and suppresses the renin–aldosterone axis. The influence of nesiritide (exogenous BNP) on renal function after ventriculectomy and removal of endogenous of BNP is poorly understood and we and others have observed that renal function declines after placement of the total artificial heart. We hypothesized that infusion of exogenous BNP after ventriculectomy would improve renal function as marked by an increase in urine output. We screened 8 consecutive patients who received the TAH (December 2010 to May 2011) with the intention of bridge to heart transplantation. To remove the confounding influence of calcineurin inhibitor exposure on renal function, 3 patients who had devices implanted for retransplantation were not included in the study. All patients met criteria for infusion of nesiritide ( 50% decrease in the estimated glomerular filtration rate [eGFR] or urine output 30 ml/h) based on their evolved oliguria pattern

Surveillance Endomyocardial Biopsy in the Modern Era Produces Low Diagnostic Yield for Cardiac Allograft Rejection.

Background The changing epidemiology of cardiac allograft rejection has prompted many to question the yield of surveillance endomyocardial biopsy (EMB) in heart transplantation (HT) patients. We sought to determine the yield of EMB in the modern era. Methods We evaluated 2597 EMBs in 182 consecutive HT patients who survived to their first EMB. The EMBs were categorized as asymptomatic or clinically driven and were compared based on era of antiproliferative therapy use at our center (early azathioprine era: 1990–2000 vs modern mycophenolate era: 2000–2011). Results In the modern era, patients had a higher prevalence of risk factors for developing rejection (≥ International Society of Heart and Lung Transplantation grade 2R); however, the frequency of rejection was decreased at all times (0–6 months: 60.2% vs 21.5%, P < 0.001, 6–12 months: 26.8% vs 1.8%, P < 0.001, 12–36 months: 32.3% vs 10.5%, P = 0.006). The yield of asymptomatic EMB decreased in the modern era between 0 and 6 months (10.9% vs 3.12%), 6 to 12 months (17% vs 0%), and years 2 to 3 (6.1% vs 1.5%). In the early era, the odds ratio of rejection during asymptomatic EMB compared to a clinically driven EMB was 0.47 (95% confidence interval, 0.31–0.71) and was decreased in the modern era (0.17 [0.07–0.42], P = 0.04). The probability of detecting rejection on asymptomatic EMB was significantly reduced in the modern era, even after adjustment for tacrolimus and induction therapy (1% vs 8%, P < 0.001). Conclusions The clinical yield of surveillance EMB has decreased in the modern era. The EMB in asymptomatic patients longer than 6 months after HT warrants further scrutiny.

Warm ischemia lung protection with pinacidil: an ATP regulated potassium channel opener.

BACKGROUND Ischemia/reperfusion injury remains a limiting factor in lung transplantation. Traditional hyperkalemic preservation solutions are associated with a host of metabolic derangements. ATP-regulated potassium channel openers (PCOs) may provide an attractive alternative to traditional solutions by utilizing inherent mechanisms of ischemic preconditioning. The purpose of this study was to assess warm ischemia graft protection with pinacidil, a nonspecific PCO. METHODS An isolated recirculating blood perfused ventilated rabbit lung model was used (n = 15). No ischemia control lungs underwent immediate reperfusion (n = 5). Warm ischemia control lungs were flushed with lactated Ringers (LR), stored at 37 degrees C for 2.5 hours and then reperfused for 2 hours (n = 5). PCO protected lungs were flushed with LR + 100 micromol/L pinacidil, stored, and then reperfused (n = 5). Intermittent blood gases were taken from the pulmonary artery and left atria. Every 30 minutes, graft function was assessed with a 10-minute 100% fractional inspired oxygen concentration challenge to measure maximal gas exchange. Lung samples were graded for histologic injury and assayed for myeloperoxidase activity. RESULTS A mixed-models repeated measures ANOVA demonstrated a significant difference between groups. Tukeys honestly significant difference multiple comparison test demonstrated significantly improved graft function and reduced histologic injury with pinacidil protection compared with the warm ischemia controls. There was no significant difference in graft function or pathology grade between the pinacidil protected lungs and the no ischemia controls. A similar trend, although not significant, was seen in myeloperoxdiase activity. CONCLUSIONS Potassium channel openers with pinacidil can provide pulmonary protection against warm ischemia reperfusion injury.

Impact of INTERMACS Profile on Clinical Outcomes for Patients Supported With the Total Artificial Heart

BACKGROUND Insufficient data delineate outcomes for Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) profile 1 patients with the total artificial heart (TAH). METHODS We studied 66 consecutive patients implanted with the TAH at our institution from 2006 through 2012 and compared outcome by INTERMACS profile. INTERMACS profiles were adjudicated retrospectively by a reviewer blinded to clinical outcomes. RESULTS Survival after TAH implantation at 6 and 12 months was 76% and 71%, respectively. INTERMACS profile 1 patients had decreased 6-month survival on the device compared with those in profiles 2-4 (74% vs 95%, log rank: P = .015). For the 50 patients surviving to heart transplantation, the 1-year posttransplant survival was 82%. There was no difference in 1-year survival when comparing patients in the INTERMACS 1 profile with less severe profiles (79% vs 84%; log rank test P = .7; hazard ratio [confidence interval] 1.3 [0.3-4.8]). CONCLUSIONS Patients implanted with the TAH as INTERMACS profile 1 had reduced survival to transplantation compared with less sick profiles. INTERMACS profile at the time of TAH implantation did not affect 1-year survival after heart transplantation.

Fracture of the total artificial heart pneumatic driveline after transition to the portable driver

The CardioWest (SynCardia Systems Inc, Tucson, AZ) total artificial heart (TAH) consists of polyurethane ventricles with pneumatically driven diaphragms and 4 mechanical tilting disk valves that replace the entire heart. A polyvinyl chloride wire–reinforced pneumatic conduit (permanent driveline) attaches to each pump. The drivelines are tunneled through the left rectus muscle to the left upper quadrant and are covered with velour to promote tissue ingrowth. The permanent drivelines are attached via connecters to longer tubing that attaches to the pneumatic driver and is replaceable. Although rehabilitation and mobility are feasible with the TAH, implantation of the device until recently required patients to remain tethered to a 418-pound inpatient driver until a heart transplant donor became available. With the introduction the TAH portable Freedom Driver (SynCardia Systems), which has not yet been approved by the Food and Drug Administration, patients may look forward to increased mobility and potential discharge from the hospital. Although improving patient quality of life, increased patient mobility could increase stress and torque

Mechanical Circulatory Support Devices in the ICU

The medical community has used implantable mechanical circulatory support devices at increasing rates for patients dying from heart failure and cardiogenic shock. Newer-generation devices offer a more durable and compact option when compared with bulky early-generation devices. This article is a succinct introduction and overview of the hemodynamic principles and complications after device implantation for ICU clinicians. We review the concepts of device physiology, clinical pearls for perioperative management, and common medical complications after device implantation.

Infections in Patients with a Total Artificial Heart Are Common but Rarely Fatal

Patients who received a total artificial heart (TAH) at Virginia Commonwealth University (VCU) between January 1, 2010 and December 31, 2011 were identified from the VCU Mechanical Circulatory Support Clinical Database. Retrospective data extraction from the medical records was performed from the time of TAH implantation until heart transplantation or death. Infections were classified as confirmed or suspected. Twenty-seven men and five women, mean age 49.5 years (range 24–68 years) received a TAH. The mean duration of TAH support was 225 days (range 1–1,334 days). Of the 32 patients, 4 (12.5%) died and 28 (87.5 %) underwent heart transplantation. Causes of death were pneumonia (n = 1), TAH malfunction (n = 1), refractory cardiogenic shock (n = 1), and respiratory failure (n = 1). Seventy documented and 13 suspected infections developed in 25 patients (78%). The most common sources of infection were urinary tract (n = 26), respiratory tract (n = 18), and bloodstream (n = 11). There were five pump infections and two driveline infections. The number of infections per patient ranged from 0 to 10. Sixteen different pathogens were identified; the most common were: Klebsiella pneumoniae (n = 15), coagulase-negative Staphylococci (n = 10), Enterococcus species (n = 9), and Enterobacter species (n = 8). Mortality directly attributable to infection was infrequent.