Stavros G. Drakos

Risk factors predictive of right ventricular failure after left ventricular assist device implantation.

Right ventricular failure (RVF) after left ventricular assist device (LVAD) implantation appears to be associated with increased mortality. However, the determination of which patients are at greater risk of developing postoperative RVF remains controversial and relatively unknown. We sought to determine the preoperative risk factors for the development of RVF after LVAD implantation. The data were obtained for 175 consecutive patients who had received an LVAD. RVF was defined by the need for inhaled nitric oxide for >/=48 hours or intravenous inotropes for >14 days and/or right ventricular assist device implantation. An RVF risk score was developed from the beta coefficients of the independent variables from a multivariate logistic regression model predicting RVF. Destination therapy (DT) was identified as the indication for LVAD implantation in 42% of our patients. RVF after LVAD occurred in 44% of patients (n = 77). The mortality rates for patients with RVF were significantly greater at 30, 180, and 365 days after implantation compared to patients with no RVF. By multivariate logistic regression analysis, 3 preoperative factors were significantly associated with RVF after LVAD implantation: (1) a preoperative need for intra-aortic balloon counterpulsation, (2) increased pulmonary vascular resistance, and (3) DT. The developed RVF risk score effectively stratified the risk of RV failure and death after LVAD implantation. In conclusion, given the progressively growing need for DT, the developed RVF risk score, derived from a population with a large percentage of DT patients, might lead to improved patient selection and help stratify patients who could potentially benefit from early right ventricular assist device implantation.

The cerebral cavernous malformation signaling pathway promotes vascular integrity via Rho GTPases

Cerebral cavernous malformation (CCM) is a common vascular dysplasia that affects both systemic and central nervous system blood vessels. Loss of function mutations in the CCM2 gene cause CCM. Here we show that targeted disruption of Ccm2 in mice results in failed lumen formation and early embryonic death through an endothelial cell autonomous mechanism. We show that CCM2 regulates endothelial cytoskeletal architecture, cell-to-cell interactions and lumen formation. Heterozygosity at Ccm2, a genotype equivalent to that in human CCM, results in impaired endothelial barrier function. On the basis of our biochemical studies indicating that loss of CCM2 results in activation of RHOA GTPase, we rescued the cellular phenotype and barrier function in heterozygous mice with simvastatin, a drug known to inhibit Rho GTPases. These data offer the prospect for pharmacological treatment of a human vascular dysplasia with a widely available and safe drug.

Pulsatility and the Risk of Nonsurgical Bleeding in Patients Supported With the Continuous-Flow Left Ventricular Assist Device HeartMate II

Background—Bleeding is an important cause of morbidity and mortality in patients with continuous-flow left ventricular assist devices (LVADs). Reduced pulsatility has been implicated as a contributing cause. The aim of this study was to assess the effects of different degrees of pulsatility on the incidence of nonsurgical bleeding. Methods and Results—The Utah Transplantation Affiliated Hospitals (U.T.A.H.) heart failure and transplant program databases were queried for patients with end-stage heart failure who required support with the continuous-flow LVAD HeartMate II (Thoratec Corp, Pleasanton, CA) between 2004 and 2012. Pulsatility was evaluated by means of the LVAD parameter pulsatility index (PI) and by the echocardiographic assessment of aortic valve opening during the first 3 months of LVAD support. PI was analyzed as a continuous variable and also stratified according to tertiles of all the PI measurements during the study period (low PI: <4.6, intermediate PI: 4.6–5.2, and high PI: >5.2). Major nonsurgical bleeding associated with a decrease in hemoglobin ≥2 g/dL (in the absence of hemolysis) was the primary end point. A total of 134 patients (median age of 60 [interquartile range: 49–68] years, 78% men) were included. Major bleeding occurred in 33 (25%) patients (70% gastrointestinal, 21% epistaxis, 3% genitourinary, and 6% intracranial). In multivariable analysis, PI examined either as a categorical variable, low versus high PI (hazard ratio, 4.06; 95% confidence interval, 1.35–12.21; P=0.04), or as a continuous variable (hazard ratio, 0.60; 95% confidence interval, 0.40–0.92; P=0.02) was associated with an increased risk of bleeding. Conclusions—Reduced pulsatility in patients supported with the continuous-flow LVAD HeartMate II is associated with an increased risk of nonsurgical bleeding, as evaluated by PI.

Magnitude and time course of changes induced by continuous-flow left ventricular assist device unloading in chronic heart failure: insights into cardiac recovery.

OBJECTIVES This study sought to prospectively investigate the longitudinal effects of continuous-flow left ventricular assist device (LVAD) unloading on myocardial structure and systolic and diastolic function. BACKGROUND The magnitude, timeline, and sustainability of changes induced by continuous-flow LVAD on the structure and function of the failing human heart are unknown. METHODS Eighty consecutive patients with clinical characteristics consistent with chronic heart failure requiring implantation of a continuous-flow LVAD were prospectively enrolled. Serial echocardiograms (at 1, 2, 3, 4, 6, 9, and 12 months) and right heart catheterizations were performed after LVAD implant. Cardiac recovery was assessed on the basis of improvement in systolic and diastolic function indices on echocardiography that were sustained during LVAD turn-down studies. RESULTS After 6 months of LVAD unloading, 34% of patients had a relative LV ejection fraction increase above 50% and 19% of patients, both ischemic and nonischemic, achieved an LV ejection fraction ≥ 40%. LV systolic function improved as early as 30 days, the greatest degree of improvement was achieved by 6 months of mechanical unloading and persisted over the 1-year follow up. LV diastolic function parameters also improved as early as 30 days after LVAD unloading, and this improvement persisted over time. LV end-diastolic and end-systolic volumes decreased as early as 30 days after LVAD unloading (113 vs. 77 ml/m(2), p < 0.01, and 92 vs. 60 ml/m(2), p < 0.01, respectively). LV mass decreased as early as 30 days after LVAD unloading (114 vs. 95 g/m(2), p < 0.05) and continued to do so over the 1-year follow-up but did not reach values below the normal reference range, suggesting no atrophic remodeling after prolonged LVAD unloading. CONCLUSIONS Continuous-flow LVAD unloading induced in a subset of patients, both ischemic and nonischemic, early improvement in myocardial structure and systolic and diastolic function that was largely completed within 6 months, with no evidence of subsequent regression.

Cardiovascular Mortality Among Heart Transplant Recipients With Asymptomatic Antibody-Mediated or Stable Mixed Cellular and Antibody-Mediated Rejection

BACKGROUND Little has been reported on the clinical significance of asymptomatic antibody-mediated rejection (AMR) alone or mixed rejection (MR), defined as concurrent cellular rejection (CR) and AMR in heart transplantation. In this study, we examined whether a differential impact on cardiovascular mortality (CVM) existed when comparing asymptomatic AMR, to stable MR or CR. METHODS The Utah Transplantation Affiliated Hospitals (UTAH) Cardiac Transplant Program pathology database of all heart transplant recipients between 1985 and 2004 was queried. Patients were classified as cellular, antibody-mediated, or mixed rejectors based on their predominant pattern of rejection type in the first three months post-transplant. Kaplan-Meier survival curves were fit to each of the three groups and analyses were adjusted for age at the time of transplant, gender, and underlying primary cardiac disease. RESULTS Eight hundred and sixty nine heart transplant recipients qualified for analysis. Over the study period, patients with asymptomatic AMR or stable MR patterns had significantly worse CVM when compared to patients with stable CR pattern (AMR, 21.2%; MR, 18.0%; CR, 12.6%; AMR vs. CR, p = 0.009; MR vs. CR, p = 0.001). In contrast, CVM was comparable in patients with asymptomatic AMR or stable MR patterns (p = 0.9). CONCLUSIONS Asymptomatic or subclinical AMR and MR are clinically relevant, should be recognized, and deserve consideration for therapeutic intervention in hopes of avoiding adverse outcomes.

Impact of Mechanical Unloading on Microvasculature and Associated Central Remodeling Features of the Failing Human Heart

OBJECTIVES This study investigates alterations in myocardial microvasculature, fibrosis, and hypertrophy before and after mechanical unloading of the failing human heart. BACKGROUND Recent studies demonstrated the pathophysiologic importance and significant mechanistic links among microvasculature, fibrosis, and hypertrophy during the cardiac remodeling process. The effect of left ventricular assist device (LVAD) unloading on cardiac endothelium and microvasculature is unknown, and its influence on fibrosis and hypertrophy regression to the point of atrophy is controversial. METHODS Hemodynamic data and left ventricular tissue were collected from patients with chronic heart failure at LVAD implant and explant (n = 15) and from normal donors (n = 8). New advances in digital microscopy provided a unique opportunity for comprehensive whole-field, endocardium-to-epicardium evaluation for microvascular density, fibrosis, cardiomyocyte size, and glycogen content. Ultrastructural assessment was done with electron microscopy. RESULTS Hemodynamic data revealed significant pressure unloading with LVAD. This was accompanied by a 33% increase in microvascular density (p = 0.001) and a 36% decrease in microvascular lumen area (p = 0.028). We also identified, in agreement with these findings, ultrastructural and immunohistochemical evidence of endothelial cell activation. In addition, LVAD unloading significantly increased interstitial and total collagen content without any associated structural, ultrastructural, or metabolic cardiomyocyte changes suggestive of hypertrophy regression to the point of atrophy and degeneration. CONCLUSIONS The LVAD unloading resulted in increased microvascular density accompanied by increased fibrosis and no evidence of cardiomyocyte atrophy. These new insights into the effects of LVAD unloading on microvasculature and associated key remodeling features might guide future studies of unloading-induced reverse remodeling of the failing human heart.

Depressed coronary flow reserve is associated with decreased myocardial capillary density in patients with heart failure due to idiopathic dilated cardiomyopathy.

OBJECTIVES We sought to examine the relationship between coronary flow reserve (CFR) and myocardial capillary density (MCD) in patients with idiopathic dilated cardiomyopathy, heart failure, and normal coronary arteries. BACKGROUND Coronary flow reserve is depressed in patients with idiopathic dilated cardiomyopathy, particularly in those with end-stage congestive heart failure. METHODS We studied 18 patients, 48 +/- 10 years of age, who had a mean New York Heart Association functional class of 2.9 +/- 1.3, mean left ventricular ejection fraction of 22 +/- 8%, and mean pulmonary capillary wedge pressure of 23 +/- 10 mm Hg. CFR measurements were made with a 0.014-inch pressure-temperature sensor-tipped guide wire placed in the distal left anterior descending coronary artery. Thermodilution curves were constructed in triplicate at baseline and during maximum hyperemia induced by intravenous adenosine. CFR was calculated from the ratio of mean transit times. Right heart endomyocardial biopsies were performed during the same procedure. Autopsied specimens from nonfailing hearts were used as controls. The tissue was histochemically stained with CD-34 for morphometric measurements of MCD. RESULTS We observed a close linear relationship between CFR and MCD (r = 0.756, p = 0.0001). The MCD in 7 patients with a CFR >or=2.5 (73.2 +/- 16) was similar to that measured in normal control patients, (85 +/- 11, p = NS). In contrast, the MCD in 11 patients with a CFR <2.5 was 33.2 +/- 14, which was significantly lower than in patients with heart failure and normal CFR (73.2 +/- 16, p = 0.001) or in controls (85 +/- 11, p < 0.0001). CONCLUSIONS A marked decrease in MCD was found in patients presenting with congestive heart failure as the result of idiopathic dilated cardiomyopathy and a depressed CFR.

Effects of exercise rehabilitation program on heart rate recovery in patients with chronic heart failure

Background Heart rate recovery (HRR1) immediately after exercise reflects parasympathetic activity, which is markedly attenuated in chronic heart failure (CHF) patients. The aim of our study was to examine both continuous and interval exercise training effects on HRR1 in these patients. Design The population study consisted of 29 stable CHF patients that participated at a rehabilitation program of 36 sessions, three times per week. Of the 29 patients, 24 completed the program. Patients were randomly assigned to interval {n = 10 [100% peak work rate (WRp) for 30 s, alternating with rest for 30 s]} and to continuous training [n = 14 (50%WRp)]. Methods All patients performed a symptom-limited cardiopulmonary exercise test on a cycle ergometer before and after the completion of the program. Measurements included peak oxygen uptake (VO2p), anaerobic threshold (AT), WRp, first degree slope of VO2 during the first minute of recovery (VO2/t-slope), chronotropic response [% chronotropic reserve (CR) = (peak HR - resting HR) × 100/(220 - age - resting HR)], HRR1 (HR difference from peak exercise to one minute after). Results After the completion of the rehabilitation program there was a significant increase of WRp, VO2p, AT and VO2/t-slope (by 30%, P=0.01; 6%, P=0.01; 10%, P=0.02; and 27%, P=0.03 respectively for continuous training and by 21%, P≤0.05; 8%, P=0.01; 6%, P=NS; and 48%, P=0.02 respectively for interval training). However, only patients exercised under the continuous training regime had a significant increase in HRR1 (15.0±9.0 to 24.0±12bpm; P=0.02) and CR (57±19 to 72±21%, P=0.02), in contrast with those assigned to interval training (HRR1: 21 ± 11 to 21 ± 8 bpm; P=NS and CR: 57 ± 18 to 59 ± 21%, P=NS). Conclusions Both continuous and interval exercise training program improves exercise capacity in CHF patients. However, continuous rather than interval exercise training improves early HRR1, a marker of parasympathetic activity, suggesting a greater contribution to the autonomic nervous system.

End-of-life decision making and implementation in recipients of a destination left ventricular assist device

BACKGROUND The use of left ventricular assist devices (LVADs) as destination therapy (DT) is increasing and has proven beneficial in prolonging survival and improving quality of life in select patients with end-stage heart failure. Nonetheless, end-of-life (EOL) issues are inevitable and how to approach them underreported. METHODS Our DT data registry was queried for eligible patients, defined as those individuals who actively participated in EOL decision making. The process from early EOL discussion to palliation and death was reviewed. We recorded the causes leading to EOL discussion, time from EOL decision to withdrawal and from withdrawal to death, and location. Primary caregivers were surveyed to qualify their experience and identify themes relevant to this process. RESULTS Between 1999 and 2009, 92 DT LVADs were implanted in 69 patients. Twenty patients qualified for inclusion (mean length of support: 833 days). A decrease in quality of life from new/worsening comorbidities usually prompted EOL discussion. Eleven patients died at home, 8 in the hospital and 1 in a nursing home. Time from EOL decision to LVAD withdrawal ranged from <1 day to 2 weeks and from withdrawal until death was <20 minutes in all cases. Palliative care was provided to all patients. Ongoing assistance from the healthcare team facilitated closure and ensured comfort at EOL. CONCLUSIONS With expanding indications and improved technology, more DT LVADs will be implanted and for longer durations, and more patients will face EOL issues. A multidisciplinary team approach with protocols involving DT patients and their families in EOL decision making allows for continuity of care and ensures dignity and comfort at EOL.

Bridge to Recovery Understanding the Disconnect Between Clinical and Biological Outcomes

Left ventricular (LV) assist devices (LVADs) are increasingly used in everyday clinical practice either as a bridge for end-stage heart failure (HF) patients to heart transplantation or as a permanent (destination) therapy.1,2 Yet, there is still significant uncertainty about the consequences of this intervention both at the level of the detailed myocardial biology (ie, biological outcomes) and at the functional cardiovascular response of the patient at the organ level (ie, clinical outcomes). The LVAD patient population presents a series of significant advantages as far as research is concerned. First, LVAD therapy offers the ability to acquire paired human myocardial tissue at LVAD implantation and again on LVAD removal. The ability to obtain human tissue and the possibility for its serial examination before and after any therapeutic investigational therapy combined with LVADs provide an important opportunity for in-depth study of the changes in the structure and function of the diseased human heart caused by the specific investigational therapy. Second, this population represents a relatively safe investigational platform because the hemodynamic support provided by VADs makes these patients significantly less vulnerable to any arrhythmic3 or hemodynamic adverse events potentially associated with new aggressive investigational therapies. Third, the volumes of potential study subjects for these investigations (ie, patients who receive LVADs) are rapidly increasing; because of a lack of donor organs and incremental progress in device design and durability, the number of advanced HF patients with LVADs has been continuously increasing.1,2 These 3 research advantages create an ideal setting for various new HF therapies to test their potential efficacy in LVAD patients. Fourth, this population offers an opportunity to investigate the effects of the LVAD-induced removal of excess mechanical load, which drives the vicious cycle of myocardial remodeling and eventually leads to the clinical HF syndrome. …