C.W. White

Short-term mechanical circulatory support for recovery from acute right ventricular failure: Clinical outcomes

BACKGROUND Acute right ventricular failure (ARVF) refractory to optimal medical management may require rescue therapy with mechanical circulatory support (MCS). The RV exhibits a greater capacity for rapid recovery than the left ventricle, making devices designed specifically for temporary RV MCS attractive. We report our experience with the Impella Right Direct (RD) and Right Peripheral (RP) temporary ventricular assist devices (Abiomed, Danvers, MA) in patients with ARVF. METHODS We conducted a retrospective cohort study examining the clinical outcomes of consecutive patients supported with the Impella RD or RP at 2 institutions during a 6-year period. RESULTS During the study period, 18 patients (67% men; mean age 57 ± 10 years) received MCS, 15 with the Impella RD and 3 with the Impella RP. Before RV MCS, all patients required intravenous inotropes, 7 (39%) required inhaled nitric oxide, 7 (39%) required intra-aortic balloon counterpulsation, and 2 (11%) had experienced a cardiac arrest. Device implantation resulted in an improvement in cardiac index (2.1 ± 0.1 liters/min/m(2) pre-implant vs 2.6 ± 0.2 liters/min/m(2) post-implant, p = 0.04) and reduced central venous pressure (22 ± 5 vs 15 ± 4 mm Hg, p < 0.01). Fourteen (78%) patients recovered sufficient RV function to facilitate device explanation after 7 days (range, 2-19 days) of support, and 4 (22%) patients died on support after 6 days (range 1-11 days). Survival to 30 days was 72% and to 1 year was 50%. At 1-year follow-up, the mean New York Heart Association functional classification was 1.3 ± 0.5, and only 1 patient demonstrated severe RV dysfunction on echocardiography. CONCLUSIONS Most patients with ARVF rapidly recover sufficient RV function to facilitate device explantation, highlighting an expanding role for minimally invasive temporary RV assist devices optimized for the treatment of recoverable ARVF.

A cardioprotective preservation strategy employing ex vivo heart perfusion facilitates successful transplant of donor hearts after cardiocirculatory death

BACKGROUND Ex vivo heart perfusion (EVHP) has been proposed as a means to facilitate the resuscitation of donor hearts after cardiocirculatory death (DCD) and increase the donor pool. However, the current approach to clinical EVHP may exacerbate myocardial injury and impair function after transplant. Therefore, we sought to determine if a cardioprotective EVHP strategy that eliminates myocardial exposure to hypothermic hyperkalemia cardioplegia and minimizes cold ischemia could facilitate successful DCD heart transplantation. METHODS Anesthetized pigs sustained a hypoxic cardiac arrest and a 15-minute warm ischemic standoff period. Strategy 1 hearts (S1, n = 9) underwent initial reperfusion with a cold hyperkalemic cardioplegia, normothermic EVHP, and transplantation after a cold hyperkalemic cardioplegic arrest (current EVHP strategy). Strategy 2 hearts (S2, n = 8) underwent initial reperfusion with a tepid adenosine-lidocaine cardioplegia, normothermic EVHP, and transplantation with continuous myocardial perfusion (cardioprotective EVHP strategy). RESULTS At completion of EVHP, S2 hearts exhibited less weight gain (9.7 ± 6.7 [S2] vs 21.2 ± 6.7 [S1] g/hour, p = 0.008) and less troponin-I release into the coronary sinus effluent (4.2 ± 1.3 [S2] vs 6.3 ± 1.5 [S1] ng/ml; p = 0.014). Mass spectrometry analysis of oxidized pleural in post-transplant myocardium revealed less oxidative stress in S2 hearts. At 30 minutes after wean from cardiopulmonary bypass, post-transplant systolic (pre-load recruitable stroke work: 33.5 ± 1.3 [S2] vs 19.7 ± 10.9 [S1], p = 0.043) and diastolic (isovolumic relaxation constant: 42.9 ± 6.7 [S2] vs 65.2 ± 21.1 [S1], p = 0.020) function were superior in S2 hearts. CONCLUSION In this experimental model of DCD, an EVHP strategy using initial reperfusion with a tepid adenosine-lidocaine cardioplegia and continuous myocardial perfusion minimizes myocardial injury and improves short-term post-transplant function compared with the current EVHP strategy using cold hyperkalemic cardioplegia before organ procurement and transplantation.

The utility of cardiac biomarkers and echocardiography for the early detection of bevacizumab- and sunitinib-mediated cardiotoxicity

The recent introduction of novel anticancer therapies, including bevacizumab (BVZ) and sunitinib (SNT), is associated with an increased risk of cardiotoxicity. However, early identification of left ventricular (LV) systolic dysfunction may facilitate dose modification and avoid the development of advanced heart failure. Using a murine model of BVZ- and SNT-mediated cardiotoxicity, we investigated whether cardiac biomarkers and/or tissue velocity imaging (TVI) using echocardiography can detect early changes in cardiac function, before a decrease in LV ejection fraction is identified. A total of 75 wild-type C57Bl/6 male mice were treated with either 0.9% saline, BVZ, or SNT. Serial monitoring of blood pressure, high-sensitivity troponin I, and echocardiographic indexes were performed over a 14-day study period, after which the mice were euthanized for histological and biochemical analyses. Mice treated with either BVZ or SNT developed systemic hypertension as early as day 7, which increased by day 14. Cardiac biomarkers, specifically high-sensitivity troponin I, were not predictive of early LV systolic dysfunction. Although conventional LV ejection fraction values decreased at day 13 in mice treated with either BVZ or SNT, TVI confirmed early LV systolic dysfunction at day 8. Histological and biochemical analysis demonstrated loss of cellular integrity, increased oxidative stress, and increased cardiac apoptosis in mice treated with BVZ or SNT therapy at day 14. In a murine model of BVZ- or SNT-mediated cardiomyopathy, noninvasive assessment by TVI detected early LV systolic dysfunction before alterations in conventional echocardiographic indexes.

Inhibition of pyruvate dehydrogenase kinase improves pulmonary arterial hypertension in genetically susceptible patients

Metabolic modulation with dichloroacetate improves hemodynamics in genetically susceptible patients with idiopathic pulmonary arterial hypertension. Progress for PAH In addition to thickening and occlusion of the pulmonary arteries, mitochondrial respiration is suppressed in pulmonary arterial hypertension (PAH). Michelakis et al. treated lungs from patients with PAH with dichloroacetate (DCA), a drug used to treat cancer and congenital mitochondrial disease that inhibits the mitochondrial enzyme pyruvate dehydrogenase kinase. DCA increased mitochondrial function; however, the response was variable, and this variable response was mirrored in a phase 1 trial, with some patients showing improved hemodynamics and functional capacity. The authors determined that patients with inactivating mutations in two genes encoding mitochondrial proteins were less responsive to DCA. This work highlights the importance of considering patient genotype in clinical trial design and identifies a drug target for PAH. Pulmonary arterial hypertension (PAH) is a progressive vascular disease with a high mortality rate. It is characterized by an occlusive vascular remodeling due to a pro-proliferative and antiapoptotic environment in the wall of resistance pulmonary arteries (PAs). Proliferating cells exhibit a cancer-like metabolic switch where mitochondrial glucose oxidation is suppressed, whereas glycolysis is up-regulated as the major source of adenosine triphosphate production. This multifactorial mitochondrial suppression leads to inhibition of apoptosis and downstream signaling promoting proliferation. We report an increase in pyruvate dehydrogenase kinase (PDK), an inhibitor of the mitochondrial enzyme pyruvate dehydrogenase (PDH, the gatekeeping enzyme of glucose oxidation) in the PAs of human PAH compared to healthy lungs. Treatment of explanted human PAH lungs with the PDK inhibitor dichloroacetate (DCA) ex vivo activated PDH and increased mitochondrial respiration. In a 4-month, open-label study, DCA (3 to 6.25 mg/kg b.i.d.) administered to patients with idiopathic PAH (iPAH) already on approved iPAH therapies led to reduction in mean PA pressure and pulmonary vascular resistance and improvement in functional capacity, but with a range of individual responses. Lack of ex vivo and clinical response was associated with the presence of functional variants of SIRT3 and UCP2 that predict reduced protein function. Impaired function of these proteins causes PDK-independent mitochondrial suppression and pulmonary hypertension in mice. This first-in-human trial of a mitochondria-targeting drug in iPAH demonstrates that PDK is a druggable target and offers hemodynamic improvement in genetically susceptible patients, paving the way for novel precision medicine approaches in this disease.

A whole blood–based perfusate provides superior preservation of myocardial function during ex vivo heart perfusion

BACKGROUND Ex vivo heart perfusion (EVHP) provides the opportunity to resuscitate unused donor organs and facilitates assessments of myocardial function that are required to demonstrate organ viability before transplantation. We sought to evaluate the effect of different oxygen carriers on the preservation of myocardial function during EVHP. METHODS Twenty-seven pig hearts were perfused ex vivo in a normothermic beating state for 6 hours and transitioned into working mode for assessments after 1 (T1), 3 (T3), and 5 (T5) hours. Hearts were allocated to 4 groups according to the perfusate composition. Red blood cell concentrate (RBC, n = 6), whole blood (RBC+Plasma, n = 6), an acellular hemoglobin-based oxygen carrier (HBOC, n = 8), or HBOC plus plasma (HBOC+Plasma, n = 7) were added to STEEN Solution (XVIVO Perfusion, Goteborg, Sweden) to achieve a perfusate hemoglobin concentration of 40 g/liter. RESULTS The perfusate composition affected the preservation of systolic (T5 dP/dtmax: RBC+Plasma = 903 ± 99, RBC = 771 ± 77, HBOC+Plasma = 691 ± 82, HBOC = 563 ± 52 mm Hg/sec; p = 0.047) and diastolic (T5 dP/dtmin: RBC+Plasma = -574 ± 48, RBC = -492 ± 63, HBOC+Plasma = -326 ± 32, HBOC = -268 ± 22 mm Hg/sec; p < 0.001) function, and the development of myocardial edema (weight gain: RBC+Plasma = 6.6 ± 0.9, RBC = 6.6 ± 1.2, HBOC+Plasma = 9.8 ± 1.7, HBOC = 16.3 ± 1.9 g/hour; p < 0.001) during EVHP. RBC+Plasma hearts exhibited less histologic evidence of myocyte damage (injury score: RBC+Plasma = 0.0 ± 0.0, RBC = 0.8 ± 0.3, HBOC+Plasma = 2.6 ± 0.2, HBOC = 1.75 ± 0.4; p < 0.001) and less troponin-I release (troponin-I fold-change T1-T5: RBC+Plasma = 7.0 ± 1.7, RBC = 13.1 ± 1.6, HBOC+Plasma = 20.5 ± 1.1, HBOC = 16.7 ± 5.8; p < 0.001). Oxidative stress was minimized by the addition of plasma to RBC and HBOC hearts (oxidized phosphatidylcholine compound fold-change T1-T5: RBC+Plasma = 1.83 ± 0.20 vs RBC = 2.31 ± 0.20, p < 0.001; HBOC+Plasma = 1.23 ± 0.17 vs HBOC = 2.80 ± 0.28, p < 0.001). CONCLUSIONS A whole blood-based perfusate (RBC+Plasma) minimizes injury and provides superior preservation of myocardial function during EVHP. The beneficial effect of plasma on the preservation of myocardial function requires further investigation.

Physiologic Changes in the Heart Following Cessation of Mechanical Ventilation in a Porcine Model of Donation After Circulatory Death: Implications for Cardiac Transplantation.

Hearts donated following circulatory death (DCD) may represent an additional source of organs for transplantation; however, the impact of donor extubation on the DCD heart has not been well characterized. We sought to describe the physiologic changes that occur following withdrawal of life‐sustaining therapy (WLST) in a porcine model of DCD. Physiologic changes were monitored continuously for 20 min following WLST. Ventricular pressure, volume, and function were recorded using a conductance catheter placed into the right (N = 8) and left (N = 8) ventricles, and using magnetic resonance imaging (MRI, N = 3). Hypoxic pulmonary vasoconstriction occurred following WLST, and was associated with distension of the right ventricle (RV) and reduced cardiac output. A 120‐fold increase in epinephrine was subsequently observed that produced a transient hyperdynamic phase; however, progressive RV distension developed during this time. Circulatory arrest occurred 7.6±0.3 min following WLST, at which time MRI demonstrated an 18±7% increase in RV volume and a 12±9% decrease in left ventricular volume compared to baseline. We conclude that hypoxic pulmonary vasoconstriction and a profound catecholamine surge occur following WLST that result in distension of the RV. These changes have important implications on the resuscitation, preservation, and evaluation of DCD hearts prior to transplantation.

Avoidance of Profound Hypothermia During Initial Reperfusion Improves the Functional Recovery of Hearts Donated After Circulatory Death

The resuscitation of hearts donated after circulatory death (DCD) is gaining widespread interest; however, the method of initial reperfusion (IR) that optimizes functional recovery has not been elucidated. We sought to determine the impact of IR temperature on the recovery of myocardial function during ex vivo heart perfusion (EVHP). Eighteen pigs were anesthetized, mechanical ventilation was discontinued, and cardiac arrest ensued. A 15‐min standoff period was observed and then hearts were reperfused for 3 min at three different temperatures (5°C; N = 6, 25°C; N = 5, and 35°C; N = 7) with a normokalemic adenosine–lidocaine crystalloid cardioplegia. Hearts then underwent normothermic EVHP for 6 h during which time myocardial function was assessed in a working mode. We found that IR coronary blood flow differed among treatment groups (5°C = 483 ± 53, 25°C = 722 ± 60, 35°C = 906 ± 36 mL/min, p < 0.01). During subsequent EVHP, less myocardial injury (troponin I: 5°C = 91 ± 6, 25°C = 64 ± 16, 35°C = 57 ± 7 pg/mL/g, p = 0.04) and greater preservation of endothelial cell integrity (electron microscopy injury score: 5°C = 3.2 ± 0.5, 25°C = 1.8 ± 0.2, 35°C = 1.7 ± 0.3, p = 0.01) were evident in hearts initially reperfused at warmer temperatures. IR under profoundly hypothermic conditions impaired the recovery of myocardial function (cardiac index: 5°C = 3.9 ± 0.8, 25°C = 6.2 ± 0.4, 35°C = 6.5 ± 0.6 mL/minute/g, p = 0.03) during EVHP. We conclude that the avoidance of profound hypothermia during IR minimizes injury and improves the functional recovery of DCD hearts.

Vocal Cord Paralysis After Thoracic Aortic Surgery: Incidence and Impact on Clinical Outcomes

BACKGROUND Vocal cord paralysis (VCP) is a serious complication associated with thoracic aortic surgery; however, there is a paucity of literature regarding the incidence and impact of VCP on postoperative outcomes. We sought to determine the incidence of VCP and its impact on clinical outcomes in patients who underwent thoracic aortic repair at our center. METHODS A retrospective chart review was conducted on all patients who underwent thoracic aortic surgery between January 2009 and September 2012. RESULTS A total of 259 patients underwent a thoracic aortic procedure during the study period. Vocal cord paralysis was diagnosed in 12 (5%) patients, a median of 6 [3 to 21] days after extubation. The incidence was 1%, 0%, 20%, and 25% in those undergoing an open ascending, hemiarch, total arch, or descending aortic procedure, respectively. Patients with VCP had an increased incidence of pneumonia (58% vs 17%, p = 0.003), readmission to the intensive care unit for respiratory failure (17% vs 2%, p = 0.047), and longer hospital length of stay (18 [11 to 43] days versus 9 [6 to 15] days, p = 0.002). A propensity-matched analysis confirmed a higher incidence of pneumonia (58% vs 17%, p = 0.020) and longer hospital length of stay (18 [11 to 43] vs 10 [7 to 14] days, p = 0.015) in patients suffering VCP. CONCLUSIONS Vocal cord paralysis is a common complication in patients undergoing open surgery of the aortic arch and descending aorta, and is associated with significant morbidity. Further research may be warranted to determine if early fiberoptic examination and consideration of a vocal cord medialization procedure may mitigate the morbidity associated with VCP.

Dual antiplatelet therapy use by Canadian cardiac surgeons.

BACKGROUND Dual antiplatelet therapy is the cornerstone treatment for patients with acute coronary syndrome. Recent Canadian Guidelines recommend the use of dual antiplatelet therapy for 1 year after coronary artery bypass grafting in patients with acute coronary syndrome, but considerable variability remains. METHODS We performed a survey of 75 Canadian cardiac surgeons to assess the use of dual antiplatelet therapy. RESULTS Whereas 58.6% of respondents indicated that the benefits of dual antiplatelet therapy were seen irrespective of how patients were managed after acute coronary syndrome, 36.2% believed that the benefits of dual antiplatelet therapy were limited to those treated medically or percutaneously. In regard to the timing of dual antiplatelet therapy administration, 57% of respondents indicated that dual antiplatelet therapy should be given upstream in the emergency department, whereas 36.2% responded that dual antiplatelet therapy should be given only once the coronary anatomy has been defined. The majority surveyed (81%) weighed bleeding risk as being more important than ischemic risk reduction. In stable patients after acute coronary syndrome, the majority of surgeons would wait approximately 4 days after the last dose of P2Y12 antagonist before coronary artery bypass grafting. Only 44.6% indicated that they routinely use dual antiplatelet therapy postrevascularization in the setting of acute coronary syndrome. Rather, most surgeons use dual antiplatelet therapy for select patients, such as those with a stented vessel without a bypass graft, endarterectomy, or off-pump coronary artery bypass grafting. CONCLUSIONS Cardiac surgeons exhibit variation in their attitudes and practice patterns toward dual antiplatelet therapy after coronary artery bypass grafting, and in approximately half of cases, their practice does not adhere to current guideline recommendations. New trials focusing on coronary artery bypass grafting cases in their primary analysis and educational initiatives for surgeons that focus on guideline recommendations may be warranted.

Functional Mitral Regurgitation: Current Understanding and Approach to Management

Functional mitral regurgitation (FMR) is a challenging clinical entity that frequently complicates ischemic and nonischemic cardiomyopathy. The underlying pathophysiology of FMR is caused primarily by ventricular and subvalvular apparatus dysfunction which causes failure of proper leaflet coaptation. Echocardiography is the primary modality used in diagnosis and characterization of FMR. Echocardiography allows for assessment of valvular and ventricular structures and their interaction. FMR portends a poor prognosis, because it is frequently associated with increased morbidity and mortality. The optimal management of FMR involves an individualized approach that incorporates medical therapy and consideration of surgical, percutaneous, and resynchronization therapies according to the severity of regurgitation, presence of symptoms, option for revascularization, and the degree of ventricular remodelling.