Matthew A. Romano

The Development of Aortic Insufficiency in Left Ventricular Assist Device-Supported PatientsClinical Perspective

Background—Aortic insufficiency (AI) following left ventricular assist device (LVAD) placement can affect device performance. The aim of this study was to examine AI development following LVAD implantation. Methods and Results—Echocardiograms (n=315) from 78 subjects undergoing HeartMate-XVE (n=25 [32%]) or HeartMate-II (n=53 [68%]) implantations from 2004 to 2008 were reviewed. Studies were obtained preoperatively and at 1, 3, 6, 12, 18, and 24 months after surgery. AI was graded on an interval scale (0=none, 0.5=trivial, 1=mild, 1.5=mild-moderate, 2=moderate, 2.5=moderate-severe, 3=severe), and the change in AI at follow-up was analyzed with significance tests. Kaplan–Meier estimates for freedom from moderate or worse AI at follow-up were generated. Mixed-model linear regression was used to identify correlates of AI progression during LVAD support. The median (25th, 75th percentile) duration of LVAD support was 239 (112, 455) days, and preoperative AI grade was 0.0 (0.0, 0.0). At 6 months, 89±4% of subjects (n=49 at risk) were free from moderate or worse AI, but this was reduced to 74±7% (n=29 at risk) and 49±13% (n=13 at risk) by 12 and 18 months, respectively. Correlates (slope±SE) of AI progression included female sex (0.002±0.001; P=0.01), smaller body surface area (−0.003±0.001 per m2; P=0.0017), and HeartMate-II model type (0.002±0.001; P=0.039). Correlates (&bgr;±SE) of progressive AI on postoperative echocardiogram included increasing aortic sinus diameter (0.04±0.01 per mm; P=0.001), an aortic valve that remained closed (0.42±0.06; P<0.001) or only intermittently opened (0.34±0.09; P<0.001), and lower left ventricular diastolic (−0.002±0.0004 per cm3; P<0.001) and systolic (−0.002±0.0004 per cm3; P<0.001) volumes. Conclusions—AI progresses over time in LVAD-supported patients. As we move toward an era of long-term cardiac support, more studies are needed to determine the clinical significance of these findings.

The Development of Aortic Insufficiency in Left Ventricular Assist Device-Supported Patients

Background—Aortic insufficiency (AI) following left ventricular assist device (LVAD) placement can affect device performance. The aim of this study was to examine AI development following LVAD implantation. Methods and Results—Echocardiograms (n=315) from 78 subjects undergoing HeartMate-XVE (n=25 [32%]) or HeartMate-II (n=53 [68%]) implantations from 2004 to 2008 were reviewed. Studies were obtained preoperatively and at 1, 3, 6, 12, 18, and 24 months after surgery. AI was graded on an interval scale (0=none, 0.5=trivial, 1=mild, 1.5=mild-moderate, 2=moderate, 2.5=moderate-severe, 3=severe), and the change in AI at follow-up was analyzed with significance tests. Kaplan–Meier estimates for freedom from moderate or worse AI at follow-up were generated. Mixed-model linear regression was used to identify correlates of AI progression during LVAD support. The median (25th, 75th percentile) duration of LVAD support was 239 (112, 455) days, and preoperative AI grade was 0.0 (0.0, 0.0). At 6 months, 89±4% of subjects (n=49 at risk) were free from moderate or worse AI, but this was reduced to 74±7% (n=29 at risk) and 49±13% (n=13 at risk) by 12 and 18 months, respectively. Correlates (slope±SE) of AI progression included female sex (0.002±0.001; P=0.01), smaller body surface area (−0.003±0.001 per m2; P=0.0017), and HeartMate-II model type (0.002±0.001; P=0.039). Correlates (&bgr;±SE) of progressive AI on postoperative echocardiogram included increasing aortic sinus diameter (0.04±0.01 per mm; P=0.001), an aortic valve that remained closed (0.42±0.06; P<0.001) or only intermittently opened (0.34±0.09; P<0.001), and lower left ventricular diastolic (−0.002±0.0004 per cm3; P<0.001) and systolic (−0.002±0.0004 per cm3; P<0.001) volumes. Conclusions—AI progresses over time in LVAD-supported patients. As we move toward an era of long-term cardiac support, more studies are needed to determine the clinical significance of these findings.

Hemolysis: A harbinger of adverse outcome after left ventricular assist device implant

BACKGROUND The clinical relevance of elevated serum markers of hemolysis during left ventricular assist device (LVAD) support has not been fully ascertained. METHODS Lactate dehydrogenase (LDH) and serum free hemoglobin (sfHg) values were tallied monthly in 182 patients on HeartMate II (Thoratec, Pleasanton, CA) LVAD support. Peak values for each marker were identified, and 2 hemolysis definitions were applied to the cohort: Hemolysis according to Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) criteria (sfHg > 40 mg/dl with signs/symptoms) and/or hemolysis defined by an LDH ≥ 600 IU/liter (2.5-times the upper limit of laboratory normal). Kaplan-Meier survival free from death, urgent United Network of Organ Sharing 1A transplant for thrombosis, device exchange for thrombosis, and stroke/peripheral embolism was estimated, and Cox hazard ratios (HR) with the 95% confidence interval (95% CI) were calculated. Areas under the receiver-operating characteristic curves (AUCs) for predicting 1-year event-free survival were calculated. RESULTS Hemolysis occurred in 32 patients (18%) by INTERMACS criteria and in 68 (37%) patients by LDH criteria. Over a median (25(th), 75(th)) support of 427 days (245, 793 days), there were 78 events. One year event-free survival after the onset of INTERMACS-defined hemolysis was 16% ± 8.3% compared with 85% ± 3.2% in non-hemolyzers (HR, 14.7; 95% CI, 7.9-27; AUC 0.70 ± 0.05; p < 0.001; ). One year event-free survival after the onset of LDH-defined hemolysis was 32% ± 7.2% compared with 89% ± 3.2% in those with persistent LDH values < 600 IU/liter (HR, 8.0; 95% CI, 4.4-14; AUC 0.87 ± 0.04; p < 0.001). Patients who met the LDH hemolysis definition had longer times from hemolysis onset to clinical events and larger magnitudes of risk for embolism and device exchange for thrombosis than those with INTERMACS hemolysis. CONCLUSIONS Serum hemolysis marker elevations are associated with increased events in LVAD patients. LDH monitoring provides an earlier diagnosis of adverse events than sfHg, supporting need for a new INTERMACS definition of VAD-associated hemolysis.

Gastrointestinal bleeding and subsequent risk of thromboembolic events during support with a left ventricular assist device

BACKGROUND Modern left ventricular assist devices (LVAD) require anti-coagulation (AC) with warfarin and anti-platelet therapy to prevent thromboembolic complications in patients. Gastrointestinal bleeding (GI) is a significant adverse event in these patients and treatment typically requires reduction or elimination of AC or anti-platelet therapy. It is not known whether alterations in AC to treat GI bleeding influence subsequent risk of thromboembolic (TE) events during LVAD support. METHODS Between July 2003 and September 2011, 389 patients (308 male) underwent implantation of a continuous-flow LVAD at the University of Michigan Health System and the Mayo Clinic. Median age at implant was 60 years (range 18 to 79 years). Outcomes were analyzed for the association of GI bleeding events and subsequent TE events, defined as stroke, transient ischemic attack, hemolysis or suspected or confirmed pump thrombosis. RESULTS Median survival was 10 months (maximum 7.2 years, total 439 patient-years). TE events occurring within the first 30 days were not counted. Overall survival and freedom from an outcome event were assessed using the Kaplan-Meier method. Associations between GI bleeding and subsequent TE events and survival impact were analyzed as time-dependent covariates. One hundred ninety-nine GI bleeding episodes occurred in 116 of 389 patients (30%) for an event rate of 0.45 GI bleed/patient-year of support. One hundred thirty-eight TE events occurred in 97 of 389 patients (25%) for an event rate of 0.31 TE event/patient-year of support. Median time from LVAD implant to first GI bleed was 5 months (range 1 to 116 months) and to first TE event was 6 months (range 1 to 29 months). For patients who had a TE event after GI bleed, the median interval was 5 months (range 0.5 to 25 months). TE events were 7.4-fold more likely in patients who had a prior GI bleed (range 4.9- to 11.1-fold) (p < 0.001); however, neither the presence of GI bleeding (0.7 to 1.2) nor a TE event (0.8 to 2.0) portended a lower overall survival. CONCLUSIONS Patients who had GI bleeding were at significantly higher risk for a subsequent TE event. Although the exact cause of this relationship is unknown, it suggests that a reduction in anti-coagulation and anti-platelet management to treat GI bleeds may contribute to this risk.

Update on Mitral Repair in Dilated Cardiomyopathy

Abstract  Heart failure is one of the leading causes of hospitalization worldwide. Mitral regurgitation (MR) is a known complication of end‐stage cardiomyopathy and is associated with a poor prognosis due to progressive mitral annular dilation. A vicious cycle of continuing volume overload, ventricular dilation, progression of annular dilation, increased LV wall tension, and worsening of MR and CHF occur. Commonly, these patients were managed medically with diuretics and afterload reduction, and frequently with mitral valve replacement, both of which have poor long term survival in patients with CHF and MR. Over a 10‐year period we prospectively studied over 200 patients with cardiomyopathy and severe MR who underwent mitral valve repair utilizing an undersizing overcorrecting annuloplasty ring. The mortality was low with one intraoperative death and eight 30‐day mortalities. There were 26 late deaths; 2 of these patients had progression of heart failure and underwent transplantation. The 1‐, 2‐, and 5‐year actuarial survivals have been 82%, 71%, and 52%, respectively. The NYHA class has improved for all patients from a preoperative mean of 3.2 ± 0.2 to 1.8 ± 0.4 postoperatively. All patients demonstrated improvement in ejection fraction, cardiac output, and end diastolic volumes with a reduction in sphericity index and regurgitant volume at 2 years post operation. All of the observed changes contribute to reverse remodeling and restoration of the normal left ventricular geometry. Mitral valve repair is a safe and effective operative intervention that corrects MR and offers a new strategy for patients with MR and end‐stage cardiomyopathy.

Device exchange after primary left ventricular assist device implantation: Indications and outcomes

BACKGROUND Patients are being supported for longer periods with implantable left ventricular assist devices (LVADs) owing to longer transplantation wait times and approval of LVADs for destination therapy. This comes with an increased potential need for device exchange when complications arise. There are few data examining this patient population. METHODS Between August 1998 and January 2012, 45 patients (34 men) underwent 57 device exchanges after primary pulsatile or continuous-flow LVAD implantation. The median age at the initial LVAD implantation was 58 years (range, 28-78 years) and the median time to first device exchange was 15 months (range, immediate-56 months). Indications for primary LVAD included bridge to transplantation in all but 10 patients, and devices included the HeartMate I (Thoratec, Pleasanton, CA) in 16 patients, the HeartMate II (Thoratec) in 21 patients, the HeartWare HVAD (HeartWare, Framingham, MA) in 2 patients, the DuraHeart I (Terumo Heart, Ann Arbor, MI) in 1 patient, and other devices in 5 patients. Indications for reoperation included device/component failure (n=24), major driveline infection (n=15), pump thrombus (n=15), and other indications (n=2). RESULTS Pumps implanted in 57 reoperations included the HeartMate I in 15 patients, the HeartMate II in 35 patients, the HeartWare HVAD in 2 patients, the DuraHeart I in 2 patients, and other devices in 3 patients. Early mortality occurred in 2/57 (3.5%) patients. Median follow-up was 18 months (range, 1-113 months); median length of LVAD therapy after the first device exchange was 13 months (range, 1-59 months). Actuarial 1-year survival and freedom from repeated device exchange after the first exchange was 89% and 79%, respectively. CONCLUSIONS Device exchange may be required after LVAD implantation. This can be performed with low early mortality and no adverse effect on late survival. Multiple reoperations may be required in some patients.

Consequences of aortic insufficiency during long-term axial continuous-flow left ventricular assist device support

BACKGROUND Although left ventricular assist device (LVAD) management strategies are undertaken to reduce the development of aortic insufficiency (AI), the effect of AI on patient morbidity and mortality is not known. METHODS Patients undergoing HeartMate II (Thoratec, Pleasanton, CA) implant were prospectively monitored with serial echocardiograms. Kaplan-Meier methods and log-rank testing were used to estimate and compare mortality and freedom from moderate or worser right ventricular hypokinesis (RVHK), moderate or worse mitral regurgitation (MR), and hemolysis according to AI severity. Mixed modelling was used to examine for correlates of AI development in the pre-operative and post-operative setting and to investigate the effect of AI on post-operative MR and RVHK. RESULTS There were 930 echocardiograms completed in 166 patients. During 291 person-years of follow-up, mild-moderate or worse AI developed in 70 (0.38 persons per year [PPY]), moderate or worse AI in 36 (0.17 PPY), moderate-severe AI in 11 (0.039 PPY), and severe AI in 2 (0.0069 PPY). Overall 2-year survival and 2-year survival after onset of moderate or worse AI was 87% ± 6.2% and 65% ± 11%, respectively, compared with 76% ± 5.1% and 76% ± 5.1%, respectively, in those with less AI (p = 0.57). Patients with moderate AI were not more likely to develop MR, hemolysis events, or worsening RVHK, but patients with pre-existing RVHK appeared to be less tolerant of AI. Three of 35 deaths were directly attributed to AI. No reoperations were performed solely for AI. CONCLUSIONS AI is common after LVAD implant but did not affect survival in this cohort. Except in those with significant RV dysfunction, this calls into question need for echocardiogram-guided device settings to ensure aortic valve opening.

HL-1 myocytes exhibit PKC and KATP channel-dependent delta opioid preconditioning

BACKGROUND Opioid preconditioning protects the myocardium against ischemia/reperfusion (IR) injury. By enhancing cardiomyocyte viability, opioids can enhance cardiac function and recovery from IR injury during acute cardiac care. The myocyte model HL-1 is an immortalized, mouse atrial cell line that expresses functional delta-opioid receptors. The HL-1 myocyte may be useful for IR injury research exploring opioid cardioprotection. MATERIALS AND METHODS In study I, microplates of HL-1 were subjected to 10 min pre-treatment with either basal media, delta-opioid agonist DADLE(10uM), or DADLE(10uM) + delta-antagonist naltrindole (10uM). Study II treatment groups included PKC inhibitor chelerythrine (2uM), K(ATP) channel closer glybenclamide (100uM), or mitochondrial K(ATP) channel opener diazoxide (100uM) administered in various combinations followed by DADLE (10uM) or control. Microplates were subjected to normal oxygen/substrate conditions or ischemic (<1% 0(2)) and substrate deficient (10 uM 2-Deoxyglucose versus 10 mM glucose) conditions, then reperfused with normal oxygen and glucose-containing media. Microplate supernatants were subjected to lactate dehydrogenase (LDH) assay. RESULTS Compared to untreated control, the LDH assay showed significant reduction in opioid-only pretreated groups at all time points. These effects were attenuated with delta-opioid antagonist co-administration. Co-administration of non-selective K(ATP) channel closer glybenclamide and DADLE abolished DADLE cytoprotection, while selective mitochondrial K(ATP) opener diazoxide mimicked DADLE cytoprotection Co-administration of chelerythrine and DADLE significantly reduced chelerythrine cytotoxicity. CONCLUSION Delta-opioid preconditioning of HL-1 myocytes significantly decreased necrosis from in vitro simulated ischemia/reperfusion as measured by LDH release; this effect was reversed by delta-antagonist naltrindole. Cytoprotection was PKC and K(ATP) channel-dependent. HL-1 myocytes exhibit opioid-induced cytoprotection from IR injury, and present a novel model of pharmacologic preconditioning.

Short- and Long-Term Survival of Patients Transferred to a Tertiary Care Center on Temporary Extracorporeal Circulatory Support

BACKGROUND Mechanical circulatory support (MCS) with temporary, extracorporeal assist devices restores hemodynamics in patients with refractory cardiogenic shock. These devices are frequently used in community hospitals, with subsequent referral to tertiary care centers. We sought to determine the outcomes of such referrals and identify prognostic variables that may influence management decisions. METHODS We performed a single-institution retrospective review of 59 consecutive patients transferred on temporary, extracorporeal MCS from 1997 to 2008. Demographics, medical history, laboratory data, and clinical status were obtained, with survival determined from the medical record and the Social Security Death Index. Univariable and multivariable analysis were performed and survival estimates were determined using the Kaplan-Meier method. RESULTS Median age was 49.6 years (range, 14 to 77 years). Forty-five patients (76%) were supported for postcardiotomy failure, and 34 (58%) required biventricular support. Twenty-five (42%) survived to hospital discharge, 11 after cardiac recovery (44%), 9 with long-term implantable MCS devices (39%), and 5 after heart transplantation (22%). Eight patients discharged with implantable MCS devices underwent heart transplantation and 1 remains alive on long-term implantable MCS support. Survival was 42% +/- 6% at 1 year and 38% +/- 6% at 5 years. Age and renal function were independent predictors of death. CONCLUSIONS Nearly half of all patients transferred on temporary extracorporeal MCS survive to discharge. Most of the long-term survivors received a heart transplant. Age and renal function were independent predictors of death, suggesting that survival is maximized by considering eligibility for cardiac transplantation.

Diagnosis and Management of Right-Sided Heart Failure in Subjects Supported With Left Ventricular Assist Devices

Opinion statementRight ventricular failure (RVF) is a cause of major morbidity and mortality in the left ventricular assist device (LVAD) population. Many LVAD candidates have clinical or subclinical right ventricular (RV) dysfunction, and the perioperative period is fraught with insults that may provoke reactive pulmonary vascular hypertension and acute or chronic development of RVF. Thus, preoperative patient optimization using diuretics, pulmonary vasodilators, and inotropes to reduce RV wall stress and improve contractility is critical. An assessment of the LVAD candidate’s risk for developing postoperative RVF is also key, especially in the destination therapy population for whom good options for long-term RV support currently are lacking. Intraoperatively, various pharmacologic and surgical interventions are available to reduce RVF risk. This review discusses RVF diagnosis and management strategies in subjects undergoing LVAD implantation.