Growth differentiation factor-15 is a new biomarker for survival and renal outcomes in light chain amyloidosis.

Growth differentiation factor-15 (GDF-15) improves prognostication in patients with cardiovascular disorders in addition to conventional cardiac markers (N-terminal pro B-type natriuretic peptide [NT-proBNP], troponins [Tns]) and has shown prognostic value in patients with renal diseases. In patients with light chain (AL) amyloidosis, cardiac involvement is the major determinant of prognosis, and cardiac markers define prognosis, whereas biomarkers of renal involvement stratify renal risk. We explored the prognostic importance of serum level of GDF-15 in patients with AL amyloidosis in 2 independent cohorts. The prognostic value of GDF-15 level was initially evaluated in a cohort of 107 consecutive previously untreated patients with AL amyloidosis from Athens, Greece, and was then validated in a second cohort of 202 consecutive previously untreated patients from Pavia, Italy. High GDF-15 level was associated with a higher risk of early death and poor overall survival independently of NT-proBNP and high-sensitivity TnT (hsTnT) or hsTnI levels. At the 6-month landmark, reduction of GDF-15 level ≥25% was associated with improved outcome. GDF-15 level ≥4000 pg/mL was associated with a high risk of progression to dialysis, independently of renal risk defined by estimated glomerular filtration rate and proteinuria, in both cohorts; failure to reduce GDF-15 below this level was associated with increased risk at either the 3- or 6-month landmark, independently of the established renal response or progression criteria. In conclusion, GDF-15 has prognostic implications for different outcomes in patients with AL and adds prognostic information independent of that provided by cardiac and renal risk biomarkers.

Clinical and prognostic significance of serum levels of von Willebrand factor and ADAMTS-13 antigens in AL amyloidosis.

Cardiac dysfunction determines prognosis in amyloid light-chain (AL) amyloidosis. The heart is the central organ of the vascular system in which endothelium function is critical for the circulatory homeostasis, but there are limited data on endothelial function in AL amyloidosis. von Willebrand factor (VWF) has been considered as a marker of endothelial activation and dysfunction, whereas a disintegrin and metalloproteinase with thrombospondin type-1 repeats 13 (ADAMTS-13) cleaves VWF multimers, but both have been associated with prognosis in cardiovascular disease. We measured the serum levels of VWF (VWF:Ag) and ADAMTS-13 antigens in 111 newly diagnosed patients with AL amyloidosis. The levels of VWF:Ag were significantly higher than in healthy controls; 76% of patients with AL had VWF:Ag levels higher than the upper levels of controls. There was no significant association of VWF:Ag levels with patterns of organ involvement, free light-chain levels, the levels of cardiac biomarkers, or renal dysfunction but correlated with low systolic blood pressure. VWF:Ag levels ≥230.0 U/dL were associated with higher probability of early death and poor survival independently of cardiac biomarkers and low systolic blood pressure (SBP). Moreover, among patients with Mayo stage III or stage IIIB (that is stage III with N-terminal pro-brain natriuretic peptide [NTproBNP] >8500 pg/mL) disease, VWF:Ag identified subgroups of patients with very poor outcome. Low ADAMTS-13 levels correlated with high levels of NTproBNP but had no independent prognostic significance. In conclusion, high VWF:Ag levels, probably representing endothelial dysfunction, are associated with prognosis in patients with AL amyloidosis, independently of other features of the disease or cardiac biomarkers.

Long-term outcomes of primary systemic light chain (AL) amyloidosis in patients treated upfront with bortezomib or lenalidomide and the importance of risk adapted strategies.

Bortezomib and lenalidomide are increasingly used in patients with AL amyloidosis, but long term data on their use as primary therapy in AL amyloidosis are lacking while early mortality remains significant. Thus, we analyzed the long term outcomes of 85 consecutive unselected patients, which received primary therapy with bortezomib or lenalidomide and we prospectively evaluated a risk adapted strategy based on bortezomib/dexamethasone to reduce early mortality. Twenty-six patients received full-dose bortezomib/dexamethasone, 36 patients lenalidomide with oral cyclophosphamide and low-dose dexamethasone and 23 patients received bortezomib/dexamethasone at a dose and schedule adjusted to the risk of early death. On intent to treat, 67% of patients achieved a hematologic response (24% hemCRs) and 34% an organ response; both were more frequent with bortezomib. An early death occurred in 20%: in 36% of those treated with full-dose bortezomib/dexamethasone, in 22% of lenalidomide-treated patients but only in 4.5% of patients treated with risk-adapted bortezomib/dexamethasone. Activity of full vs. adjusted dose bortezomib/dexamethasone was similar; twice weekly vs. weekly administration of bortezomib also had similar activity. After a median follow up of 57 months, median survival is 47 months and is similar for patients treated with bortezomib vs. lenalidomide-based regimens. However, risk adjusted-bortezomib/dexamethasone was associated with improved 1-year survival vs. full-dose bortezomib/dexamethasone or lenalidomide-based therapy (81% vs. 56% vs. 53%, respectively). In conclusion, risk-adapted bortezomib/dexamethasone may reduce early mortality and preserve activity while long term follow up indicates that remissions obtained with lenalidomide or bortezomib may be durable, even without consolidation with alkylators.

Noncompaction cardiomyopathy and pregnancy: An alarming coexistence ending in a favourable outcome.

Noncompaction of the left ventricular myocardium has gained increasing recognition over the past 25 years. This rare disease is caused by the arrest of myocardial morphogenesis. The classical triad of complications are heart failure, arrhythmias, including sudden cardiac death, and systemic embolic events. There is a paucity of data regarding women with left ventricular noncompaction cardiomyopathy and pregnancy outcome. The first report of an uneventful vaginal delivery without deterioration of left ventircular noncompaction cardiomyopathy is presented.

Is left ventricular dysfunction reversed after treatment of active acromegaly?

It has been suggested that control of GH and IGF excess can arrest the progression of cardiovascular abnormalities and normalize cardiac performance. The aim of the present study was to investigate the reversibility of acromegalic cardiomyopathy in patients with active and inactive disease and to evaluate the effect of the inactivity of the disease on left ventricular (LV) diastolic dysfunction, irrespective of the applied treatment. The patient population consisted of 55 patients who were studied in the active and/or inactive phase. A complete M-mode, two-dimensional and color-flow Doppler echocardiographic examination was performed. LV mass index and posterior wall index were significantly lower in patients with inactive acromegaly compared to those with active disease (P < 0.03 respectively). Diastolic dysfunction was improved in patients with inactive compared to those with active disease (E/A ratio P < 0.009). IGF was positively correlated with LV mass index (r = 0.28, P < 0.02). Multivariate linear regression analysis showed that in active patients the E/A ratio was independently related to age (ß = -0.674, P < 0.001) and GH (ß = 0.282, P < 0.03), whereas in inactive patients none of the parameters were related significantly with the E/A ratio. In a subgroup of 15 patients who were studied in both the active and inactive phase of the disease, the reduction in GH levels was correlated positively with the reduction in LV mass index (r = 0.89, P < 0.0001) and negatively with the improvement in E/A ratio (r = -0.74, P < 0.001). In conclusion, the results of the present study indicate an improvement of left ventricular diastolic function and a significant improvement of cardiac hypertrophy in patients with inactive acromegaly and normal systolic cardiac function compared to those with active disease.

Real-time three-dimensional echocardiography in evaluating Libman-Sacks vegetations.

Libman-Sacks endocarditis, characterized by sterile fibrofibrinous vegetations that have the potential to develop anywhere on the endocardial surface, was originally reported in 1924. The mitral valve is most commonly affected, followed by the aortic valve, whereas tricuspid and pulmonary valves are seldom involved. Libman-Sacks vegetations can be found in approximately 1 of 10 patients with systemic lupus erythematosus by transoesophageal echocardiography (TTE), and they are variably associated with lupus duration, disease activity, anticardiolipin antibodies, and antiphospholipid syndrome manifestations. The capability to perform real-time 3D (RT3D) imaging in the evaluation of Libman-Sacks vegetation size may strengthen the already established role of transthoracic echocardiogram and TTE. The exact estimation of vegetation size may influence therapeutic interventions. Therefore, we are trying to highlight the role of RT3D echocardiography in assessing vegetation size in a patient with Libman-Sacks endocarditis.

Effect of pacing mode and pacing site on torsional and strain parameters and on coronary flow.

BACKGROUND: Right ventricular apical pacing may induce detrimental effects on left ventricular function and coronary flow. In this study, the effects of pacing site and mode on cardiac mechanics and coronary blood flow were evaluated. METHODS: This prospective study included 25 patients who received dual-chamber pacemakers with the ventricular lead placed in the right ventricular apex and presented in sinus rhythm (SR) at their regularly scheduled visits at the pacemaker clinic. Patients underwent complete transthoracic echocardiographic examinations while in SR, followed by noninvasive Doppler assessment of coronary flow in the left anterior descending coronary artery (LAD) and speckle-tracking echocardiography of short-axis planes in SR, atrial pacing (AAI-P), atrioventricular (dual-chamber) pacing (DDD-P), and ventricular pacing (VVI-P). RESULTS: Rotation of the base was significantly decreased with VVI-P compared with AAI-P. Left ventricular twist decreased significantly with DDD-P compared with AAI-P. Circumferential strain of the base significantly decreased with DDD-P and VVI-P compared with SR. The velocity-time integral of diastolic flow in the LAD decreased significantly with DDD-P compared with SR (10.7 ± 2.2 vs 10.2 ± 2.2 vs 8.9 ± 1.6 vs 8.7 ± 2.6 cm in SR and with AAI-P, DDD-P, and VVI-P, respectively, P = .003). Basal rotation and time from onset of the QRS complex to peak basal rotation as a percentage of systole were independently associated with the velocity-time integral of diastolic flow in the LAD during SR and the three pacing modes. CONCLUSIONS: Acute right ventricular apical pacing showed a detrimental effect on left ventricular twist and basal mechanics, with the latter being independently associated with decreased LAD diastolic flow velocity parameters.

Atrioventricular left ventricular apical pacing improves haemodynamic, rotational, and deformation variables in comparison to pacing at the lateral wall in intact myocardium: experimental study.

Aim. To assess the effect on left ventricular (LV) function of atrioventricular (AV) and ventricular pacing at the LV apical or lateral wall and to compare the normal torsional and deformation pattern of the intact LV myocardium with those created by the aforementioned LV pacing modes and sites. Methods. Experiments were conducted in pigs (n = 21) with normal LV function to investigate the acute hemodynamic effects of epicardial AV and ventricular LV pacing at the LV apical or lateral wall. Torsional and deformation indices of LV function were assessed using speckle tracking echocardiography. Results. AV pacing at the apex revealed a significant reduction in the radial strain of the base (P < 0.03), without affecting significantly the ejection fraction and the LV torsion or twist. In contrast, AV pacing at the lateral wall produced, in addition to the reduction of the radial strain of the base (P < 0.01), significant reduction of the circumferential and the radial strain of the apex (both P < 0.01) as well as of the ejection fraction (P < 0.002) and twist (P < 0.05). Conclusions. In pig hearts with intact myocardium, LV function is maintained at sinus rhythm level when AV pacing is performed at the LV apex.

Apical rotation as an early indicator of left ventricular systolic dysfunction in acute anterior myocardial infarction: experimental study.

INTRODUCTION: The aim of this study was to determine whether left ventricular (LV) apical rotation assessed by speckle tracking echocardiography (STE) can predict global LV systolic dysfunction after acute anterior myocardial infarction (AMI). METHODS: STE analysis was applied to LV short-axis images at the basal and apical levels in 21 open-chest pigs, before and after left anterior descending coronary artery ligation. LV radial and circumferential strain and strain rate, apical and basal rotation, and LV torsion were recorded. RESULTS: LV apical rotation (3.68 ± 1.73° pre-AMI vs. 2.19 ± 1.64° post-AMI, p<0.009), peak systolic rotation rate, and radial and circumferential strain as well as strain rate decreased significantly 30 min postAMI. The LV global torsion decreased significantly. Strain and rotational changes of the LV apex were primarily correlated with ejection fraction (EF), but those of the LV base were not. EF had a significant correlation with the global LV twist (r=0.31, p<0.05). On multivariate linear regression analysis, fractional shortening of the long-axis (FSL) (b=0.58, p<0.001), rotation of the LV apex (b=0.32, p<0.006) and LV dp/dtmax (b=0.26, p<0.02) were independently related with EF. On analysis, of the receiver operating characteristic curve, the area under the curve for apical rotation was 0.765, p<0.006; the best cutoff value of 2.92° had sensitivity 80% and specificity 71% in predicting EF<40%. CONCLUSION: Apical rotation assessed by STE is a potential noninvasive early indicator of global LV systolic dysfunction in AMI and has a satisfactory association with LVEF. Its assessment could be valuable in clinical and research cardiology.

The impact of ultrasound contrast medium administration on the right ventricle in patients with heart failure.

BACKGROUND: The purpose of the present study was to examine the effect of SonoVue™ on right ventricular (RV) dimensions and contractility in patients with heart failure. PATIENTS AND METHODS: Twenty-four patients were divided into two groups. Group A consisted of 15 patients with heart failure and group B (control) of nine patients without heart disease. SonoVue was administered at low (2 ml) and high (4 ml) doses in both groups separately, in a random order. RV dimensions, contractility, peak systolic pressure gradient from tricuspid regurgitation (TRPG) and the time to maximal RV end-diastolic dimension (EDD), as well as the time for RV-EDD to return to the baseline value (recovery), were calculated in every cardiac cycle starting before the administration of SonoVue (baseline) until the recovery of RV-EDD. RESULTS: Low-(group A, p<0.001 and group B, p<0.05) and high-dose (group A, p<0.0001 and group B, p<0.01) contrast infusion increased the RV-EDD compared to baseline values. TRPG increased significantly (p<0.05) in both groups, under low-as well as high-dose. In group A, high-dose compared to low-dose produced a significant delay in the time duration to max RV-EDD (p<0.05) and in the time to RV-EDD recovery (p<0.0001). CONCLUSION: The administration of SonoVue in patients with heart failure was followed by an acute, transient, dose-dependent increase in RV-EDD and TRPG, without any effect on RV contractility.

Effect of early changes in functional geometry of left ventricular contraction on the development of ventricular fibrillation during acute myocardial ischaemia. An experimental study.

OBJECTIVE: The early appearance of ventricular fibrillation (VF) following acute myocardial infarction (MI) is associated with adrenergic effects and electrical interactions although some early "mechanical" changes may also occur. The aim of the present experimental study was to examine whether early changes in the functional geometry of left ventricular (LV) contraction may be associated with ventricular arrhythmias occurring during the first 120min of MI. METHODS: In 11 swine left anterior descending (LAD) coronary artery ligation was performed. Aortic flow, LV end-diastolic pressure (LVEDP), LV long and short axis lengths were measured and their fractional shortening (FS) was calculated before and during the initial 120min period of MI. RESULTS: LV long axis FS and aortic flow decreased (p<0.001) whereas LVEDP increased (p<0.01) in all 11 animals within 30min following LAD ligation. LV long and short axis lengths and LV short axis FS did not change significantly. VF occurred in 5 of the 11 animals within this 30min period. LV short axis FS decreased (p<0.05) in all 5 animals prior to VF and increased (p<0.05) in all 6 animals without VF. In 3 of the 6 animals that had no VF during the initial 30min VF occurred later. Similarly, LV short axis FS decreased prior to VF in all those 3 animals. LV short axis FS did not decrease in any of the remaining 3 swine without VF during the same period of time. CONCLUSION: Early changes in the functional geometry of LV contraction, in the form of a reduction of LV short axis FS, are associated with a greater incidence of VF in experimental acute MI.

The acute effect of an echo-contrast agent on right ventricular dimensions and contractility in pigs.

BACKGROUND: : The aim of the present study was to examine the effect of the second-generation ultrasound contrast agent (2nd GUCA) SonoVue on right ventricular (RV) dimensions and contractility and to investigate whether a dose-related interaction exists between the contrast agent and RV function. METHODS: : Twenty-eight pigs were randomly assigned to 3 groups for intravenous administration: a low-dose group (0.5 cc of SonoVue), a high-dose group (1 cc of SonoVue), and a control group (2 cc of normal saline). RV end-diastolic (EDD) and end-systolic dimension (ESD) and pulmonary pressure (PP) were measured, and the fractional shortening (FS%) was calculated before the administration of SonoVue or normal saline and after the return of the RV-EDD or PP to the baseline value. The time to reach maximal RV-EDD or PP value and the time until the return of RV-EDD or PP to the baseline value were also measured. RESULTS: : Contrast agent infusion was followed by an acute transient increase of RV-EDD, RV-ESD, FS, and PP in both the low-dose and high-dose groups, but the increase was greater in the high-dose group. FS and PP did not change significantly in the control group. A dose-dependent delay in the time from baseline to maximum RV-EDD and PP was detected in the high-dose group (P < 0.001 for both) as well as a delay in the return from maximum to the baseline values (P < 0.001 for both). CONCLUSIONS: : Administration of the 2nd GUCA SonoVue is associated with an acute, transient, dose-dependent RV dilatation and an increase in pulmonary pressure with a consequent impact on RV contractility.

The association of coronary flow changes and inflammatory indices to ischaemia-reperfusion microvascular damage and left ventricular remodelling.

BACKGROUND: The aim of this study was to investigate the effect of coronary flow (CF) changes and inflammatory indices on myocardial microcirculation--assessed by myocardial contrast echocardiography (MCE)--and on left ventricular remodelling, in an experimental ischaemia-reperfusion model. METHODS: In 15 pigs, weighing 30 +/- 5 kg, ligation of the left anterior descending (LAD) coronary artery was performed, followed by reperfusion for 120 min. Peak, mean, duration and volume of systolic and diastolic components of CF distal to the LAD ligation were measured using a butterfly flowmeter and their ratio was calculated. The following two-dimensional echocardiography indices of LV geometry/function were measured from the apical four-chamber view: LV end-systolic (ESD) and end-diastolic (EDD) dimension long- (Ls, Ld) and short-axis (Ss, Sd) and their ratio (Ld/Sd, Ls/Ss, defined as the sphericity index). Interleukin (IL) 1beta, 6, 10 and tumour necrosis factor (TNF) were measured in samples obtained from the LV cavity and coronary sinus. A 0.5 ml/min injection slow bolus over 30 s of SonoVue was made into the left ventricle (LV) in order to assess myocardial perfusion by MCE. Standard apical four-chamber views were digitally acquired and stored for off-line analysis using the Echofit system. The peak intensity (Ac) of the microbubbles at the apex, distally to ligation, was normalised with respect to the peak intensity of the microbubbles in the LV cavity. All parameters were recorded at baseline, immediately after ligation and at 5, 15, 30, 60, 120 min during reperfusion. The percentage changes of CF indices, echocardiographic parameters, interleukins and Ac between baseline and reperfusion were calculated. RESULTS: Mean systolic CF, systolic volume, peak and mean diastolic flow (MDF) changes and epicardial mean CF, Ld/Sd, Ls/Ss changes and coronary sinus IL-6 (IL-6 cs) were inversely correlated with Ac changes during reperfusion. At 5 and 15 min of reperfusion (hyperaemic phase), the greatest median increase of mean diastolic (172% and 86%), and mean systolic CF (713% and 344%) and the greatest reduction of Ac (-41% at 5 min) compared to baseline (P < 0.05) were observed. The maximum increase of IL-6 cs (40%) was detected at 120 min. ROC analysis showed that of all examined echocardiography indices an increase of mean diastolic CF > 22% was the best predictor of a >25% reduction of Ac with 76% sensitivity and 65% specificity (area 71%, CI 54%-85%, P = 0.02). In addition an >32% increase of IL-6 at 120 min of reperfusion predicted a >25% reduction of Ac with a 76% sensitivity and 65% specificity (area 71% CI 61%-97%, P = 0.01). CONCLUSION: Changes of mean diastolic CF and IL-6 cs are associated with alterations in myocardial microvascular integrity after ischaemia-reperfusion and may be used as a predictor of myocardial dysfunction.

Papel de la resonancia magnética cardiovascular en el diagnóstico y evaluación de la hipertensión arterial pulmonar / Cardiovascular magnetic resonance: its role in the diagnosis and evaluation of pulmonary arterial hypertension

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