Raffi Bekeredjian

Transcatheter Aortic Valve Implantation in Failed Bioprosthetic Surgical Valves

IMPORTANCE Owing to a considerable shift toward bioprosthesis implantation rather than mechanical valves, it is expected that patients will increasingly present with degenerated bioprostheses in the next few years. Transcatheter aortic valve-in-valve implantation is a less invasive approach for patients with structural valve deterioration; however, a comprehensive evaluation of survival after the procedure has not yet been performed. OBJECTIVE To determine the survival of patients after transcatheter valve-in-valve implantation inside failed surgical bioprosthetic valves. DESIGN, SETTING, AND PARTICIPANTS Correlates for survival were evaluated using a multinational valve-in-valve registry that included 459 patients with degenerated bioprosthetic valves undergoing valve-in-valve implantation between 2007 and May 2013 in 55 centers (mean age, 77.6 [SD, 9.8] years; 56% men; median Society of Thoracic Surgeons mortality prediction score, 9.8% [interquartile range, 7.7%-16%]). Surgical valves were classified as small (≤21 mm; 29.7%), intermediate (>21 and <25 mm; 39.3%), and large (≥25 mm; 31%). Implanted devices included both balloon- and self-expandable valves. MAIN OUTCOMES AND MEASURES Survival, stroke, and New York Heart Association functional class. RESULTS Modes of bioprosthesis failure were stenosis (n = 181 [39.4%]), regurgitation (n = 139 [30.3%]), and combined (n = 139 [30.3%]). The stenosis group had a higher percentage of small valves (37% vs 20.9% and 26.6% in the regurgitation and combined groups, respectively; P = .005). Within 1 month following valve-in-valve implantation, 35 (7.6%) patients died, 8 (1.7%) had major stroke, and 313 (92.6%) of surviving patients had good functional status (New York Heart Association class I/II). The overall 1-year Kaplan-Meier survival rate was 83.2% (95% CI, 80.8%-84.7%; 62 death events; 228 survivors). Patients in the stenosis group had worse 1-year survival (76.6%; 95% CI, 68.9%-83.1%; 34 deaths; 86 survivors) in comparison with the regurgitation group (91.2%; 95% CI, 85.7%-96.7%; 10 deaths; 76 survivors) and the combined group (83.9%; 95% CI, 76.8%-91%; 18 deaths; 66 survivors) (P = .01). Similarly, patients with small valves had worse 1-year survival (74.8% [95% CI, 66.2%-83.4%]; 27 deaths; 57 survivors) vs with intermediate-sized valves (81.8%; 95% CI, 75.3%-88.3%; 26 deaths; 92 survivors) and with large valves (93.3%; 95% CI, 85.7%-96.7%; 7 deaths; 73 survivors) (P = .001). Factors associated with mortality within 1 year included having small surgical bioprosthesis (≤21 mm; hazard ratio, 2.04; 95% CI, 1.14-3.67; P = .02) and baseline stenosis (vs regurgitation; hazard ratio, 3.07; 95% CI, 1.33-7.08; P = .008). CONCLUSIONS AND RELEVANCE In this registry of patients who underwent transcatheter valve-in-valve implantation for degenerated bioprosthetic aortic valves, overall 1-year survival was 83.2%. Survival was lower among patients with small bioprostheses and those with predominant surgical valve stenosis.

Transcatheter Aortic Valve Replacement for Degenerative Bioprosthetic Surgical Valves: Results from the Global Valve-in-Valve Registry

Background— Transcatheter aortic valve-in-valve implantation is an emerging therapeutic alternative for patients with a failed surgical bioprosthesis and may obviate the need for reoperation. We evaluated the clinical results of this technique using a large, worldwide registry. Methods and Results— The Global Valve-in-Valve Registry included 202 patients with degenerated bioprosthetic valves (aged 77.7±10.4 years; 52.5% men) from 38 cardiac centers. Bioprosthesis mode of failure was stenosis (n=85; 42%), regurgitation (n=68; 34%), or combined stenosis and regurgitation (n=49; 24%). Implanted devices included CoreValve (n=124) and Edwards SAPIEN (n=78). Procedural success was achieved in 93.1% of cases. Adverse procedural outcomes included initial device malposition in 15.3% of cases and ostial coronary obstruction in 3.5%. After the procedure, valve maximum/mean gradients were 28.4±14.1/15.9±8.6 mm Hg, and 95% of patients had ≤+1 degree of aortic regurgitation. At 30-day follow-up, all-cause mortality was 8.4%, and 84.1% of patients were at New York Heart Association functional class I/II. One-year follow-up was obtained in 87 patients, with 85.8% survival of treated patients. Conclusions— The valve-in-valve procedure is clinically effective in the vast majority of patients with degenerated bioprosthetic valves. Safety and efficacy concerns include device malposition, ostial coronary obstruction, and high gradients after the procedure. # Clinical Perspective {#article-title-38}Background— Transcatheter aortic valve-in-valve implantation is an emerging therapeutic alternative for patients with a failed surgical bioprosthesis and may obviate the need for reoperation. We evaluated the clinical results of this technique using a large, worldwide registry. Methods and Results— The Global Valve-in-Valve Registry included 202 patients with degenerated bioprosthetic valves (aged 77.7±10.4 years; 52.5% men) from 38 cardiac centers. Bioprosthesis mode of failure was stenosis (n=85; 42%), regurgitation (n=68; 34%), or combined stenosis and regurgitation (n=49; 24%). Implanted devices included CoreValve (n=124) and Edwards SAPIEN (n=78). Procedural success was achieved in 93.1% of cases. Adverse procedural outcomes included initial device malposition in 15.3% of cases and ostial coronary obstruction in 3.5%. After the procedure, valve maximum/mean gradients were 28.4±14.1/15.9±8.6 mm Hg, and 95% of patients had ⩽+1 degree of aortic regurgitation. At 30-day follow-up, all-cause mortality was 8.4%, and 84.1% of patients were at New York Heart Association functional class I/II. One-year follow-up was obtained in 87 patients, with 85.8% survival of treated patients. Conclusions— The valve-in-valve procedure is clinically effective in the vast majority of patients with degenerated bioprosthetic valves. Safety and efficacy concerns include device malposition, ostial coronary obstruction, and high gradients after the procedure.

Ultrasound-Targeted Microbubble Destruction Can Repeatedly Direct Highly Specific Plasmid Expression to the Heart

Background—Noninvasive, tissue-specific delivery of therapeutic agents would be a valuable clinical tool. We have previously shown that ultrasound-targeted microbubble destruction can direct expression of an adenoviral reporter to the heart. The present study shows that this method can be applied to selectively deliver plasmid vectors to the heart. Methods and Results—We used albumin and lipid microbubbles containing plasmids with a luciferase transgene to target the heart in rats. After 4 days, organs were harvested and analyzed for reporter gene expression. In a second set of experiments, the hearts of rats treated with plasmids were harvested at various time points during a 4-week period. Both luciferase activity and mRNA concentrations were measured. Luciferase transfection with plasmids showed highly specific gene expression in the heart, with hardly any activity in control organs. Time course evaluation showed high transgene expression in the first 4 days, with a rapid decline thereafter. Repeated treatment produced a second peak of transgene expression with similar decay. Conclusions—Ultrasound-mediated destruction of microbubbles directs plasmid transgene expression to the heart with much greater specificity than viral vectors and can be regulated by repeated treatments. This noninvasive technique is a promising method for cardiac gene therapy.

Rapamycin extends murine lifespan but has limited effects on aging.

Aging is a major risk factor for a large number of disorders and functional impairments. Therapeutic targeting of the aging process may therefore represent an innovative strategy in the quest for novel and broadly effective treatments against age-related diseases. The recent report of lifespan extension in mice treated with the FDA-approved mTOR inhibitor rapamycin represented the first demonstration of pharmacological extension of maximal lifespan in mammals. Longevity effects of rapamycin may, however, be due to rapamycins effects on specific life-limiting pathologies, such as cancers, and it remains unclear if this compound actually slows the rate of aging in mammals. Here, we present results from a comprehensive, large-scale assessment of a wide range of structural and functional aging phenotypes, which we performed to determine whether rapamycin slows the rate of aging in male C57BL/6J mice. While rapamycin did extend lifespan, it ameliorated few studied aging phenotypes. A subset of aging traits appeared to be rescued by rapamycin. Rapamycin, however, had similar effects on many of these traits in young animals, indicating that these effects were not due to a modulation of aging, but rather related to aging-independent drug effects. Therefore, our data largely dissociate rapamycins longevity effects from effects on aging itself.

Optimization of ultrasound parameters for cardiac gene delivery of adenoviral or plasmid deoxyribonucleic acid by Ultrasound-Targeted microbubble destruction

OBJECTIVES This study was undertaken to optimize echocardiographic parameters for successful gene delivery to the heart and to extend the method from adenoviral to plasmid deoxyribonucleic acid (DNA). BACKGROUND We have previously shown that ultrasound-targeted microbubble destruction can direct tissue expression of adenoviral transgenes to the heart. The optimal echocardiographic parameters for this technique have not been reported. METHODS Adenoviral or plasmid DNA encoding the luciferase reporter gene was incorporated into liposome microbubbles and infused intravenously into anesthetized rats. We systematically evaluated the effects of ultrasound parameters known to influence microbubble destruction, including electrocardiogram (ECG) triggering, ultrasound frequency, mode of ultrasound, and mechanical index, on gene expression in rat myocardium four days after treatment. In addition, gene expression in heart, liver, and skeletal muscle were compared between adenoviral and plasmid DNA. RESULTS Optimal ultrasound parameters for this technique include low-transmission frequency (1.3 MHz), maximal mechanical index, and ECG triggering to allow complete filling of the myocardial capillary bed by microbubbles. No difference was seen between ultraharmonics and power Doppler mode. Using adenoviral DNA, optimal ultrasound parameters yielded myocardial luciferase activity on the order of 104 relative light units/mg protein/min but with even higher liver activity. Plasmid DNA was expressed in rat myocardium at similar levels but without detectable liver expression. CONCLUSIONS Ultrasound-targeted microbubble destruction can be used to deliver adenoviral or plasmid DNA to the myocardium. This technique holds great promise in applying the rapidly expanding repertoire of gene therapies being developed for cardiac disease.

MitraClip therapy in daily clinical practice: initial results from the German transcatheter mitral valve interventions (TRAMI) registry

A substantial percentage of patients with mitral regurgitation (MR) in need of mitral valve repair are currently considered not suitable for conventional surgery. In Germany, the largest cohort of patients studied to date has been treated using a percutaneous, catheter‐based approach. We report the acute outcomes of patients enrolled in the investigator‐initiated German transcatheter mitral valve interventions (TRAMI) registry.

Valvular Heart Disease Aortic Regurgitation

Aortic regurgitation (AR) is characterized by diastolic reflux of blood from the aorta into the left ventricle (LV). Acute AR typically causes severe pulmonary edema and hypotension and is a surgical emergency. Chronic severe AR causes combined LV volume and pressure overload. It is accompanied by systolic hypertension and wide pulse pressure, which account for peripheral physical findings, such as bounding pulses. The afterload excess caused by systolic hypertension leads to progressive LV dilation and systolic dysfunction. The most important diagnostic test for AR is echocardiography. It provides the ability to determine the cause of AR and to assess the severity of AR and its effect on LV size, function, and hemodynamics. Many patients with chronic severe AR may remain clinically compensated for years with normal LV function and no symptoms. These patients do not require surgery but can be followed carefully for the onset of symptoms or LV dilation/dysfunction. Surgery should be considered before the LV ejection fraction falls below 55% or the LV end-diastolic dimension reaches 55 mm. Symptomatic patients should undergo surgery unless there are excessive comorbidities or other contraindications. The primary role of medical therapy with vasodilators is to delay the need for surgery in asymptomatic patients with normal LV function or to treat patients in whom surgery is not an option. The goal of vasodilator therapy is to achieve a significant decrease in systolic arterial pressure. Future therapies may focus on molecular mechanisms to prevent adverse LV remodeling and fibrosis.

Cardiac AAV9-S100A1 Gene Therapy Rescues Post-Ischemic Heart Failure in a Preclinical Large Animal Model

A protein that regulates cellular calcium, delivered percutaneously to the heart by gene therapy, improves cardiac function in pigs with heart failure and may also be effective in humans. Paving the Way for a Gene Therapy Trial for Heart Failure Heart failure, also known as congestive heart failure, results when, for any number of reasons, the heart no longer pumps enough blood to keep organs perfused and oxygenated. Common in the Western world, heart failure’s first-line treatment is diuretics, which help to remove the excess fluid that pools in the body during heart failure, and β-adrenergic receptor–blocking drugs to interfere with the deleterious effects of the excess catecholamines that accompany this disease. These treatments are effective but do not restore normal heart function; more than half of patients with heart failure die within 5 years. The authors of Pleger et al. now present evidence that a gene therapy approach to augmenting the failing heart’s damaged ability to handle intracellular calcium produces marked improvements in heart function in pigs with heart failure. These results provide enough evidence, the authors say, to justify a clinical trial to see whether this approach could improve patient’s quality of life and survival when added to current treatments. The investigators injected an adenovirus gene therapy vector (AAV9) carrying the gene for S100A1 into pigs experiencing heart failure, induced by the experimental occlusion of a coronary artery. They chose to deliver S100A1 to the failing heart because this calcium-binding protein becomes depleted as the heart fails and is needed for proper regulation of the calcium dynamics within myocardial cells. Two weeks after infarction, the vector (under control of a cardiac-specific promoter) was delivered to non-infarcted regions of the heart (which would eventually fail without treatment). Twelve weeks later, S100A1 protein expression increased and heart function improved. By several measures, calcium handling within the cardiomyocytes was improved, as were markers of mitochondrial energy production. The authors saw no toxic effects of the therapy and verified the cardiac-specific expression of the vector. Although similar gene therapy tests were shown previously to be effective in mice, a test in a large animal model was especially important to verify that this approach is likely to be safe and effective in patients. The volume of successfully transduced tissue in a pig heart is similar to that required for humans. Unlike the rodent, the pig’s heart rate, sarcomeric proteins, and cardiomyocyte calcium handling are all similar to human, and therapeutic vector delivery through a percutaneous catheter, which will be required in patients, could be mimicked in pigs. If the value of this therapy is confirmed in clinical trials, it would be available for patients already suffering heart failure. It would likely prove most useful as an adjunct therapy to currently existing drugs where it could augment the strength of the heart’s contraction. As a prerequisite for clinical application, we determined the long-term therapeutic effectiveness and safety of adeno-associated virus (AAV)–S100A1 gene therapy in a preclinical large animal model of heart failure. S100A1, a positive inotropic regulator of myocardial contractility, becomes depleted in failing cardiomyocytes in humans and animals, and myocardial-targeted S100A1 gene transfer rescues cardiac contractile function by restoring sarcoplasmic reticulum calcium (Ca2+) handling in acutely and chronically failing hearts in small animal models. We induced heart failure in domestic pigs by balloon occlusion of the left circumflex coronary artery, resulting in myocardial infarction. After 2 weeks, when the pigs displayed significant left ventricular contractile dysfunction, we administered, by retrograde coronary venous delivery, AAV serotype 9 (AAV9)–S100A1 to the left ventricular, non-infarcted myocardium. AAV9-luciferase and saline treatment served as control. At 14 weeks, both control groups showed significantly decreased myocardial S100A1 protein expression along with progressive deterioration of cardiac performance and left ventricular remodeling. AAV9-S100A1 treatment prevented and reversed these functional and structural changes by restoring cardiac S100A1 protein levels. S100A1 treatment normalized cardiomyocyte Ca2+ cycling, sarcoplasmic reticulum calcium handling, and energy homeostasis. Transgene expression was restricted to cardiac tissue, and extracardiac organ function was uncompromised. This translational study shows the preclinical feasibility of long-term therapeutic effectiveness of and a favorable safety profile for cardiac AAV9-S100A1 gene therapy in a preclinical model of heart failure. Our results present a strong rationale for a clinical trial of S100A1 gene therapy for human heart failure that could potentially complement current strategies to treat end-stage heart failure.

One-year outcomes and predictors of mortality after MitraClip therapy in contemporary clinical practice: results from the German transcatheter mitral valve interventions registry

Abstract Aims The transcatheter mitral valve interventions (TRAMI) registry was established in order to assess safety and efficacy of catheter-based mitral valve interventional techniques in Germany, and prospectively enrolled 828 MitraClip patients (median age 76 years, median log. EuroSCORE I 20.0%) between August 2010 and July 2013. We present the 1-year outcome in this MitraClip cohort—which is the largest published to date. Methods and results Seven forty-nine patients (90.5%) were available for 1-year follow-up and included in the following analyses. Mortality, major adverse cardiovascular event rates, and New York Heart Association (NYHA) classes were recorded. Predictors of 1-year mortality were identified by multivariate analysis using a Cox regression model with stepwise forward selection. The 1-year mortality was 20.3%. At 1 year, 63.3% of TRAMI patients pertained to NYHA functional classes I or II (compared with 11.0% at baseline), and self-rated health status (on EuroQuol visual analogue scale) also improved significantly by 10 points. Importantly, a significant proportion of patients regained the complete independence in self-care after MitraClip implantation (independence in 74.0 vs. 58.6% at baseline, P = 0.005). Predictors of 1-year mortality were NYHA class IV (hazard ratio, HR 1.62, P = 0.02), anaemia (HR 2.44, P = 0.02), previous aortic valve intervention (HR 2.12, P = 0.002), serum creatinine ≥1.5 mg/dL (HR 1.77, P = 0.002), peripheral artery disease (HR 2.12, P = 0.0003), left ventricular ejection fraction <30% (HR 1.58, P = 0.01), severe tricuspid regurgitation (HR 1.84, P = 0.003), and procedural failure (defined as operator-reported failure, conversion to surgery, failure of clip placement, or residual post-procedural severe mitral regurgitation) (HR 4.36, P < 0.0001). Conclusions Treatment of significant MR with MitraClip resulted in significant clinical improvements in a high proportion of TRAMI patients after 12 months. In the TRAMI cohort, the failure of procedural success exhibited the highest hazard ratio concerning the prediction of 1-year mortality.

Acute outcomes after MitraClip therapy in highly aged patients: results from the German TRAnscatheter Mitral valve Interventions (TRAMI) Registry.

AIMS The influence of age on baseline demographics and outcomes of patients selected for MitraClip has not been previously investigated. METHODS AND RESULTS Baseline demographics and acute outcomes in 1,064 patients from the German TRAMI registry were stratified by age (525 patients ≥76 years and 539 patients <76 years). In elderly patients, logistic EuroSCORE was higher (25[15-40]% vs. 18[10-31]%, p<0.0001) and the proportion of women was greater (47.2% vs. 29.3%, p<0.0001). Elderly patients were more likely to have preserved left ventricular ejection fraction >50% (40.1% vs. 21.8%, p<0.0001) and degenerative mitral regurgitation (DMR, 35.3% vs. 25.6%, p<0.01). Age was the most frequent reason for non-surgical treatment in the elderly (69.4% vs. 36.1%, p<0.0001). The intrahospital MACCE (death, myocardial infarction, stroke) was low in both groups (3.5% vs. 3.4%, p=0.93) and the proportion of non-severe mitral regurgitation at discharge was similar (95.8% vs. 96.4%, p=0.73). A logistic regression model did not reveal any significant impact of age on acute efficacy and safety of MitraClip therapy. In both groups, the majority of patients were discharged home (81.8% vs. 86.2%, p=0.06). CONCLUSIONS Elderly and younger patients have similar benefits from MitraClip therapy. Age was the most frequent cause for denying surgery in elderly patients.