Francesco Musca

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.

Influence of CoreValve ReValving System Implantation on Mitral Valve Function: An Echocardiographic Study in Selected Patients

Objectives: The purpose of this study is to verify whether transcatheter aortic valve implantation (TAVI) determined changes in mitral valve (MV) function, in terms of mitral regurgitation (MR) and stenosis. Background: Little data is available regarding the effects of TAVI on global MV function, often derived from analysis primarily focused on clinical and aortic related outcomes. Methods: From May 2008 to March 2010, 73 patients with severe symptomatic aortic stenosis underwent TAVI with the CoreValve ReValving System. The study population consisted of 58 patients (27 males, mean age 82 ± 7 years) who underwent transthoracic echocardiography at least ≥1 month after implantation (mean follow‐up 7.8 ± 5.4 months). Results: In patients with a left ventricular dysfunction (ejection fraction, EF, <45%) at the baseline, EF significantly increased from 37 ± 6% to 48 ± 7% after TAVI (P = 0.003). Before TAVI, 42 patients had no or mild MR, 13 mild‐to‐moderate, and 3 moderate or moderate‐to‐severe. During follow‐up, the MR degree was unchanged in the majority of patients (55%), 12% reduced, and 33% worsened. Variables associated with worsening in MR were depth of aortic prosthesis (P = 0.02 for the distance between the ventricular end and the right coronary cusp; P = 0.04 for mean distance right‐left coronary cusps) and left atrium area at the baseline (P = 0.02). After TAVI, six patients (10%) developed mild or moderate mitral stenosis, often in a native valve with anterior calcifications. Conclusions: In the majority of patients no significant changes occurred in the degree of MR in native valve, but we found that if the aortic valve was deeply implanted in the left ventricle outflow tract, a worsening in MR can be observed. A mitral stenosis development must be sought in patients with heavy calcifications of the anterior leaflet.

Clinical and echocardiographic correlations of exercise-induced pulmonary hypertension in systemic sclerosis: A multicenter study

BACKGROUND Patients with systemic sclerosis (SSc) are at risk for developing pulmonary hypertension, which is associated with a poor prognosis. Exercise Doppler echocardiography enables the identification of exercise-induced increase in pulmonary artery systolic pressure (PASP) and may provide a thorough noninvasive hemodynamic evaluation. AIM The aim of this study was to evaluate the clinical and echocardiographic determinants of exercise-induced increase in PASP in a large population of patients with SSc. METHODS We selected 164 patients with SSc (age 58 ± 13 years, 91% female) with normal resting PASP (<40 mm Hg) who underwent a comprehensive 2-dimensional and Doppler echocardiography and graded bicycle semisupine exercise Doppler echocardiography. Pulmonary artery systolic pressure, cardiac output, and pulmonary vascular resistance (PVR) were estimated noninvasively. Cutoff values of PASP ≥50 mm Hg and PVR ≥3.0 Wood Units at peak exercise were considered a significant exercise-induced increase in PASP and PVR, respectively. RESULTS Sixty-nine (42%) patients showed a significant exercise-induced increase in PASP. Among them, peak PVR ≥3 Wood Units was present only in 11% of patients, about 5% of the total population. Univariate analysis showed that age, presence of interstitial lung disease, and both right and left diastolic dysfunction are predictors of peak PASP ≥50 mm Hg, but none of these parameters predict elevated peak PVR. CONCLUSIONS Exercise-induced increase in PASP occurs in almost one-half of patients with SSc with normal resting PASP. Peak exercise PASP is affected by age, interstitial lung disease, and right and left ventricular diastolic dysfunction and, only in 5% of the patients, is associated with an increase in PVR during exercise, suggesting heterogeneity of the mechanisms underlying exercise-induced pulmonary hypertension in SSc.

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.

Neopterin levels are independently associated with cardiac remodeling in patients with chronic heart failure

OBJECTIVES Neopterin, a marker of inflammation and monocyte activation, is found increased in patients with heart failure (HF). This study investigates whether neopterin levels correlate with left ventricular (LV) remodeling and brain natriuretic peptide (BNP), a marker of cardiac stress, in chronic HF (CHF) patients with different severity of disease. DESIGN AND METHODS The relationship between neopterin and LV dimensions, NT-proBNP, and pro-inflammatory cytokines were studied in 98 CHF patients, while nineteen healthy subjects were enrolled as controls. Nineteen (19%) patients were in NYHA class I, 38 (39%) in NYHA class II, 27 (28%) in NYHA class III, and 14 (14%) in NYHA class IV. RESULTS Neopterin levels were higher in CHF patients than in age- and gender-matched healthy controls, and related with indexed LV end-diastolic volume (LVEDVi). Prospectively CHF patients were separated into tertiles of low, medium and high neopterin levels. Among patients, male gender, LVEDVi, diuretic treatment, NYHA class I, NT-proBNP and IL-8 levels were significant determinants of urine neopterin levels by bivariate analysis. Neopterin levels were associated only to LV remodeling, as assessed by LVEDVi, and IL-8 levels, a crucial monocyte chemoattractant, by multivariate ordinal regression analysis. CONCLUSIONS The relationship between elevated neopterin levels and LV enlargement in CHF patients suggests a crucial role of monocyte activation in the development of cardiac dysfunction in CHF patients. Assessment of neopterin levels is a potential biomarker to evaluate the progression of LV remodeling in CHF patients.

Effects of Cancer Therapy Targeting Vascular Endothelial Growth Factor Receptor on Central Blood Pressure and Cardiovascular System.

BACKGROUND In the last 2 decades, new drugs that oppose the effects of vascular endothelial growth factor receptor (VEGFR), and thus angiogenesis, have considerably improved treatment of solid tumors. These anti-VEGFR drugs, however, are burdened by several side effects, particularly relevant on heart and vessels. The aim of this study was to analyze the changes in cardiovascular structure and function associated with use of anti-VEGFR drugs. METHODS Twenty-nine patients (27 affected by renal and 2 by thyroid cancer), received treatment with anti-VEGFR drugs. Brachial blood pressure (BP), central BP, carotid-femoral pulse wave velocity (cfPWV), augmentation index (Aix), and several echocardiographic markers of systolic and diastolic left ventricular functions including global longitudinal strain were measured before starting treatment (T0), after 2 (T1), and 6 weeks (T2) of treatment. RESULTS Anti-VEGFR treatment was accompanied by a significant increase of both peripheral (systolic BP +13±15.5mm Hg, diastolic BP +7.1±9.3mm Hg, P < 0.001) and central BP (systolic BP +14±14.2mm Hg, diastolic BP +7.3±10.4mm Hg, P < 0.001) and a significant raise of cfPWV (+1.3±1.8 m/sec, P = 0.003). There was also a significant alteration of markers of diastolic and subclinical left ventricular systolic function, including global longitudinal strain (-19.9±3.8% at T0, -17.8±2.6% at T2, P < 0.05). All the changes were already evident at T1, worsened at T2 in patients who maintained oncological treatment, but disappeared at T2 in patients in whom treatment was stopped. CONCLUSIONS All the changes regarding BP and cfPWV appear early after treatment initiation and seem to be reversible if treatment is stopped, instead diastolic and systolic left ventricular function are persistently altered by anti-VEGFR drugs.

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

A life-threatening presentation of eosinophilic granulomatosis with polyangiitis

: Necrotizing eosinophilic myocarditis (NEM) is a life-threatening condition that needs rapid diagnosis by endomyocardial biopsy and hemodynamic support usually by mechanical circulatory systems. We present the case of a 25-year-old Caucasian man who developed a refractory cardiogenic shock due to a NEM that was supported with a peripheral veno-arterial extracorporeal membrane oxygenation associated with intravenous steroids and recovered after 2 weeks. Further instrumental investigations lead to the final diagnosis of NEM as first presentation of eosinophilic granulomatosis with polyangiitis (formerly Churg-Strauss syndrome), remarking the importance of identifying the systemic disorder that usually triggers the eosinophilic damage of the myocardium.

Cardiac metastatic melanoma: Imaging diagnostic clues

A 47-year-old male was admitted to hospital for severe pericardial effusion; he had undergone surgical removal of cutaneous melanoma 10 years before. Echocardiography-guided pericardiocentesis revealed the presence of intramyocardial masses, which were better defined and characterized, together with pericardial involvement, by cardiac magnetic resonance. Pericardial fluid drained was negative for malignant cells, so video-assisted thoracoscopy was performed and pathologic tissue was biopsied, leading to the diagnosis of metastatic melanoma. Multidisciplinary approach and multimodality imaging played a key role in allowing the diagnostic workup in this complex case. <Learning objective: The diagnosis of cardiac metastases is challenging and histologic characterization is necessary to guide therapy. Multimodality imaging and minimally invasive thoracoscopy are key tools to achieve these goals.>.

Annexin A5 in treated hypertensive patients and its association with target organ damage

Objective: Annexin A5 (AnxA5) has been previously linked to the presence of carotid and cardiac target organ damage (TOD) in the context of heart failure and rheumatologic patients. However, information is scant in the context of hypertension. Aim of our study was to evaluate AnxA5 in treated hypertension patients compared with normotensive controls and to determine whether it is associated with vascular and heart TOD evaluated as arterial stiffness, carotid plaque and left ventricular hypertrophy. Methods: We enrolled 123 consecutive treated hypertension and 124 normotensive controls. TOD was evaluated as pulse wave velocity (PWV, complior), left ventricular hypertrophy (echocardiography) and intima–media thickness and carotid plaque presence (ecographic methods). AnxA5 levels was dosed and compared in patients with and without hypertension and with and without TOD. Results: With similar age hypertension patients showed higher SBP, DBP and AnxA5 levels (13.9 ± 11.1 vs 10.1 ± 8.4 ng/ml, P < 0.001) compared with controls. Regarding TOD hypertension showed higher PWV (8.5 ± 1.8 vs 7.6 ± 1.5 m/s, P < 0.001) and LVMI (121.7 ± 29.3 vs 113.5 ± 21.1 g/m2, P < 0.05), whereas carotid intima–media thickness was superimposable. AnxA5 correlates with PWV (r = 0.13, P < 0.05) and DBP (r = 0.15, P < 0.01), whereas it has never been found as a significant independent predictor of TOD in linear regression analysis. Conclusion: Our data have shown that AnxA5 levels are increased in treated hypertension patients. In this condition, it is probably released in the plasma as a defensive mechanism through its anti-inflammatory and anticoagulants effects. We found a significant association with arterial stiffness, but AnxA5 was not found to be a significant predictor of TOD.