Donna Mancini

ACC/AHA 2005 Guideline Update for the Diagnosis and Management of Chronic Heart Failure in the Adult

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Development and Prospective Validation of a Clinical Index to Predict Survival in Ambulatory Patients Referred for Cardiac Transplant Evaluation

BACKGROUND Risk stratification of patients with end-stage congestive heart failure is a critical component of the transplant candidate selection process. Accurate identification of individuals most likely to survive without a transplant would facilitate more efficient use of scarce donor organs. METHODS AND RESULTS Multivariable proportional hazards survival models were developed with the use of data on 80 clinical characteristics from 268 ambulatory patients with advanced heart failure (derivation sample). Invasive and noninvasive models (with and without catheterization-derived data) were constructed. A prognostic score was determined for each patient from each model. Stratum-specific likelihood ratios were used to develop three prognostic-score risk groups. The models were prospectively validated on 199 similar patients (validation sample) by calculation of the area under the receiver operating characteristic curve for 1-year event-free survival, the censored c-index for event-free survival, and comparison of event-free survival curves for prognostic-score risk strata. Outcome events were defined as urgent transplant or death without transplant. The noninvasive model performed well in both samples, and increased performance was not attained by the addition of catheterization-derived variables. Prognostic-score risk groups derived from the noninvasive model in the derivation sample effectively stratified the risk of an outcome event in both samples (1-year event-free survival for derivation and validation samples, respectively: low risk, 93% and 88%; medium risk, 72% and 60%; high risk, 43% and 35%). CONCLUSIONS Selection of candidates for cardiac transplantation may be improved by use of this noninvasive risk-stratification model.

Clinician's guide to cardiopulmonary exercise testing in adults: A scientific statement from the American heart association

Exercise testing remains a remarkably durable and versatile tool that provides valuable diagnostic and prognostic information regarding patients with cardiovascular and pulmonary disease. Exercise testing has been available for more than a half century and, like many other cardiovascular procedures, has evolved in its technology and scope. When combined with exercise testing, adjunctive imaging modalities offer greater diagnostic accuracy, additional information regarding cardiac structure and function, and additional prognostic information. Similarly, the addition of ventilatory gas exchange measurements during exercise testing provides a wide array of unique and clinically useful incremental information that heretofore has been poorly understood and underutilized by the practicing clinician. The reasons for this are many and include the requirement for additional equipment (cardiopulmonary exercise testing [CPX] systems), personnel who are proficient in the administration and interpretation of these tests, limited or absence of training of cardiovascular specialists and limited training by pulmonary specialists in this technique, and the lack of understanding of the value of CPX by practicing clinicians. Modern CPX systems allow for the analysis of gas exchange at rest, during exercise, and during recovery and yield breath-by-breath measures of oxygen uptake (Vo2), carbon dioxide output (Vco2), and ventilation (Ve). These advanced computerized systems provide both simple and complex analyses of these data that are easy to retrieve and store, which makes CPX available for widespread use. These data can be readily integrated with standard variables measured during exercise testing, including heart rate, blood pressure, work rate, electrocardiography findings, and symptoms, to provide a comprehensive assessment of exercise tolerance and exercise responses. CPX can even be performed with adjunctive imaging modalities for additional diagnostic assessment. Hence, CPX offers the clinician the ability to obtain a wealth of information beyond standard exercise electrocardiography testing that when appropriately applied and interpreted …

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).

Contribution of skeletal muscle atrophy to exercise intolerance and altered muscle metabolism in heart failure.

Background The purpose of this study was to investigate the prevalence of skeletal muscle atrophy and its relation to exercise intolerance and abnormal muscle metabolism in patients with heart failure (HF). Methods and Results Peak Vo2, percent ideal body weight (% IBW), 24-hour urine creatinine (Cr), and anthropometrics were measured in 62 ambulatory patients with HF. 31P magnetic resonance spectroscopy (MRS) and imaging (MRI) of the calf were performed in 15 patients with HF and 10 control subjects. Inorganic phosphorus (Pi), phosphocreatine (PCr), and intracellular pH were measured at rest and during exercise. Calf muscle volume was determined from the sum of the integrated area of muscle in 1-cm-thick contiguous axial images from the patella to the calcaneus. A reduced skeletal muscle mass was noted in 68% of patients, as evidenced by a decrease in Cr-to-height ratio of <7.4 mg/cm and/or upper arm circumference of <5% of normal. Calf muscle volume (MRI) was also reduced in the patients with HF (controls, 675±84 cm3/m2; HF, 567±112 cm3/m2; p < 0.05). Fat stores were largely perserved with triceps skinfold of <5% of normal and/or IBW of <80% in only 8% of patients. Modest linear correlations were observed between peak Vo2 and both calf muscle volume per meter squared (r = 0.48) and midarm muscle area (r = 0.36) (both p < 0.05). 31P metabolic abnormalities during exercise were observed in the patients with HF, which is consistent with intrinsic oxidative abnormalities. The metabolic changes were weakly correlated with muscle volume (r = −0.42, p<0.05). Conclusions These findings indicate that patients with chronic HF frequently develop significant skeletal muscle atrophy and metabolic abnormalities. Atrophy contributes modestly to both the reduced exercise capacity and altered muscle metabolism.

Outcomes of Left Ventricular Assist Device Implantation as Destination Therapy in the Post-REMATCH Era Implications for Patient Selection

Background— The landmark Randomized Evaluation of Mechanical Assistance for the Treatment of Congestive Heart Failure (REMATCH) trial first demonstrated that implantation of left ventricular assist devices (LVADs) as destination therapy (DT) can provide survival superior to any known medical treatment in patients with end-stage heart failure who are ineligible for transplantation. In the present study, we describe outcomes of DT in the post-REMATCH era in the United States. Methods and Results— The present study included 280 patients who underwent HeartMate XVE LVAD implantation between November 2001 and December 2005. A preoperative risk score for in-hospital mortality after LVAD implantation was established in 222 patients with complete data. All patients were followed up until death or December 2006. The 1-year survival after LVAD implantation was 56%. The in-hospital mortality after LVAD surgery was 27%. The main causes of death included sepsis, right heart failure, and multiorgan failure. The most important determinants of in-hospital mortality were poor nutrition, hematological abnormalities, markers of end-organ or right ventricular dysfunction, and lack of inotropic support. Stratification of DT candidates into low (n=65), medium (n=111), high (n=28), and very high (n=18) risk on the basis of the risk score calculated from these predictors corresponded with 1-year survival rates of 81%, 62%, 28%, and 11%, respectively. Conclusions— Appropriate selection of candidates and timing of LVAD implantation are critical for improved outcomes of DT. Patients with advanced heart failure who are referred for DT before major complications of heart failure develop have the best chance of achieving an excellent 1-year survival with LVAD therapy.

Effect of Erythropoietin on Exercise Capacity in Patients With Moderate to Severe Chronic Heart Failure

Background—Patients with chronic heart failure (CHF) are frequently anemic. An increase in hemoglobin could enhance exercise performance by increasing oxygen delivery. We investigated the effect of erythropoietin (EPO) on exercise performance in anemic patients with CHF. Methods and Results—Twenty-six anemic patients aged 57±11 years were randomized to receive EPO (15 000 to 30 000 IU per week) or placebo for 3 months. Parameters measured at baseline and end therapy included blood parameters (hemoglobin, hematocrit, plasma volume), exercise parameters (peak oxygen consumption [&OV0312;o2], exercise duration, 6-minute walk), muscle aerobic metabolism (half-time of &OV0312;o2 and near infrared recovery), and forearm vasodilatory function. EPO was well tolerated by all patients. Twelve patients in the EPO group felt improvement versus 1 in the placebo group (P <0.05). There were significant increases in hemoglobin (11.0±0.5 to 14.3±1.0 g/dL, P <0.05), peak &OV0312;o2 (11.0±1.8 to 12.7±2.8 mL · min−1 · kg−1, P <0.05) and exercise duration (590±107 to 657±119 s, P <0.004) in the EPO group but no significant changes in the control group. Resting and hyperemic forearm vascular resistance and indices of the rate of muscle oxidative capacity were unchanged in both groups. Conclusion—EPO significantly enhances exercise capacity in patients with CHF. One mechanism of improvement in &OV0312;o2 is increased oxygen delivery from increased hemoglobin concentration.

A randomized active-controlled trial of mycophenolate mofetil in heart transplant recipients : Mycophenolate Mofetil Investigators

BACKGROUND After heart transplantation, 1-year and 5-year survival rates are 79% and 63%, respectively, with rejection, infection, and allograft coronary artery disease accounting for the majority of deaths. Mycophenolate mofetil (MMF), an inhibitor of the de novo pathway for purine biosynthesis, decreases rejection in animals and in human renal transplantation. METHODS In a double-blind, active-controlled trial, 28 centers randomized 650 patients undergoing their first heart transplant to receive MMF (3000 mg/day) or azathioprine (1.5-3 mg/kg/day), in addition to cyclosporine and corticosteroids. Rejection and survival data were obtained for 6 and 12 months, respectively. Because 11% of the patients withdrew before receiving study drug, data were analyzed on all randomized patients (enrolled patients) and on patients who received study medications (treated patients). RESULTS Survival and rejection were similar in enrolled patients (MMF, n=327; azathioprine, n=323). In treated patients (MMF, n=289; azathioprine, n=289), the MMF group compared with the azathioprine group was associated with significant reduction in mortality at 1 year (18 [6.2%] versus 33 deaths [11.4%]; P=0.031) and a significant reduction in the requirement for rejection treatment (65.7% versus 73.7%; P=0.026). There was a trend for fewer MMF patients to have > or = grade 3A rejection (45.0% versus 52.9%; P=0.055) or require the murine monoclonal anti-CD3 antibody or antithymocyte globulin (15.2% versus 21.1%; P=0.061). Opportunistic infections, mostly herpes simplex, were more common in the MMF group (53.3% versus 43.6%; P=0.025). CONCLUSIONS Substitution of MMF for azathioprine may reduce mortality and rejection in the first year after cardiac transplantation.

Calcium Upregulation by Percutaneous Administration of Gene Therapy in Cardiac Disease (CUPID) A Phase 2 Trial of Intracoronary Gene Therapy of Sarcoplasmic Reticulum Ca2+-ATPase in Patients With Advanced Heart Failure

Background— Adeno-associated virus type 1/sarcoplasmic reticulum Ca2+-ATPase was assessed in a randomized, double-blind, placebo-controlled, phase 2 study in patients with advanced heart failure. Methods and Results— Thirty-nine patients received intracoronary adeno-associated virus type 1/sarcoplasmic reticulum Ca2+-ATPase or placebo. Seven efficacy parameters were assessed in 4 domains: symptoms (New York Heart Association class, Minnesota Living With Heart Failure Questionnaire), functional status (6-minute walk test, peak maximum oxygen consumption), biomarker (N-terminal prohormone brain natriuretic peptide), and left ventricular function/remodeling (left ventricular ejection fraction, left ventricular end-systolic volume), plus clinical outcomes. The primary end point success criteria were prospectively defined as achieving efficacy at 6 months in the group-level (concordant improvement in 7 efficacy parameters and no clinically significant worsening in any parameter), individual-level (total score for predefined clinically meaningful changes in 7 efficacy parameters), or outcome end points (cardiovascular hospitalizations and time to terminal events). Efficacy in 1 analysis had to be associated with at least a positive trend in the other 2 analyses. This combination of requirements resulted in a probability of success by chance alone of 2.7%. The high-dose group versus placebo met the prespecified criteria for success at the group-level, individual-level, and outcome analyses (cardiovascular hospitalizations) at 6 months (confirmed at 12 months) and demonstrated improvement or stabilization in New York Heart Association class, Minnesota Living With Heart Failure Questionnaire, 6-minute walk test, peak maximum oxygen consumption, N-terminal prohormone brain natriuretic peptide levels, and left ventricular end-systolic volume. Significant increases in time to clinical events and decreased frequency of cardiovascular events were observed at 12 months (hazard ratio=0.12; P=0.003), and mean duration of cardiovascular hospitalizations over 12 months was substantially decreased (0.4 versus 4.5 days; P=0.05) on high-dose treatment versus placebo. There were no untoward safety findings. Conclusions— The Calcium Upregulation by Percutaneous Administration of Gene Therapy in Cardiac Disease (CUPID) study demonstrated safety and suggested benefit of adeno-associated virus type 1/sarcoplasmic reticulum Ca2+-ATPase in advanced heart failure, supporting larger confirmatory trials. Clinical Trial Registration— http://www.clinicaltrials.gov. Unique identifier: NCT00454818.Background— Adeno-associated virus type 1/sarcoplasmic reticulum Ca2+-ATPase was assessed in a randomized, double-blind, placebo-controlled, phase 2 study in patients with advanced heart failure. Methods and Results— Thirty-nine patients received intracoronary adeno-associated virus type 1/sarcoplasmic reticulum Ca2+-ATPase or placebo. Seven efficacy parameters were assessed in 4 domains: symptoms (New York Heart Association class, Minnesota Living With Heart Failure Questionnaire), functional status (6-minute walk test, peak maximum oxygen consumption), biomarker (N-terminal prohormone brain natriuretic peptide), and left ventricular function/remodeling (left ventricular ejection fraction, left ventricular end-systolic volume), plus clinical outcomes. The primary end point success criteria were prospectively defined as achieving efficacy at 6 months in the group-level (concordant improvement in 7 efficacy parameters and no clinically significant worsening in any parameter), individual-level (total score for predefined clinically meaningful changes in 7 efficacy parameters), or outcome end points (cardiovascular hospitalizations and time to terminal events). Efficacy in 1 analysis had to be associated with at least a positive trend in the other 2 analyses. This combination of requirements resulted in a probability of success by chance alone of 2.7%. The high-dose group versus placebo met the prespecified criteria for success at the group-level, individual-level, and outcome analyses (cardiovascular hospitalizations) at 6 months (confirmed at 12 months) and demonstrated improvement or stabilization in New York Heart Association class, Minnesota Living With Heart Failure Questionnaire, 6-minute walk test, peak maximum oxygen consumption, N-terminal prohormone brain natriuretic peptide levels, and left ventricular end-systolic volume. Significant increases in time to clinical events and decreased frequency of cardiovascular events were observed at 12 months (hazard ratio=0.12; P =0.003), and mean duration of cardiovascular hospitalizations over 12 months was substantially decreased (0.4 versus 4.5 days; P =0.05) on high-dose treatment versus placebo. There were no untoward safety findings. Conclusions— The Calcium Upregulation by Percutaneous Administration of Gene Therapy in Cardiac Disease (CUPID) study demonstrated safety and suggested benefit of adeno-associated virus type 1/sarcoplasmic reticulum Ca2+-ATPase in advanced heart failure, supporting larger confirmatory trials. Clinical Trial Registration— . Unique identifier: [NCT00454818][1]. # Clinical Perspective {#article-title-37} [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT00454818&atom=%2Fcirculationaha%2F124%2F3%2F304.atom

ACC/AHA 2005 Guideline Update for the Diagnosis and Management of Chronic Heart Failure in the Adult—Summary Article

The American College of Cardiology (ACC)/American Heart Association (AHA) Task Force on Practice Guidelines regularly reviews existing guidelines to determine when an update or full revision is needed. This process gives priority to areas where major changes in text, particularly recommendations,