Francesco Salinaro

Systemic cardiac amyloidoses: disease profiles and clinical courses of the 3 main types.

Background— Most studies of amyloidotic cardiomyopathy consider as a single entity the 3 main systemic cardiac amyloidoses: acquired monoclonal immunoglobulin light-chain (AL); hereditary, mutated transthyretin-related (ATTRm); and wild-type transthyretin-related (ATTRwt). In this study, we compared the diagnostic/clinical profiles of these 3 types of systemic cardiac amyloidosis. Methods and Results— We conducted a longitudinal study of 233 patients with clear-cut diagnosis by type of cardiac amyloidosis (AL, n=157; ATTRm, n=61; ATTRwt, n=15) at 2 large Italian centers providing coordinated amyloidosis diagnosis/management facilities since 1990. Average age at diagnosis was higher in AL than in ATTRm patients; all ATTRwt patients except 1 were elderly men. At diagnosis, mean left ventricular wall thickness was higher in ATTRwt than in ATTRm and AL. Left ventricular ejection fraction was moderately depressed in ATTRwt but not in AL or ATTRm. ATTRm patients less often displayed low QRS voltage (25% versus 60% in AL; P<0.0001) or low voltage-to-mass ratio (1.1±0.5 versus 0.9±0.5; P<0.0001). AL patients appeared to have greater hemodynamic impairment. On multivariate analysis, ATTRm was a strongly favorable predictor of survival, and ATTRwt predicted freedom from major cardiac events. Conclusions— AL, ATTRm, and ATTRwt should be considered 3 different cardiac diseases, probably characterized by different pathophysiological substrates and courses. Awareness of the diversity underlying the cardiac amyloidosis label is important on several levels, ranging from disease classification to diagnosis and clinical management.

Prevention of Recurrent Lone Atrial Fibrillation by the Angiotensin-II Converting Enzyme Inhibitor Ramipril in Normotensive Patients

OBJECTIVES The aim of the present study was to verify whether angiotensin-II converting enzyme (ACE) inhibition is also effective in preventing relapses of lone atrial fibrillation (LAF), that is, in the absence of hypertension and/or heart disease. BACKGROUND Several studies have shown that ACE inhibitors are effective in preventing atrial fibrillation (AF) relapses in patients with arterial hypertension or several forms of heart disease, that is, in the presence of clinical conditions that are recognized as causing a higher risk of atrial arrhythmias. METHODS Sixty-two patients admitted to the emergency department of our institution for a first-ever episode of LAF were enrolled in the study after excluding the presence of cardiac or extracardiac conditions known to be associated with an increased risk of AF, by medical history, physical examination, complete echocardiographic study, and the evaluation of blood pressure, thyroid function, urinary catecholamines, serum electrolytes, blood glucose, red blood cell count, and arterial blood gases. After cardioversion to sinus rhythm by intravenous propafenone, patients were randomized to either ramipril 5 mg/day (n = 31) or placebo (n = 31). Holter monitoring and clinical examination were performed every 3 months. RESULTS After a 3-year follow-up, AF relapses were observed in 3 patients treated with ramipril and in 10 patients allocated to placebo (p < 0.03, Kaplan-Meier, log-rank test). During follow-up, none of the patients developed arterial hypertension or other cardiac or extracardiac condition known to be associated with increased risk of AF, that is, in all patients the diagnosis of LAF was confirmed. CONCLUSIONS Ramipril is effective in preventing relapses of LAF.

Heart Failure Resulting From Age-Related Cardiac Amyloid Disease Associated With Wild-Type Transthyretin: A Prospective, Observational Cohort Study.

Background— Heart failure caused by wild-type transthyretin amyloidosis (ATTRwt) is an underappreciated cause of morbidity and mortality in the aging population. The aims of this study were to examine features of disease and to characterize outcomes in a large ATTRwt cohort. Methods and Results— Over 20 years, 121 patients with ATTRwt were enrolled in a prospective, observational study. Median age at enrollment was 75.6 years (range, 62.6–87.8 years); 97% of patients were white. The median survival, measured from biopsy diagnosis, was 46.69 months (95% confidence interval, 41.95–56.77); 78% of deaths were attributable to cardiac causes. By Kaplan–Meier analysis, 5-year survival was 35.7% (95% confidence interval, 25–46). Impaired functional capacity (mean VO2max, 13.5 mL·kg−1·min−1) and atrial fibrillation (67%) were common clinical features. Multivariate predictors of reduced survival were elevated serum brain natriuretic peptide (482±337 pg/mL) and uric acid (8.2±2.6 mg/dL), decreased left ventricular ejection fraction (50% median; range, 10%–70%), and increased relative wall thickness (0.75±0.19). Conclusions— In this series of patients with biopsy-proven ATTRwt, poor functional capacity and atrial arrhythmias were common clinical features. Elevated brain natriuretic peptide and uric acid, decreased left ventricular ejection fraction, and increased relative wall thickness were associated with limited survival of only 35.7% at 5 years for the group as a whole. These data establish the natural history of ATTRwt, provide statistical basis for the design of future interventional clinical trials, and highlight the need for more sensitive diagnostic tests and disease-specific treatments for this disease.

Prognostic value of depressed midwall systolic function in cardiac light-chain amyloidosis.

Background: Cardiac amyloidosis represents an archetypal form of restrictive heart disease, characterized by profound diastolic dysfunction. As ejection fraction is preserved until the late stage of the disease, the majority of patients do fulfill the definition of diastolic heart failure, that is, heart failure with preserved ejection fraction (HFpEF). In another clinical model of HFpEF, that is, pressure-overload hypertrophy, depressed midwall fractional shortening (mFS) has been shown to be a powerful prognostic factor. Objective and methods: To assess the potential prognostic role of mFS in cardiac light-chain amyloidosis with preserved ejection fraction, we enrolled 221 consecutive untreated patients, in whom a first diagnosis of cardiac light-chain amyloidosis was concluded between 2008 and 2010. HFpEF was present in 181 patients. Patients in whom cardiac involvement was excluded served as controls (n = 121). Prognosis was assessed after a median follow-up of 561 days. Results: When compared with light-chain amyloidosis patients without myocardial involvement, cardiac light-chain amyloidosis was characterized by increased wall thickness (P <0.001), reduced end-diastolic left ventricular volumes (P <0.001), and diastolic dysfunction (P <0.001). In patients with preserved ejection fraction, mFS was markedly depressed [10.6% (8.7–13.5) vs. 17.8% (15.9–19.5) P <0.001]. At multivariable analysis, mFS, troponin I, and NT-pro-brain natriuretic peptide were the only significant prognostic determinants (P <0.001), whereas other indices of diastolic (E/E’ ratio, transmitral and pulmonary vein flow velocities) and systolic function (tissue Doppler systolic indices, ejection fraction), or the presence/absence of congestive heart failure did not enter the model. Conclusion: In cardiac light-chain amyloidosis with normal ejection fraction, depressed circumferential mFS, a marker of myocardial contractile dysfunction, is a powerful predictor of survival.

Echocardiographic and biohumoral characteristics in patients with AL and TTR amyloidosis at diagnosis

Few studies have analyzed the clinical and echocardiographic differences between light‐chain (AL) and transthyretin (TTR) amyloidosis.

Longitudinal systolic strain, cardiac function improvement, and survival following treatment of light-chain (AL) cardiac amyloidosis

Aims To determine whether echocardiographic longitudinal systolic strain (LS) parameters identify short-term improvement following chemotherapy for light-chain (AL) cardiac amyloidosis (CA). Among patients with CA, standard echocardiographic measures are commonly unchanged at 1 year following successful chemotherapy, despite observed reductions in cardiac biomarkers. Methods and results We retrospectively identified 61 patients with AL-CA treated with high-dose melphalan or bortezomib-based regimens. Patients were classified by hematologic response at 1 year into two groups: complete response (CR; n = 18, or 30%) or non-CR (non-CR; n = 43, or 70%), and followed for 20 months. Serum free light chains (FLC), B-type natriuretic peptide (BNP), troponin I (TnI), and echocardiography including LS, were acquired at baseline and 1 year. Seven patients died (11.5%), all in the non-CR group (P < 0.01). At 1 year, while reductions were observed in BNP (44% CR, 18% non-CR) and FLC (94% CR, 73% non-CR), both P < 0.05 from baseline, there were no differences in wall thickness, EF, or diastolic function in either group. LS improved only in the CR group with notable improvement in apical to basal strain ratio (P < 0.05). Strain improvement and BNP reduction were correlated (R = 0.6, P < 0.01). Baseline global LS < -10.2% was associated with survival and proved superior to BNP and TnI. The addition of global LS to biomarkers identified the patients at highest risk of mortality. Conclusion These data suggest that LS is a sensitive measure of pre-treatment cardiac functional impairment in AL-CA, can predict survival over and above that of cardiac biomarkers, and detect early cardiac functional improvement following chemotherapy.

Early development of metabolic syndrome in patients subjected to lung transplantation

Cardiovascular disease is a common cause of morbidity and mortality after solid organ transplantation, due to a combination of pre‐existing cardiovascular risk factors and immunosuppressive drug toxicity. The prevalence of new‐onset hypertension, dyslipidemia, diabetes mellitus, and metabolic syndrome was assessed after lung transplantation in a cohort of 67 patients (mean age: 48 ± 14 yr). The prevalence of hypertension increased from 19.4% to 70.1% at the three‐yr follow‐up visit (p < 0.01). The concomitant prevalence of diabetes and dyslipidemia raised from 13.4% to 31.3%, and from 6.0% to 40.3%, respectively (p < 0.01 for both), and body mass index increased from 22.4 ± 3.7 to 26.1 ± 3.9 kg/m2 (p < 0.01). The prevalence of metabolic syndrome increased from 3.0% to 23.9% after the first year, to remain stable thereafter, associated with a strict control of cardiovascular risk factors. A large number of lung transplant recipients develop new‐onset hypertension, diabetes, dyslipidemia after transplantation, and in more than one‐fifth metabolic syndrome can be diagnosed after the first year. The increased cardiovascular risk of these patients should be taken into account during follow‐up, to better define a proper and timely cardiovascular prevention. Adequate control of cardiovascular risk factors, preventing further metabolic syndrome development, is recommended and feasible in lung transplant recipients.

Functional correlates of N-terminal natriuretic peptide type B (NT-proBNP) response to therapy in cardiac light chain (AL) amyloidosis

In cardiac (light chain) AL amyloidosis, a decrease in circulating free light chains (FLCs) higher than 50% is associated with reduced Nterminal natriuretic peptide type B (NT-proBNP) serum concentration, improvement of heart failure symptoms, and prolonged survival. To assess the functional correlates of these changes, echocardiographic indices of systolic and diastolic regional function were compared at diagnosis and after response achievement in 32 patients. FLCs and NT-proBNP were concomitantly measured. No significant change in left ventricular wall thicknesses, chamber dimensions, indices of diastolic dysfunction or ejection fraction was observed after chemotherapy. In contrast, systolic longitudinal excursion of both the interventricular septum and the lateral wall was increased (from 5.2+ 1.4 to 6.8+ 1.5 and from 6.2+ 1.3 to 7.7+ 1.4 mm, respectively; p5 0.05 for both). These changes were significantly correlated with the extent of FLCs (p1⁄4 0.05) and NTproBNP (p1⁄4 0.05) reduction. In cardiac AL amyloidosis, hematological response to chemotherapy and reduction of cardiac biomarkers are associated with improved indices of regional systolic function. Introduction: In patients with AL amyloidosis and cardiac involvement, a decrease in circulating free light chains (FLCs) higher than 50% is associated with a reduction in N-terminal natriuretic peptide type B (NT-proBNP) serum concentration, improvement of symptoms of heart failure, and prolonged survival [1], despite the amount of cardiac amyloid deposits remains unaltered, as measured by echocardiography. Notably, it has been recently suggested that NT-proBNP changes may not ‘track’ FLCs reduction when immune modulator drugs are included in the chemotherapy schedule [2]. However, since NT-proBNP has been shown as a robust prognostic marker in the setting of cardiac AL [3,4], it is important to assess what are the functional correlates of the reduction of the circulating amyloidogenic precursor caused by chemotherapy, in parallel with both FLCs and NT-proBNP changes. Aim of the present study was therefore to assess changes in cardiac function associated with reduction in circulating FLCs and serum NT-proBNP concentration in patients with cardiac AL amyloidosis achieving hematologic response. Methods: In 32 patients with cardiac AL amyloidosis who achieved hematologic response (defined as a reduction of circulating FLCs by more than 50% [1]) after three cycles of chemotherapy, echocardiographic indices of systolic, and diastolic regional function, as well as serum NT-proBNP were compared at diagnosis and after response achievement. Echocardiography was performed by a single operator via an Acuson Sequoia 512 machine (Siemens Healthcare, Milano, Italy). Left ventricular (LV) wall thicknesses and chamber dimensions were measured by 2D-guided M-mode evaluation in the longitudinal parasternal view, according to the standards of the American Society of Echocardiography [5]. Diastolic function was characterized in terms of: transmitral Doppler early (E) and atrial (A) velocities, E deceleration time, pulmonary venous flow velocity, early tissue Doppler (TDI) peak velocity (E’) and E/E’ ratio. Systolic function was evaluated as: LV ejection fraction (EF), longitudinal excursion of the mitral annulus at the septum, and at lateral wall. Patients with significant valve disease, previous myocardial infarction, atrial fibrillation, or chronic obstructive lung disease were excluded from the analysis. Results and discussion: Chemotherapy-related reduction in circulating FLCs was paralleled by a 47% median decrease in serum NT-proBNP, thereby confirming previous observations [1]. No significant change in LV wall thicknesses, end-diastolic and end-systolic chamber dimensions, global systolic function, or indices of diastolic function was observed after chemotherapy. In detail, when comparing data at diagnosis and after treatment, interventricular septum thickness was 14.2+ 2.1 and 14.3+ 2.3 mm, posterior wall thickness was 13.9+ 2.1 and 13.9+ 2.3 mm, LV diameters were 42+ 3 and 44+ 4 mm at end-diastole and 30+ 2 and 29+ 4 at end-systole, and EF was 55+ 4% and 54+ 4%, respectively (p1⁄4ns for all comparisons). No significant change in transmitral Doppler peak velocities, E deceleration time, pulmonary venous flow velocity, early TDI peak velocity (E’), and E/E’ ratio was observed. In contrast, longitudinal excursion of both the interventricular septum and the 96

Direct renin inhibition: another weapon to modulate the renin-angiotensin system in postinfarction remodeling?

The process of cardiac healing and recovery after an acute myocardial infarction encompasses profound changes in the necrotic area (“infarct zone”), in the neighboring ischemic zone (“area at risk”), and in the nonischemic myocardium (“nonischemic region”). Patient’s prognosis ultimately depends on the functional, biochemical, electric, and structural changes taking place in these 3 different areas as a consequence of the acute ischemic event. These extracellular, cellular, and subcellular events are globally referred to as “postinfarction remodeling,” and therapeutic interventions able to slow or reverse its progression have a favorable impact on patient prognosis.1 A pivotal role in these processes is played by the renin-angiotensin-aldosterone system (RAAS) that is undoubtedly hyperactivated after myocardial infarction, together with other neural and endocrine systems. Locally synthesized angiotensin II has been suggested to act as an autocrine, paracrine, and intracrine modulator of cardiac function.2 Notably, the major components of the RAAS components have been shown in cardiac tissue, and extracardiac renin uptake is associated with local release by myocardial mast cells.3 Angiotensin II intracellular signal transduction involves the phosphorylation of several proteins, such as membrane transporters and selective ion channels, structural and contractile proteins, and enzymes that regulate metabolism, protein synthesis, and gene expression. These multiple actions are mediated via complex intracellular signaling pathways, including stimulation of the phospholipase C-inositol 1,4,5-trisphosphate-1,2-diacylglycerol cascade, mitogen-activated protein kinases, tyrosine kinases, RhoA/Rho kinase, and reactive oxygen species generation through vascular NADPH oxidase activation. Beyond directly affecting vasomotor tone, angiotensin II potentiates the effects of several vasoconstrictor hormones, facilitates the central and …

A SIMPLE VOLTAGE/MASS INDEX IMPROVES DIAGNOSIS OF CARDIAC AMYLOIDOSIS: AN ELECTROCARDIOGRAPHIC AND ECHOCARDIOGRAPHIC STUDY OF 570 PATIENTS WITH LEFT VENTRICULAR HYPERTROPHY

Amyloidotic cardiomyopathy (AC) can mimic other diseases with left ventricular (LV) hypertrophy, including hypertrophic cardiomyopathy (HCM) and hypertensive heart disease (HHD). Low QRS voltage on ECG provides valuable clues for the non-invasive suspicion of AC. However its sensitivity is limited