Rationale, application and clinical qualification for NT-proBNP as a surrogate end point in pivotal clinical trials in patients with AL amyloidosis.

Amyloid light-chain (LC) amyloidosis (AL amyloidosis) is a rare and fatal disease for which there are no approved therapies. In patients with AL amyloidosis, LC aggregates progressively accumulate in organs, resulting in organ failure that is particularly lethal when the heart is involved. A significant obstacle in the development of treatments for patients with AL amyloidosis, as well as for those with any disease that is rare, severe and heterogeneous, has been satisfying traditional clinical trial end points (for example, overall survival or progression-free survival). It is for this reason that many organizations, including the United States Food and Drug Administration through its Safety and Innovation Act Accelerated Approval pathway, have recognized the need for biomarkers as surrogate end points. The international AL amyloidosis expert community is in agreement that the N-terminal fragment of the pro-brain natriuretic peptide (NT-proBNP) is analytically validated and clinically qualified as a biomarker for use as a surrogate end point for survival in patients with AL amyloidosis. Underlying this consensus is the demonstration that NT-proBNP is an indicator of cardiac response in all interventional studies in which it has been assessed, despite differences in patient population, treatment type and treatment schedule. Furthermore, NT-proBNP expression is directly modulated by amyloidogenic LC-elicited signal transduction pathways in cardiomyocytes. The use of NT-proBNP will greatly facilitate the development of targeted therapies for AL amyloidosis. Here, we review the data supporting the use of NT-proBNP, a biomarker that is analytically validated, clinically qualified, directly modulated by LC and universally accepted by AL amyloidosis specialists, as a surrogate end point for survival.

Echocardiographic assessment of pressure volume relations in heart failure and valvular heart disease: using imaging to understand physiology.

Pressure volume (PV) based analysis, using classic hemodynamic principles, has served as a basis for our understanding of cardiac physiology and disease states for decades. However, PV analysis has been restricted to primarily the basic research setting and for preclinical testing and has not be widely applied in part because of the invasive nature of the procedure and the expertise required to obtain adequate data using the conductance catheter. Development of single beat methodologies that rely on echocardiographic measurements of ventricular volume and Doppler and peripheral estimates of ventricular pressure and timing of the cardiac cycle has enabled broader application of PV analysis. This review explores the physiologic background, basic methodology, and recent and potential future applications of noninvasive PV analysis.

Predictors of survival in patients with systemic light-chain amyloidosis and cardiac involvement initially ineligible for stem cell transplantation and treated with oral melphalan and dexamethasone.

The treatment of systemic light-chain (AL) amyloidosis with symptomatic cardiac involvement at diagnosis remains a challenge. We report the results of 40 consecutive newly diagnosed AL cardiac patients who were not candidates for stem cell transplant and therefore received monthly oral melphalan and dexamethasone. Median survival was 10.5 months and baseline predictors of survival included gender, troponin I and interventricular septal thickness. The most significant predictor of survival was response to therapy. The haematological response rate was 58% (23/40) with 13% (5/40) complete responses; most responses were noted in <3 cycles. Achievement of a rapid response to therapy extends survival.

Upright posture and postprandial hypotension in elderly persons.

BACKGROUND: Syncope and falls are common in elderly persons and often result from the interaction of multiple clinical abnormalities. Both orthostatic hypotension and postprandial hypotension increase in prevalence with age. OBJECTIVE: To determine whether meal ingestion enhances orthostatic hypotension in elderly persons. DESIGN: Controlled paired comparison. SETTING: Clinical research center. PATIENTS: 50 functionally independent elderly persons recruited from local senior centers (n = 47) and from patients hospitalized with an unexplained fall or syncope (n = 3) (mean age, 78 years [range, 61 to 96 years]). Twenty-five participants (50%) were taking antihypertensive medication. MEASUREMENTS: Sequential head-up tilt-table testing at 60 degrees was performed before and 30 minutes after ingestion of a standardized warm liquid meal that was high in carbohydrates. Heart rate and blood pressure were continuously monitored. RESULTS: Meal ingestion (P < 0.01) and time spent upright (P < 0.001) were significantly associated with systolic blood pressure, but no significant interaction was found between meal ingestion and time spent upright (P > 0.2). These findings suggest that the association between meal ingestion and head-up tilt-table testing were additive and not synergistic. However, the proportion of participants with symptomatic hypotension increased during head-up tilt-table testing after meal ingestion (12% during preprandial testing and 22% during postprandial testing). Symptomatic hypotension tended to occur more often and sooner after meal ingestion than before meal ingestion (P = 0.03). CONCLUSIONS: Meal ingestion and head-up tilt-table testing are associated with increasing occurrences of symptomatic hypotension. After meal ingestion and head-up tilt-table testing, 22% of functionally independent elderly persons had symptomatic hypotension.

Prevalence and prognostic significance of exercise-induced supraventricular tachycardia in apparently healthy volunteers.

The prevalence, characteristics, and prognostic significance of supraventricular tachycardia (SVT) occurring during maximal treadmill exercise testing were examined in 843 male and 540 female asymptomatic volunteers aged 20 to 94 years from the Baltimore Longitudinal Study of Aging who underwent exercise testing a mean of 2.3 times between 1977 and 1991. Exercise-induced SVT occurred during at least 1 test in 51 men (6.0%) and 34 women (6.3%), p = NS for gender. The 85 subjects with exercise-induced SVT were significantly older than the 1,298 free from this arrhythmia (66.0 +/- 13.5 vs 49.7 +/- 18.0 years, respectively, p < 0.001). The prevalence of SVT increased with age in men (p < 0.001) but not in women. Ninety-eight percent of the 141 discrete episodes of exercise-induced SVT were paroxysmal SVT, with heart rates varying from 105 to 290 beats/min (mean 186.3 +/- 43.3); only 16% were > 10 beats in duration and only 4% of subjects were symptomatic. Nearly half (44%) of SVT episodes occurred at peak effort. Coronary risk factors, echocardiographic left atrial size (3.3 +/- 6.7 vs 3.3 +/- 0.6 cm), and the prevalence of exercise-induced ischemic ST-segment depression (11% vs 13%) were similar in 85 subjects with SVT and 170 control subjects matched for age and sex.(ABSTRACT TRUNCATED AT 250 WORDS)