Preserved Functional Capacity Research Articles

Patisiran Treatment in Patients with Transthyretin Cardiac Amyloidosis

BackgroundTransthyretin amyloidosis, also called ATTR amyloidosis, is associated with accumulation of ATTR amyloid deposits in the heart and commonly manifests as progressive cardiomyopathy. Patisiran, an RNA interference therapeutic agent, inhibits the production of hepatic transthyretin.MethodsIn this phase 3, double-blind, randomized trial, we assigned patients with hereditary, also known as variant, or wild-type ATTR cardiac amyloidosis, in a 1:1 ratio, to receive patisiran (0.3 mg per kilogram of body weight) or placebo once every 3 weeks for 12 months. A hierarchical procedure was used to test the primary and three secondary end points. The primary end point was the change from baseline in the distance covered on the 6-minute walk test at 12 months. The first secondary end point was the change from baseline to month 12 in the Kansas City Cardiomyopathy Questionnaire–Overall Summary (KCCQ-OS) score (with higher scores indicating better health status). The second secondary end point was a composite of death from any cause, cardiovascular events, and change from baseline in the 6-minute walk test distance over 12 months. The third secondary end point was a composite of death from any cause, hospitalizations for any cause, and urgent heart failure visits over 12 months.ResultsA total of 360 patients were randomly assigned to receive patisiran (181 patients) or placebo (179 patients). At month 12, the decline in the 6-minute walk distance was lower in the patisiran group than in the placebo group (Hodges–Lehmann estimate of median difference, 14.69 m; 95% confidence interval [CI], 0.69 to 28.69; P=0.02); the KCCQ-OS score increased in the patisiran group and declined in the placebo group (least-squares mean difference, 3.7 points; 95% CI, 0.2 to 7.2; P=0.04). Significant benefits were not observed for the second secondary end point. Infusion-related reactions, arthralgia, and muscle spasms occurred more often among patients in the patisiran group than among those in the placebo group.ConclusionsIn this trial, administration of patisiran over a period of 12 months resulted in preserved functional capacity in patients with ATTR cardiac amyloidosis. (Funded by Alnylam Pharmaceuticals; APOLLO-B ClinicalTrials.gov number, NCT03997383.)

Abstract 9912: A Case of Left Ventricle Non-Compaction in an Asymptomatic Athlete

Introduction: Left ventricle non-compaction (LVNC) is defined as a primary genetic cardiomyopathy by the American Heart Association and as an unclassified cardiomyopathy by the European Society of Cardiology. Phenotypically, it is characterized by prominent trabeculations and intertrabecular recesses in the ventricular cavity. The clinical manifestations of LVNC range from an asymptomatic state to progressive heart failure and life-threatening arrhythmias. The following case highlights an athletic patient with LVNC. Case Presentation: A 22-year-old male presented to the cardiology clinic for evaluation prior to enrolling in the police academy. At age 15, an echo revealed prominent trabeculations. The patient has been a competitive soccer player since high school. Upon presentation, he was asymptomatic with non-specific T wave changes noted on ECG, stress echocardiography revealed preserved functional capacity, prominent trabeculations, and EF 55%. No arrhythmias were noted. CMR revealed a hyper-trabeculated LV predominantly at the mid-ventricular and apical segments, moderate left and right ventricular enlargement with EF 55%. No LGE enhancement was noted. Discussion: LVNC is estimated to affect 8-12 patients per 1 million annually, but the actual number is likely higher as many individuals are asymptomatic. Although the cause of LVNC is unclear, it has been associated with mutations in sarcomere encoding genes including MYH7 and MYBPC3. It remains controversial whether LVNC is a distinct disorder since it has been reported in other cardiomyopathies and since it has been reported in pregnancy and trained athletes. The current diagnostic criteria for LVNC include a ratio of non-compacted to compacted myocardium >2.1:1 as demonstrated by echo or a ratio of >2.3:1 by CMR. However, it has been proposed that trabeculation formation represents a physiological adaptation to increased loading conditions seen in pregnancy and vigorously trained athletes. Therefore, it remains unclear whether the current diagnostic criteria apply to an athletic population. Furthermore, the prognostic implications of prominent trabeculations meeting accepted diagnostic criteria for LVNC remain uncertain.

Clinical biochemistry profile of biventricular heart failure in a mixed-breed bitch

A six-year old mixed-breed bitch was presented for chronic ascites. A diagnostic work-up was crafted to ascertain the cause of fluid accumulation in the peritoneal cavity. Clinical biochemistry tests for status of the liver and kidneys were performed. Elevations in absolute concentrations of the liver enzymes aspartate aminotransferase (AST) and alkaline phosphatase (ALP) were useful in evaluation of hepatocellular damage associated with right-sided heart failure. Normal levels of serum albumin and bilirubin, however, underscored the preserved functional capacity of the liver in spite of hepatocellular damage. Elevation of blood urea nitrogen, but not creatinine, was significant in appraisal of low cardiac output chronic renal failure resulting from left-sided heart failure. Increase in blood urea nitrogen was a valuable prognostic indicator of subsequent death resulting from biventricular heart failure, in contrast to serum bilirubin or albumin concentrations. Clinical biochemical profiles for liver and kidney functions in heart failure patients allow for estimation of the extent of hepatic and renal complications. Renal dysfunction carries a grave prognosis.

Abstract 13539: Functional Evaluation in Aortic Stenosis: Determinant of Exercise Capacity

Background: Aortic stenosis (AS) is clinically characterized by dyspnea and intolerance to exercise. Clinical interpretation of such symptoms is often difficult due to the advanced age of AS patients. We aimed at identifying cardiac determinants of exercise intolerance in AS (Aortic Vmax >3 m/s). Methods and results: We performed cardiopulmonary exercise test (CPET) simultaneously combined with exercise echocardiography in 43 patients with AS referred for functional assessment. Severe AS were evaluated because of symptoms not certainly related to valvular disease. Patients underwent a symptoms-limited maximal exercise, considering the 75% of predicted VO2 consumption as a marker of preserved functional capacity. Twenty-three patients had preserved functional capacity (group A), showing higher work, maximal VO2, O2 pulse and better VE/VCO2 and heart rate recovery. No differences were found in terms of rest systolic function and AS severity, while group A had higher peak heart rate (HR), higher peak cardiac power output (cardiac output x systolic pressure) and higher peak-rest transaortic mean gradient difference (ΔMG). At multivariate analysis, only ΔMG resulted independently associated with impaired functional capacity (p =0.048; CI 1.001-1.323). Conclusions: AS patients can present functional impairment which is related to cardiac response to exercise rather than to stenosis severity. These results suggest the role of inotropic and contractile reserve supporting the routinely evaluation of cardiac reserve as a determinant of symptoms development.

A discordance in rosiglitazone mediated insulin sensitization and skeletal muscle mitochondrial content/activity in Type 2 diabetes mellitus

Skeletal muscle mitochondrial dysfunction is hypothesized to contribute to the pathophysiology of insulin resistance and Type 2 diabetes. Whether thiazolidinedione therapy enhances skeletal muscle mitochondrial function as a component of its insulin-sensitizing effect is unknown. To test this, we evaluated skeletal muscle mitochondria and exercise capacity in Type 2 diabetic subjects with otherwise normal cardiopulmonary function in response to rosiglitazone therapy. Twenty-three subjects were treated for 12 wk and underwent pre- and posttherapy metabolic stress testing and skeletal muscle biopsies. Rosiglitazone significantly ameliorated fasting glucose, insulin, and free fatty acid levels but did not augment the subjects' maximal oxygen consumption (Vo(2max)) or their skeletal muscle mitochondrial copy number. The baseline Vo(2max) correlated strongly with muscle mitochondrial copy number (r = 0.56, P = 0.018, n = 17) and inversely with the duration of diabetes (r = -0.67, P = 0.004, n = 23). Despite the global lack of effect of rosiglitazone-mediated insulin sensitization on skeletal muscle mitochondria, subjects with the most preserved functional capacity demonstrated some plasticity in their mitochondria biology as evidenced by an upregulation of electron transfer chain proteins and in citrate synthase activity. This study demonstrates that the augmentation of skeletal muscle mitochondrial electron transfer chain content and/or bioenergetics is not a prerequisite for rosiglitazone-mediated improved insulin sensitivity. Moreover, in diabetic subjects, Vo(2max) reflects the duration of diabetes and skeletal muscle mitochondrial content. It remains to be determined whether longer-term insulin sensitization therapy with rosiglitazone will augment skeletal muscle mitochondrial bioenergetics in those diabetic subjects with relatively preserved basal aerobic capacity.

Global dysfunction of CD4 T-lymphocyte cytokine expression in simian-human immunodeficiency virus/SIV-infected monkeys is prevented by vaccination.

Human immunodeficiency virus type 1 infection results in a dysfunction of CD4(+) T lymphocytes. The intracellular events contributing to that CD4(+) T-lymphocyte dysfunction remain incompletely elucidated, and it is unclear whether aspects of that dysfunction can be prevented. The present studies were pursued in a rhesus monkey model of AIDS to explore these issues. Loss of the capacity of peripheral blood CD4(+) T lymphocytes to express cytokines was first detected in simian immunodeficiency virus-infected monkeys during the peak of viral replication during primary infection and persisted thereafter. Moreover, infected monkeys with progressive disease had peripheral blood CD4(+) T lymphocytes that expressed significantly less cytokine than infected monkeys that had undetectable viral loads and intact CD4(+) T-lymphocyte counts. Importantly, CD4(+) T lymphocytes from vaccinated monkeys that effectively controlled the replication of a highly pathogenic immunodeficiency virus isolate following a challenge had a preserved functional capacity. These observations suggest that an intact cytokine expression capacity of CD4(+) T lymphocytes is associated with stable clinical status and that effective vaccines can mitigate against CD4(+) T-lymphocyte dysfunction following an AIDS virus infection.

Activity of angiotensin-converting enzyme and risk of severe hypoglycaemia in type 1 diabetes mellitus

The insertion (I) allele of the angiotensin-converting-enzyme (ACE) gene occurs at increased frequency in endurance athletes. This association suggests that low ACE activity is favourable for performance in conditions with limited substrate availability. Such conditions occur in endurance athletes during competition and in diabetic patients during insulin-induced hypoglycaemia. Patients rely on preserved functional capacity to recognise hypoglycaemic episodes and avoid progression by self-treatment. We studied whether ACE activity is related to the risk of severe hypoglycaemia in type 1 diabetes. Consecutive adult outpatients with type 1 diabetes, untreated with ACE inhibitors or angiotensin-II-receptor antagonists (n=207) reported their experience of mild and severe hypoglycaemia during the previous 1 year and 2 years. The patients were further characterised by diabetes history, degree of hypoglycaemia awareness, measurement of C-peptide, haemoglobin A(1c), and serum ACE concentrations, and determination of ACE genotype. Patients with the DD genotype had a relative risk of severe hypoglycaemia in the preceding 2 years of 3.2 (95% CI 1.4-7.4) compared with those who had the II genotype. There was a significant relation between serum ACE activity and the rate of severe hypoglycaemia (relative risk per 10 U/L increment 1.4 [1.2-1.6]), corresponding to a 3.5 times higher risk for patients in the highest quartile than for those in the lowest quartile. Multiple regression analysis showed that the effect of the ACE genotype was explained by its influence on serum ACE activity and that the only other significant determinants of the risk of severe hypoglycaemia were the degree of hypoglycaemia awareness, b-cell function, and duration of diabetes of more than 20 years. ACE activity is a clinically significant marker of the risk of severe hypoglycaemia in patients with type 1 diabetes, especially in those with impaired defence against hypoglycaemia. These findings need to be confirmed in prospective studies.

Radiation tolerance of cirrhotic livers in relation to the preserved functional capacity: Analysis of patients with hepatocellular carcinoma treated by focused proton beam radiotherapy

Purpose : To determine the preserved functional capacity of the liver as a probable determinant of radiation tolerance in patients with cirrhosis and hepatocellular carcinoma, who underwent proton beam radiotherapy. Materials and Methods : We reviewed computed tomographic (CT) scans of 26 patients with cirrhosis and hepatocellular carcinoma during a period of 12–27 months after proton beam radiotherapy. Tumors were treated with focused proton beams with target doses of 140–186 TDF (time, dose, and fractionation). We measured the degree of hypertrophy of the untreated liver volume by measuring the total liver volume and the treated liver volume which was radiologically identified on contrast-enhanced CT scans. The risk of radiation-induced liver failure was estimated using the prediction score (PS) originally used for estimating posthepatectomy liver failure, substituting the planned treated liver volume for the resection liver volume. Results : The degree of hypertrophy ranged from —19% to 51%, and was significantly positively correlated with the ratio of the planned treated liver volume to the functional liver volume. The PS agreed well with observed radiation tolerance in 21 patients, but underestimated the tolerance in 5. This underestimation was diminished when the PS was recalculated using the identified untreated liver volume in lieu of the planned untreated liver volume. Conclusion : As in surgical treatment, radiation tolerance of the cirrhotic liver after focused treatement is closely related to the preserved functional capacity of the identified untreated liver volume, which shows compensatory hypertrophy following radiotherapy.

Radiation tolerance of the liver in relation to the preserved functional capacity.

The radiation tolerance of the liver was investigated in 12 patients, 11 of them with liver cirrhosis, treated for hepatocellular carcinoma by partial liver irradiation with doses between 50 and 77 Gy. The tolerance was assessed by the complication probability (Lyman's model), which concerned the injured tissue itself, and by a prediction score used for postsurgical liver failure, which concerned the preserved functional capacity, assuming that the > or = 30 Gy volume was equivalent to the resected volume. The prediction score corresponded better with the observed risk of fatal liver failure than the complication probability. The liver volume after radiotherapy correlated largely with the untreated volume and the low-dose volume. Thus the preserved functional capacity gives a better expression of the radiation tolerance than direct measures of the extent of injured tissue.