Amrut V. Ambardekar

Reverse Remodeling With Left Ventricular Assist Devices: A Review of Clinical, Cellular, and Molecular Effects

Over the last 2 decades, numerous advancements in medical therapies have improved patient outcomes in heart failure (HF). However, a significant number of patients still progress to end-stage HF, in which treatment options are largely limited to cardiac transplantation. As patient demands for transplant continue to exceed the supply of available organs, mechanical assist devices—specifically, the left ventricular assist device (LVAD)—were initially introduced as a bridge to cardiac transplantation. LVADs have 2 important beneficial effects. First, LVADs are placed in parallel to the native left ventricle (LV), causing pressure and volume unloading of the LV. Second, LVADs restore cardiac output and subsequent perfusion to the organs. As a result of these 2 effects, it became evident that some patients had actual improvement in LV function after LVAD placement. The term reverse remodeling was used to describe the improvement in myocardial function that was observed in patients with a seemingly end-stage disease. With reverse remodeling, a new hope for the treatment of HF was born—using LVADs as a bridge to recovery; however, to date, this promise has largely been unrealized. This probably is reflective of the fact that the sequela of mechanical ventricular unloading are quite complex and appear to involve the engagement of competing biological pathways including regression of cardiomyocyte hypertrophy as well as progressive cell atrophy. Although the promise of ventricular recovery still persists, its actualization will await a more comprehensive dissection of these competing biological processes. This review will discuss the beneficial clinical effects of LVAD support as well as review what is known about the cellular and molecular response to mechanical unloading and mechanisms of reverse remodeling. Key research findings have been summarized in the Table. View this table: Table. Summary of Research of LVAD Support on Clinical Effects and the Cellular and Molecular Changes That May Contribute to Reverse …

Incomplete Recovery of Myocyte Contractile Function Despite Improvement of Myocardial Architecture With Left Ventricular Assist Device Support

Background—Unloading a failing heart with a left ventricular assist device (LVAD) can improve ejection fraction (EF) and LV size; however, recovery with LVAD explantation is rare. We hypothesized that evaluation of myocyte contractility and biochemistry at the sarcomere level before and after LVAD may explain organ-level changes. Methods and Results—Paired LV tissue samples were frozen from 8 patients with nonischemic cardiomyopathy at LVAD implantation (before LVAD) and before cardiac transplantation (after LVAD). These were compared with 8 nonfailing hearts. Isolated skinned myocytes were purified and attached to a force transducer, and dimensions, maximum calcium-saturated force, calcium sensitivity, and myofilament cooperativity were assessed. Relative isoform abundance and phosphorylation levels of sarcomeric contractile proteins were measured. With LVAD support, the unloaded EF improved (10.0±1.0% to 25.6±11.0%, P=0.007), LV size decreased (LV internal dimension at end diastole, 7.6±1.2 to 4.9±1.4 cm; P<0.001), and myocyte dimensions decreased (cross-sectional area, 1247±346 to 638±254 &mgr;m2; P=0.001). Maximum calcium-saturated force improved after LVAD (3.6±0.9 to 7.3±1.8 mN/mm2, P<0.001) implantation but was still lower than in nonfailing hearts (7.3±1.8 versus 17.6±1.8 mN/mm2, P<0.001). An increase in troponin I (TnI) phosphorylation after LVAD implantation was noted, but protein kinase C phosphorylation of TnI decreased. Biochemical changes of other sarcomeric proteins were not observed after LVAD. Conclusions—There is significant improvement in LV and myocyte size with LVAD, but there is only partial recovery of EF and myocyte contractility. LVAD support was associated only with biochemical changes in TnI, suggesting that alternate mechanisms might contribute to contractile changes after LVAD and that additional interventions may be needed to alter biochemical remodeling of the sarcomere to further enhance myofilament and organ-level recovery.

Patterns and Predictors of Evidence-Based Medication Continuation Among Hospitalized Heart Failure Patients (from Get With the Guidelines–Heart Failure)

Hospitalized patients with heart failure and decreased ejection fraction are at substantial risk for mortality and rehospitalization, yet no acute therapies are proven to decrease this risk. Therefore, in-hospital use of medications proved to decrease long-term mortality is a critical strategy to improve outcomes. Although endorsed in guidelines, predictors of initiation and continuation of angiotensin-converting enzyme (ACE) inhibitors/angiotensin receptor blockers (ARBs), β blockers, and aldosterone antagonists have not been well studied. We assessed noncontraindicated use patterns for the 3 medications using the Get With the Guidelines-Heart Failure (GWTG-HF) registry from February 2009 through March 2010. Medication continuation was defined as treatment on admission and discharge. Multivariable logistic regression using generalized estimating equations was used to determine factors associated with discharge use. In total 9,474 patients were enrolled during the study period. Of those treated before hospitalization, overall continuation rates were 88.5% for ACE inhibitors/ARBs, 91.6% for β blockers, and 71.9% for aldosterone-antagonists. Of patients untreated before admission, 87.4% had ACE inhibitors/ARBs and 90.1% had β blocker initiated during hospitalization or at discharge, whereas only 25.2% were started on an aldosterone antagonist. In multivariate analysis, admission therapy was most strongly associated with discharge use (adjusted odds ratios 7.4, 6.0, and 20.9 for ACE inhibitors/ARBs, β blockers, and aldosterone antagonists, respectively). Western region, younger age, and academic affiliation were also associated with higher discharge use. Although ACE inhibitor/ARB and β-blocker continuation rates were high, aldosterone antagonist use was lower despite potential eligibility. In conclusion, being admitted on evidence-based medications is the most powerful, independent predictor of discharge use.

Implantable cardioverter-defibrillator shocks in patients with a left ventricular assist device

BACKGROUND Left ventricular assist device (LVAD) use is becoming increasingly common for patients with end-stage heart failure. However, the rate of implantable cardioverter-defibrillator (ICD) shocks and the effect of these shocks on outcomes in patients with LVADs remain unknown. METHODS Medical records were reviewed from patients with both an ICD and a LVAD from September 2000 to February 2009. The association between ICD shocks and survival while receiving device support was assessed using Cox proportional hazards modeling. RESULTS Thirty-three of 61 patients with a LVAD also had an ICD and form the basis of this report. The mean duration of LVAD support was 238 days. One or more ICD shocks were delivered to 14 patients (42%) with 8 (24%) receiving appropriate shocks for ventricular arrhythmias and 6 (18%) receiving inappropriate shocks. No patients received both appropriate and inappropriate shocks. When compared with receiving no ICD shock, receiving any ICD shock or an appropriate ICD shock were both associated with an increase in the risk of death (hazard ratio [HR] 4.5, 95% confidence interval [CI] 1.2 to 17.3, p = 0.027, and HR 5.3, 95% CI 1.3 to 22.6, p = 0.023, respectively); receipt of an inappropriate shock showed a non-significant trend for an increased risk of death (HR 3.2, 95% CI 0.7 to 16.1, p = 0.151). CONCLUSIONS ICD shocks are common after implantation of LVADs, with nearly equal numbers of appropriate and inappropriate shocks. ICD shocks are associated with higher mortality. Larger studies are needed for assessing the independent relationship of ICDs to a variety of clinical outcomes in patients with LVADs.

Quality of Care and In-Hospital Outcomes in Patients With Coronary Heart Disease in Rural and Urban Hospitals (from Get With the Guidelines–Coronary Artery Disease Program)

Previous studies have suggested that patients with coronary artery disease (CAD) in rural areas may have worse outcomes due to limited availability of specialists, fewer resources, and less institutional funding. Data were collected from hospitals participating in the Get With the Guidelines-Coronary Artery Disease Program (GWTG-CAD) from January 2000 to December 2008. In-hospital outcomes and quality of care were stratified by care at rural versus urban hospitals. Multivariate logistic regression analysis was used to determine the association of rural locale with in-hospital mortality, length of stay, and compliance with the GWTG-CAD performance measurements including (1) early aspirin use, (2) smoking cessation counseling and discharge prescriptions of (3) aspirin, (4) angiotensin-converting enzyme inhibitors, or angiotensin receptor blockers for left ventricular systolic dysfunction, (5) beta-blockers, and (6) lipid-lowering therapy and a composite of all 6 measurements. Data were collected from 22,096 patients at 71 rural centers and 329,938 patients at 477 urban centers. Unadjusted rates of compliance with performance measurements were lower in rural (range 82.4% to 90.5%) compared to urban (range 81.3% to 95.0%) hospitals including the composite (74.7% vs 80.6%, p <0.0001). In multivariate analysis, rural status was not independently associated with lower compliance with any of the performance measurements. Unadjusted mortality rates were higher in rural versus urban hospitals (5.7% vs 4.4%, p <0.0001), but this was not significant in multivariate analysis (odds ratio 1.05, 95% confidence interval 0.87 to 1.26). In conclusion, within the GWTG-CAD quality improvement initiative, patients with CAD treated at rural hospitals receive similar quality of care and have similar outcomes as those at urban centers.

Clinical problem-solving. Missing elements of the history.

A 59-year-old woman with a history of bilateral total hip replacements and a total knee replacement sees her physician for cough, exertional dyspnea, and foot swelling that had developed 2 weeks earlier while she was on vacation in Europe.

Effect of left ventricular assist device placement on preexisting implantable cardioverter-defibrillator leads.

BACKGROUND The left ventricular assist device (LVAD) is a therapy for patients with end-stage heart failure, many of whom have a preexisting implantable cardioverter-defibrillator (ICD). We investigated whether the implantation of a LVAD affects ICD function. METHODS AND RESULTS Patients implanted with a LVAD between September 2000 and February 2009 were studied. Right ventricular (RV), right atrial, and left ventricular lead impedance, sensing, and capture thresholds were recorded before and after LVAD placement and subsequent lead-related interventions were noted. Of the 61 patients receiving a LVAD, data were collected from 30 patients who had preexisting ICDs. Significant pre-post differences were noted for all RV lead parameters: sensing amplitude decreased from 9.2+/-3.1 to 5.7+/-3.6 millivolts (P < .001); impedance decreased from 479+/-118 to 418+/-94 ohms (P=.008); and threshold increased from 4.3+/-6.7 to 11.0+/-16.8 microjoules (P=.021). As a result of alterations in lead parameters, 4 patients (13%) required lead revisions and 6 patients (20%) required ICD testing. CONCLUSIONS Differences in ICD lead function were observed after LVAD placement resulting in clinically significant interventions. These data suggest that ICD interrogation be performed post-LVAD placement and that patients be counseled for the potential need for lead revisions and ICD testing when consented for a LVAD.

Changes in Aortic Wall Structure, Composition, and Stiffness With Continuous-Flow Left Ventricular Assist Devices: A Pilot Study

Background—The effects of nonpulsatile flow on the aorta are unknown. Our aim was to examine the structure of the aorta from patients with continuous-flow left ventricular assist devices (LVADs) and directly measure aortic wall composition and stiffness. Methods and Results—Age-matched aortic wall samples were collected from consecutive patients with heart failure (HF) at the time of transplantation and compared with nonfailing donor hearts. An unbiased stereological approach was used to quantify aortic morphometry and composition, and biomechanical testing was performed to determine the stress–strain relationship of the vessel. Data were obtained from 4 patients without a left ventricular assist device (HF group: mean age, 58.3±8.0 years), 7 patients with a continuous-flow LVAD (HF+LVAD group: mean, 57.7±5.6 years), and 3 nonfailing donors (mean, 53.3±12.9 years). Compared with HF, the aortic walls from HF+LVAD had an increase in wall thickness, collagen, and smooth muscle content accompanied by a reduction in elastin and mucinous ground-substance content. Stress–strain curves from the aortas revealed increased vessel stiffness in HF+LVAD compared with HF and nonfailing. The physiological modulus of the aorta progressively stiffened from 74.3±5.5 kPa in the nonfailing to 134.4±35.0 kPa in the HF to 201.7±36.4kPa in the HF+LVAD groups (P<0.001). Conclusions—Among continuous-flow LVAD patients without aortic valve opening, there are changes in the structure and composition of the aorta as well as an increase in aortic wall stiffness compared with age-matched HF patients and nonfailing donors. Further studies examining the role of nonpulsatile blood flow on aortic function and the potential resultant systemic sequelae are needed.

Preoperative evaluation and perioperative management of right ventricular failure after left ventricular assist device implantation.

Right ventricular (RV) failure continues to be a major cause of morbidity and mortality after left ventricular assist device (LVAD) implantation. Preoperative evaluation of RV function with a variety of clinical, laboratory, echocardiographic, and hemodynamic variables is essential to ensure appropriate patient selection for LVAD therapy but remains imperfect. Therefore, clinicians involved in the care of these patients need to be prepared to manage RV failure after LVAD placement. Perioperative management of RV failure after LVAD implantation requires minimization of intraoperative RV ischemia, maintenance of appropriate filling pressure, supportive therapy with pulmonary vasodilators and inotropes, and surgical interventions such as RV assist devices in select cases. This article reviews the incidence of RV failure with LVAD implantation, preoperative predictors of RV failure, and perioperative management strategies.

High early event rates in patients with questionable eligibility for advanced heart failure therapies: Results from the Medical Arm of Mechanically Assisted Circulatory Support (Medamacs) Registry

BACKGROUND The prognosis of ambulatory patients with advanced heart failure (HF) who are not yet inotrope dependent and implications for evaluation and timing for transplant or destination therapy with a left ventricular assist device (DT-LVAD) are unknown. We hypothesized that the characteristics defining eligibility for advanced HF therapies would be a primary determinant of outcomes in these patients. METHODS Ambulatory patients with advanced HF (New York Heart Association class III-IV, Interagency Registry for Mechanically Assisted Circulatory Support profiles 4-7) were enrolled across 11 centers from May 2013 to February 2015. Patients were stratified into 3 groups: likely transplant eligible, DT-LVAD eligible, and ineligible for both transplant and DT-LVAD. Clinical characteristics were collected, and patients were prospectively followed for death, transplant, and left ventricular assist device implantation. RESULTS The study enrolled 144 patients with a mean follow-up of 10 ± 6 months. Patients in the ineligible cohort (n = 43) had worse congestion, renal function, and anemia compared with transplant (n = 51) and DT-LVAD (n = 50) eligible patients. Ineligible patients had higher mortality (23.3% vs 8.0% in DT-LVAD group and 5.9% in transplant group, p = 0.02). The differences in mortality were related to lower rates of transplantation (11.8% in transplant group vs 2.0% in DT-LVAD group and 0% in ineligible group, p = 0.02) and left ventricular assist device implantation (15.7% in transplant group vs 2.0% in DT-LVAD group and 0% in ineligible group, p < 0.01). CONCLUSIONS Ambulatory patients with advanced HF who were deemed ineligible for transplant and DT-LVAD had markers of greater HF severity and a higher rate of mortality compared with patients eligible for transplant or DT-LVAD. The high early event rate in this group emphasizes the need for timely evaluation and decision making regarding lifesaving therapies.