Andrea M. Cordero-Reyes

Increased right-to-left ventricle diameter ratio is a strong predictor of right ventricular failure after left ventricular assist device.

BACKGROUND Predictors of right ventricular failure (RVF) in patients with left ventricular assist devices (LVADs) have not been fully elucidated and are comprised mostly of clinical variables. We evaluated echocardiographic parameters associated with adverse outcomes in this population. METHODS Transthoracic echocardiograms (TTEs) before continuous-flow LVAD implantation were analyzed in 109 patients. Twenty-six 2-dimensional and Doppler parameters were assessed for their association with the primary outcome of 30-day RVF, defined as a requirement of an RV assist device or ≥ 14 consecutive days of inotropic support, and the secondary composite outcome of 30-day death or RVF. Multivariate analysis adjusted for known clinical risk prediction models was performed. RESULTS Overall, 25 (22.9%) and 27 (24.8%) patients reached the primary and secondary end-points, respectively. An increased RV/LV diameter ratio was the only TTE variable independently associated with both the primary (odds ratio [OR] = 5.40; 95% confidence interval [CI] 2.40 to 12.40; p = 0.012) and secondary (OR = 2.70; 95% CI 1.06 to 6.22; p = 0.03) outcomes after multivariate analysis. Scatterplot analysis with regression determined the optimal cut-off value for RV/LV diameter to be 0.75. Based on receiver operating characteristic curves, an increased RV/LV diameter ratio provided an additional predictive value to clinical risk scores. CONCLUSIONS A TTE-measured RV/LV diameter ratio of ≥0.75 is independently associated with a higher risk for RVF in patients with continuous-flow LVAD. When used alone, this simple, easily derived, practical echocardiographic measurement has a predictive value equivalent to known clinical risk scores, whereas their combination provides stronger risk prediction for adverse outcomes.

Percutaneous Placement of an Intra-Aortic Balloon Pump in the Left Axillary/Subclavian Position Provides Safe, Ambulatory Long-Term Support as Bridge to Heart Transplantation

OBJECTIVES This study evaluated the feasibility, tolerability, and efficacy of a strategy for percutaneous intra-aortic balloon pump (IABP) placement through the left axillary-subclavian artery to provide mechanical circulatory support in patients with end-stage heart failure as a bridge to heart transplantation. BACKGROUND The transfemoral approach to IABP placement is associated with major disadvantages, including the risk for infection and limitation of patient mobility in those requiring extended support. METHODS We developed a percutaneous technique for placing IABPs in the left axillary artery that permits upright sitting and ambulation. We performed a retrospective review of data from patients who had undergone left axillary IABP implantation between 2007 and 2012. RESULTS Fifty patients who received a left axillary IABP as a bridge to transplantation were identified, of whom 42 (84%) underwent heart or heart-multiorgan transplantation. Cumulative survival on IABP support was 92%, and post-transplant 90-day survival was 90%. Median duration of support was 18 days. Four of 50 patients (8%) died while on IABP support, and 3 (6%) received greater mechanical circulatory support. Four patients (8%) had clinically significant thromboembolic or bleeding events without long-term sequelae. The most common minor adverse event was IABP malposition, in 22 patients (44%). Prolonged IABP support in the heart-transplantation cohort was associated with significant improvements in mean pulmonary artery pressure and in creatinine and total bilirubin concentrations. CONCLUSIONS Percutaneous insertion of an IABP through the left axillary artery is a feasible and relatively well-tolerated strategy to bridge patients with end-stage heart failure to heart transplantation. This form of mechanical-device treatment permits upright sitting and ambulation in those requiring extended support.

Leveraging nanochannels for universal, zero-order drug delivery in vivo

Drug delivery is essential to achieve effective therapy. Herein we report on the only implantable nanochannel membrane with geometrically defined channels as small as 2.5 nm that achieves constant drug delivery in vivo. Nanochannels passively control the release of molecules by physico-electrostatic confinement, thereby leading to constant drug diffusion. We utilize a novel design algorithm to select the optimal nanochannel size for each therapeutic agent. Using nanochannels as small as 3.6 and 20 nm, we achieve sustained and constant plasma levels of leuprolide, interferon α-2b, letrozole, Y-27632, octreotide, and human growth hormone, all delivered at clinically-relevant doses. The device was demonstrated in dogs, rats, and mice and was capable of sustaining target doses for up to 70 days. To provide evidence of therapeutic efficacy, we successfully combined nanochannel delivery with a RhoA pathway inhibitor to prevent chronic rejection of cardiac allografts in a rat model. Our results provide evidence that the nanochannel platform has the potential to dramatically improve long-term therapies for chronic conditions.

A simplified echocardiographic technique for detecting continuous-flow left ventricular assist device malfunction due to pump thrombosis.

BACKGROUND Malfunction of a continuous-flow left ventricular assist device (CF-LVAD) due to device thrombosis is a potentially life-threatening event that currently presents a diagnostic challenge. We aimed to propose a practical echocardiographic assessment to diagnose LVAD malfunction secondary to pump thrombosis. METHODS Among 52 patients implanted with a CF-LVAD from a single center who underwent echocardiographic pump speed-change testing, 12 had suspected pump thrombosis as determined by clinical, laboratory, and/or device parameters. Comprehensive echocardiographic evaluation was performed at baseline pump speed and at each 1,000-rpm interval from the low setting of 8,000 rpm to the high setting of 11,000 rpm in 11 of these patients. RESULTS Receiver operating characteristic curves and stepwise logistic regression analyses showed that the best diagnostic parameters included changes in the LV end-diastolic diameter (<0.6 cm), aortic valve opening time (<80 msec), and deceleration time of mitral inflow (<70 msec) from lowest to highest pump speed. One parameter was predictive of pump malfunction, with 100% sensitivity and 89% specificity, whereas 2 of 3 parameters increased the sensitivity to 100% and specificity to 95%. CONCLUSIONS The 3 echocardiographic variables of measured changes in LV end-diastolic diameter, aortic valve opening time, and deceleration time of mitral inflow between the lowest (8,000 rpm) and highest pump speed settings (11,000 rpm) during echo-guided pump speed-change testing appear highly accurate in diagnosing device malfunction in the setting of pump thrombosis among patients supported with CF-LVAD. Further investigation is warranted to create and validate a prediction score.

Cellular Evidence of Reverse Cardiac Remodeling Induced by Cardiac Resynchronization Therapy

Left ventricular assist devices (LVADs) induce reverse cardiac remodeling by reducing myocyte size and collagen deposition. On the other hand, cardiac resynchronization therapy (CRT) induces reverse cardiac remodeling by improving electromechanical synchronization. The clinical and structural changes produced by CRT in failing myocardium are known, but whether these changes are accompanied by reverse cellular remodeling is unknown. A total of 12 patients with chronic heart failure (CHF) who underwent CRT and 15 patients who had LVAD therapy as clinically indicated and 8 healthy controls were compared. Demographics, echocardiographic data, and histologic samples from myocardial biopsies were analyzed and compared among groups. The authors found significant increases in myocyte size, myocardial fibrosis, and inflammation in both CHF groups who underwent CRT or LVAD, compared with healthy controls. After CRT or LVAD therapy, a significant decrease in myocyte size and tumor necrosis factor α (TNF-α) expression compared with healthy controls (P < .05) was found. In the CRT group, 6 of 8 patients demonstrated reduction in myocyte size and interstitial fibrosis. In addition, there was a decrease in myocyte size by 13%, total collagen by 27% and TNF-α by 49% in the CRT group vs 28%, 45%, and 45% in the LVAD group. CRT produces cellular reverse remodeling in failing human hearts that are comparable with those produced by LVAD therapy.

Atrial arrhythmias after lung transplant: Underlying mechanisms, risk factors, and prognosis

BACKGROUND Atrial arrhythmias (AAs) early after lung transplant are frequent and have a significant impact on morbidity and mortality. However, the pathogenesis of AAs after lung transplant remains incompletely understood. In this study we aimed to determine the prevalence of atrial fibrillation (AF) and other AAs, as well as risk factors, clinical outcomes and possible underlying mechanisms associated with AAs after lung transplant. METHODS A retrospective analysis was performed on 382 patients who underwent lung transplantation from 2000 to 2010. A 12-lead electrocardiogram (ECG) was obtained and AAs classified as AF and other AAs (atrial flutter [AFL] and supraventricular tachycardia [SVT]). Multivariate logistic regression analysis was performed to determine predictors, and Kaplan-Meier survival curves were constructed. RESULTS The incidence of AAs was 25%; 17.8% developed AF and 7.6% other AAs (AFL/SVT). The major indication for transplant was idiopathic pulmonary fibrosis (IPF, 35%). Significant predictors of AF were as follows: age; IPF; left atrial enlargement; diastolic dysfunction; and history of coronary artery disease (CAD). Risk factors for other AAs (AFL/SVT) were: age; right ventricle dysfunction; right ventricular enlargement; and elevated right atrial pressure (RAP). One-year mortality was higher in the arrhythmia group (21.5% arrhythmia vs 15.7% no-arrhythmia group; p < 0.05). In addition, patients treated with anti-arrhythmic medications had higher mortality (p < 0.05). CONCLUSIONS AAs are common after lung transplantation. Risk factors for developing either AF or other AAs (AFL/SVT) are different. The development of early AAs post-transplant is associated with prolonged post-operative stay and increased mortality. A rate-control strategy should be used as first-line therapy and anti-arrhythmic agents reserved for those patients who do not respond to the initial treatment.

Full Expression of Cardiomyopathy Is Partly Dependent on B‐Cells: A Pathway That Involves Cytokine Activation, Immunoglobulin Deposition, and Activation of Apoptosis

Background Limited information exists on the role of B‐cell‐dependent mechanisms in the progression of heart failure (HF). However, in failing human myocardium, there is evidence of deposition of activated complement components as well as anticardiac antibodies. We aimed to determine the contribution of B‐cells in HF progression using a nonsurgical mouse model of nonischemic cardiomyopathy (CMP). Methods and Results CMP protocol involved the use of l‐NAME and NaCl in the drinking water and angiotensin‐II infusion for 35 days. At day 35, mice were analyzed by cardiac magnetic resonance imaging, gene expression, and histology. Mice (12 weeks old) were divided into 4 groups, all in C57BL/6 background: wild‐type (WT) CMP; severe combined immunodeficiency (SCID) CMP (T‐ and B‐cell deficient); CD22− CMP (B‐cell depleted); and Nude CMP (T‐cell deficient), with their respective controls. We performed B‐cell depletion and reconstitution protocols. The protective effect of B‐cell depletion was demonstrated by a significant reduction of cell hypertrophy and collagen deposition and a preserved ejection fraction in the CD22− CMP group compared to WT CMP. Once SCID mice underwent B‐cell reconstitution with isolated CMP B‐cells, the CMP phenotype was restored. Furthermore, deposition of IgG3 and apoptosis in the myocardium follows the development of CMP; in addition, in vitro studies demonstrated that activated B‐cells stimulate collagen production by cardiac fibroblasts. Conclusions The absence of B‐cells in this model of HF resulted in less hypertrophy and collagen deposition, preservation of left ventricular function, and, in association with these changes, a reduction in expression of proinflammatory cytokines, immunoglobulin G deposition, and apoptosis in the myocardium. Taken together, these data suggest that B‐cells play a contributory role in an angiotensin‐II‐induced HF model.

Usefulness of routine surveillance endomyocardial biopsy 6 months after heart transplantation

BACKGROUND Endomyocardial biopsy (EMB) remains the gold standard for detecting rejection episodes in orthotopic heart transplant (OTH) patients. Follow-up protocols vary widely between transplant centers. At our center, we have implemented a conservative strategy protocol and here we report our outcomes. METHODS Patients from 2 cohorts were used for comparison analysis. OHT recipients from 1990 to 1995 comprised the standard strategy group, and those from 2004 to 2009 comprised the conservative strategy group. Survival outcomes and rejection episodes were compared between groups. RESULTS Mean age at OHT was 56 ± 10 years in the standard strategy group and 53 ± 10 years in the conservative strategy group. Both groups were predominantly composed of white men. The etiology of congestive heart failure was ischemic cardiomyopathy in more than 50% of the patients in both groups. From 6 to 12 months after OHT, we found that the number of episodes of rejection/total number of EMBs was 4.9% (8/163) in the standard group vs 2.0% (1/50) in the conservative group. From 12 to 24 months after transplant, the rate was 2.5% (8/320) in the standard group vs 11.9% (5/42) in the conservative group (p < 0.05). CONCLUSIONS Surveillance EMB after 6 months post-OHT in patients receiving contemporary immunosuppression is associated with a low yield of EMB-confirmed rejection in the absence of a clinical indication or echocardiographic findings that support clinical rejection. Most episodes of cellular rejection are mild and do not warrant treatment or a change in immunosuppression. The frequency of EMBs did not correlate with an increased risk of cardiac allograft vasculopathy or death.

A specifically designed nanoconstruct associates, internalizes, traffics in cardiovascular cells, and accumulates in failing myocardium: a new strategy for heart failure diagnostics and therapeutics.

Ongoing inflammation and endothelial dysfunction occurs within the local microenvironment of heart failure, creating an appropriate scenario for successful use and delivery of nanovectors. This study sought to investigate whether cardiovascular cells associate, internalize, and traffic a nanoplatform called mesoporous silicon vector (MSV), and determine its intravenous accumulation in cardiac tissue in a murine model of heart failure.

A REVIEW OF INFECTIONS IN PATIENTS WITH LEFT VENTRICULAR ASSIST DEVICES: PREVENTION, DIAGNOSIS AND MANAGEMENT

Since the advent of ventricular assist devices with smaller configurations and continuous-flow technology, survival rates for patients with end-stage heart failure have dramatically improved. While the burden of infectious complications is decreased in patients on continuous-flow ventricular assist devices compared to bulkier pulsatile-flow devices, infection remains one of the most common causes of morbidity and mortality. The majority of infections occur at the driveline exit site, beginning with a disruption or trauma to the barrier between the skin and driveline and sometimes spreading deeper. Once infections develop, they can be difficult to eradicate. Depending on the degree of infection, treatment options may include local wound care, antibiotics, or surgical treatment. Preventive strategies and careful surveillance are crucial to improve patient outcomes.