Juan M. Aranda

Extended Mechanical Circulatory Support With a Continuous-Flow Rotary Left Ventricular Assist Device

OBJECTIVES This study sought to evaluate the use of a continuous-flow rotary left ventricular assist device (LVAD) as a bridge to heart transplantation. BACKGROUND LVAD therapy is an established treatment modality for patients with advanced heart failure. Pulsatile LVADs have limitations in design precluding their use for extended support. Continuous-flow rotary LVADs represent an innovative design with potential for small size and greater reliability by simplification of the pumping mechanism. METHODS In a prospective, multicenter study, 281 patients urgently listed (United Network of Organ Sharing status 1A or 1B) for heart transplantation underwent implantation of a continuous-flow LVAD. Survival and transplantation rates were assessed at 18 months. Patients were assessed for adverse events throughout the study and for quality of life, functional status, and organ function for 6 months. RESULTS Of 281 patients, 222 (79%) underwent transplantation, LVAD removal for cardiac recovery, or had ongoing LVAD support at 18-month follow-up. Actuarial survival on support was 72% (95% confidence interval: 65% to 79%) at 18 months. At 6 months, there were significant improvements in functional status and 6-min walk test (from 0% to 83% of patients in New York Heart Association functional class I or II and from 13% to 89% of patients completing a 6-min walk test) and in quality of life (mean values improved 41% with Minnesota Living With Heart Failure and 75% with Kansas City Cardiomyopathy questionnaires). Major adverse events included bleeding, stroke, right heart failure, and percutaneous lead infection. Pump thrombosis occurred in 4 patients. CONCLUSIONS A continuous-flow LVAD provides effective hemodynamic support for at least 18 months in patients awaiting transplantation, with improved functional status and quality of life. (Thoratec HeartMate II Left Ventricular Assist System [LVAS] for Bridge to Cardiac Transplantation; NCT00121472).

Transition From Chronic Compensated to Acute Decompensated Heart Failure Pathophysiological Insights Obtained From Continuous Monitoring of Intracardiac Pressures

Background— Approximately half of all patients with chronic heart failure (HF) have a decreased ejection fraction (EF) (systolic HF [SHF]); the other half have HF with a normal EF (diastolic HF [DHF]). However, the underlying pathophysiological differences between DHF and SHF patients are incompletely defined. The purpose of this study was to use echocardiographic and implantable hemodynamic monitor data to examine the pathophysiology of chronic compensated and acute decompensated HF in SHF versus DHF patients. Methods and Results— Patients were divided into 2 subgroups: 204 had EF <50% (SHF) and 70 had EF ≥50% (DHF). DHF patients had EF of 58±8%, end-diastolic dimension of 50±10 mm, estimated resting pulmonary artery diastolic pressure (ePAD) of 16±9 mm Hg, and diastolic distensibility index (ratio of ePAD to end-diastolic volume) of 0.11±0.06 mm Hg/mL. In contrast, SHF patients had EF of 24±10%, end-diastolic dimension of 68±11 mm, ePAD of 18±7 mm Hg, and diastolic distensibility index of 0.06±0.04 mm Hg/mL (P<0.05 versus DHF for all variables except ePAD). In SHF and DHF patients who developed acute decompensated HF, these events were associated with a significant increase in ePAD, from 17±7 to 22±7 mm Hg (P<0.05) in DHF and from 21±9 to 24±8 mm Hg (P<0.05) in SHF. As a group, patients who did not have acute decompensated HF events had no significant changes in ePAD. Conclusions— Significant structural and functional differences were found between patients with SHF and those with DHF; however, elevated diastolic pressures play a pivotal role in the underlying pathophysiology of chronic compensated and acute decompensated HF in both SHF and DHF.

Coronary artery aneurysms: Study of their etiology, clinical course and effect on left ventricular function and prognosis

Coronary artery aneurysms were found in 16 men between 37 and 62 years of age, mean 51 years. Aneurysms were of two types: saccular and fusiform. They involved the right coronary artery in 13 (87 per cent), the circumflex artery in eight (50 per cent) and the left anterior descending artery in five (31 per cent). In some patients, more than one vessel was involved. Twelve patients presented with angina pectoris, three with congestive heart failure and one with both. Five were in functional class II, eight were in class III and three were in class IV at the beginning of the study. The electrocardiogram showed evidence of previous myocardial infarction in four patients; four patients had left ventricular hypertrophy, one had left axis deviation, one had left bundle branch block, one had right bundle branch block, two had first degree atrioventricular block and seven had abnormalities in the S-T segment and T wave. Obstructive coronary disease was present in all; the obstruction score was from 1 to 4 in three patients, from 5 to 9 in four patients and from 10 to 14 in the remaining nine. Similar aneurysms were found in the pulmonary artery of one patient and in the abdominal aorta of three patients; in seven of 14 patients with adequate venous angiograms, varicosities of the coronary venous tree were observed. Left ventricular dysfunction and angina pectoris were noted in patients with significant obstructive coronary disease (greater than 70 per cent) and also in patients without obstruction but with coronary aneurysms. Ten patients were treated surgically; nine underwent aortocoronary bypass and one mitral valve replacement. Criteria for bypass was the presence of obstructive disease and medically unresponsive angina pectoris. All but one surgically treated patient showed improvement. The functional class in medically treated patients was unchanged. Fourteen patients were still alive at the completion of the study. The findings of this study suggest that angina pectoris and left ventricular dysfunction can occur with coronary artery aneurysm without coronary artery obstructions. Coronary aneurysms may be a subset of atherosclerosis, and this process may involve other vascular territories. The prognosis in those patients appears to be no worse than in patients with obstructive coronary disease and no aneurysms.

Beta1-adrenergic receptor polymorphisms and left ventricular remodeling changes in response to beta-blocker therapy.

OBJECTIVE Large variability exists in the improvement in left ventricular (LV) function from beta-blocker treatment. We hypothesized that polymorphisms at codon 389 (Arg389Gly) and 49 (Ser49Gly) in the beta1-adrenergic receptor (AR) gene were associated with LV reverse remodeling changes in response to beta-blocker therapy among heart failure patients. METHODS We prospectively enrolled 61 beta-blocker naive patients with systolic heart failure. Patients underwent baseline echocardiography followed by metoprolol CR/XL. The dose was doubled on a biweekly basis up to 200 mg/day or attainment of maximum tolerated dose. Echocardiography was repeated after the patient received the target or highest tolerated dose for 3 months. RESULTS Among patients with the Arg389Arg genotype, ejection fraction (EF) increased from 23+/-5 to 29+/-10 (P=0.008). Gly389 carriers did not demonstrate any significant change in EF (22+/-9 to 23+/-11; P=0.45). There was a significant between-group difference in EF by genotype (P=0.04). The Arg389Arg genotype was also associated with significantly greater reductions in LV end-diastolic and end-systolic diameters compared to Gly389 carriers. Patients with the Gly49 variant also had a significantly greater reduction in LV end-diastolic diameter compared to Ser49 homozygotes. Multiple regression analysis modeling revealed that the codon 389 polymorphism was a significant predictor of an improvement in EF and both codon 49 and 389 polymorphisms were significant predictors of final LV end-diastolic diameter. CONCLUSIONS Heart failure patients with the Arg389Arg genotype and Gly49 carriers had greater improvements in LV remodeling from beta-blocker treatment.

Renal and Hepatic Function Improve in Advanced Heart Failure Patients During Continuous-Flow Support With the HeartMate II Left Ventricular Assist Device

Background— The effects of continuous blood flow and reduced pulsatility on major organ function have not been studied in detail. Methods and Results— We evaluated renal (creatinine and blood urea nitrogen) and hepatic (aspartate transaminase, alanine transaminase, and total bilirubin) function in 309 (235 male, 74 female) advanced heart failure patients who had been supported with the HeartMate II continuous-flow left ventricular assist device for bridge to transplantation. To determine whether patients with impaired renal and hepatic function improve over time with continuous-flow left ventricular assist device support or whether there are any detrimental effects in patients with normal organ function, we divided patients into those with above-normal and normal laboratory values before implantation and measured blood chemistry over time during left ventricular assist device support. There were significant improvements over 6 months in all parameters in the above-normal groups, with values in the normal groups remaining in the normal range over time. Mean blood urea nitrogen and serum creatinine in the above-normal groups decreased significantly from 37±14 to 23±10 mg/dL (P<0.0001) and from 1.8±0.4 to 1.4±0.8 mg/dL (P<0.01), respectively. There were decreases in aspartate transaminase and alanine transaminase in the above-normal groups from 121±206 and 171±348 to 36±19 and 31±22 IU (P<0.001), respectively. Total bilirubin for the above-normal group was 2.1±0.9 mg/dL at baseline; after an acute increase at week 1, it decreased to 0.9±0.5 mg/dL by 6 months (P<0.0001). Both renal and liver values from patients in the normal groups remained normal during support with the left ventricular assist device. Conclusions— The HeartMate II continuous-flow left ventricular assist device improves renal and hepatic function in advanced heart failure patients who are being bridged to transplantation, without evidence of detrimental effects from reduced pulsatility over a 6-month time period. Clinical Trial Registration Information— URL: http://www.clinicaltrials.gov. Unique identifier: NCT00121472.

Electrocardiographic antecedents of primary ventricular fibrillation. Value of the R-on-T phenomenon in myocardial infarction.

Primary ventricular fibrillation was seen in 20 of 450 consecutive patients (4-4%) admitted within 24 hours after the onset of acute myocardial infarction. Compared with patients without primary ventricular fibrillation they showed a lower mean age group and a higher incidence of anterior infarction. Warning ventricular arrhythmias preceded primary ventricular fibrillation in 58% of cases. However, warning arrhythmias were also present in 55% of patients without primary ventricular fibrillation. The following mechanisms of initiation of primary ventricular fibrillation were seen. 1) In one patient, it was initiated by supraventricular premature beats showing aberrant intraventricular conduction. 2) In 2 patients, ventricular tachycardia degenerated into primary ventricular fibrillation. 3) In 17 patients, it was initiated by a ventricular premature beat; in 10 of these, the premature beat showed early coupling (RR/QT less than 1--the R-on-T phenomenon). However, ventricular premature beats showing the R-on-T phenomenon were also observed in 49% of patients without primary ventricular fibrillation. In 7, primary ventricular fibrillation was initiated by a late-coupled ventricular premature beat (RR/QT greater than 1); in 2, the very late coupling resulted in a ventricular fusion beat. The study suggests that warning arrhythmias and the R-on-T phenomenon are poor predictors of primary ventricular fibrillation in acute myocardial infarction. The observation that 41% of primary ventricular fibrillation was initiated by a late-coupled ventricular premature beat suggests that ventricular vulnerability during acute myocardial infarction may extend throughout most of the cardiac cycle and is not necessarily confined to the QT interval.

The Impact of Aging on Mitochondrial Function and Biogenesis Pathways in Skeletal Muscle of Sedentary High- and Low-Functioning Elderly Individuals

Age‐related loss of muscle mass and strength (sarcopenia) leads to a decline in physical function and frailty in the elderly. Among the many proposed underlying causes of sarcopenia, mitochondrial dysfunction is inherent in a variety of aged tissues. The intent of this study was to examine the effect of aging on key groups of regulatory proteins involved in mitochondrial biogenesis and how this relates to physical performance in two groups of sedentary elderly participants, classified as high‐ and low‐functioning based on the Short Physical Performance Battery test. Muscle mass was decreased by 38% and 30% in low‐functioning elderly (LFE) participants when compared to young and high‐functioning elderly participants, respectively, and positively correlated to physical performance. Mitochondrial respiration in permeabilized muscle fibers was reduced (41%) in the LFE group when compared to the young, and this was associated with a 30% decline in cytochrome c oxidase activity. Levels of key metabolic regulators, SIRT3 and PGC‐1α, were significantly reduced (50%) in both groups of elderly participants when compared to young. Similarly, the fusion protein OPA1 was lower in muscle from elderly subjects; however, no changes were detected in Mfn2, Drp1 or Fis1 among the groups. In contrast, protein import machinery components Tom22 and cHsp70 were increased in the LFE group when compared to the young. This study suggests that aging in skeletal muscle is associated with impaired mitochondrial function and altered biogenesis pathways and that this may contribute to muscle atrophy and the decline in muscle performance observed in the elderly population.

Tricuspid annular motion as a predictor of severe right ventricular failure after left ventricular assist device implantation.

BACKGROUND Right ventricular (RV) failure after left ventricular assist device (LVAD) implantation is associated with a high rate of morbidity and mortality. We sought to determine pre-operative right heart echocardiographic predictors of post-LVAD severe RV failure. METHODS RV failure, defined as the need for inotropic support or pulmonary vasodilators for >or=14 days post-operatively, was evaluated in 33 patients (age 54 +/- 13 years) with LVADs. Preoperative RV systolic and diastolic echocardiographic parameters, including RV fractional area change, tricuspid annular motion, right atrial volume index, RV index of myocardial performance, hepatic vein Doppler velocities, tricuspid regurgitation severity, and RV systolic pressures (RVSPs) in patients with and without RV failure were compared. RESULTS Of the 33 patients evaluated, 11 (33%) had post-LVAD RV failure (2 needed RVAD support). Patients with post-LVAD RV failure had significantly lower pre-operative tricuspid annular motion (8 +/- 4 vs 15 +/- 6 mm, p < 0.01) and higher RVSPs (60 +/- 14 vs 46 +/- 11 mm Hg, p = 0.02). In 13 patients (39%) with moderate tricuspid regurgitation, pre-operative tricuspid annular motion remained significantly reduced (6.0 +/- 0.5 vs 13.5 +/- 5.0 mm, p = 0.045). Other echocardiographic parameters were not significantly different between patients. Tricuspid annular motion of <7.5 mm provides 91% specificity and 46% sensitivity in predicting post-LVAD RV failure. CONCLUSION Tricuspid annular motion is a predictor of post-LVAD RV failure. Using tricuspid annular motion in addition to conventional criteria may aid in early identification of patients with prolonged inotropic support or severe RV failure and allow for better pre-operative planning.

β‐adrenergic Receptor Polymorphisms and Responses during Titration of Metoprolol Controlled Release/extended Release in Heart Failure

β‐Blockers require careful initiation and titration when used in patients with heart failure. Some patients tolerate β‐blocker therapy initiation without difficulty, whereas in other patients this period presents clinical challenges. We tested the hypothesis that polymorphisms at codons 389 (Arg389Gly) and 49 (Ser49Gly) of the β1‐adrenergic receptor would be associated with differences in initial tolerability of β‐blocker therapy in patients with heart failure. We also tested whether polymorphisms in the β2‐adrenergic receptor, G‐protein αs subunit (Gsα), and cytochrome P450 (CYP) 2D6 genes or S‐metoprolol plasma concentrations were associated with β‐blocker tolerability.

Anti-CD20 monoclonal antibody (rituximab) therapy for acute cardiac humoral rejection: a case report.

Humoral or antibody-mediated rejection in cardiac transplant recipients is mediated by donor-specific cytotoxic antibodies and is histologically defined by linear deposits of immunoglobulin and complement in the myocardial capillaries. Antibody-mediated rejection often is accompanied by hemodynamic compromise and is associated with reduced long-term graft survival. Standard immunosuppression, designed to target T cell immune function, is largely ineffective against this B cell-driven process. Current treatment options for humoral rejection are limited by a lack of specific anti-B cell therapies. We present the case of a 50-year-old woman with hemodynamically significant humoral rejection resistant to steroids, cyclophos-phamide, and plasmapheresis who responded to the addition of anti-CD20 monoclonal antibody therapy (rituximab). One year posttransplant, the patient is rejection-free, with normal left ventricular systolic function and coronary arteries.