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.

Factors Influencing the twisting and untwisting properties of the left ventricle during normal pregnancy.

AIMS: During pregnancy, important hemodynamic changes occur, consistent with an increase in preload and decrease in afterload and systemic vascular resistance. The aim of the present study was to investigate the changes in left ventricular (LV) strain and rotational properties during the 3 trimesters of normal pregnancy and to examine the factors that drive these changes. METHODS AND RESULTS: Twenty-seven pregnant women (29.7 ± 6.9 years) and 11 age-matched nonpregnant controls (29.9 ± 5.4 years) were evaluated. Conventional echocardiography and two-dimensional speckle tracking imaging were performed at 8-12 (1st trimester), 21-28 (2nd trimester), and 33-36 (3rd trimester) weeks of pregnancy. LV rotation, twist, untwisting rate, and circumferential strain were measured using the parasternal short-axis views at basal and apical levels. Global longitudinal strain was calculated from the LV apical views. Peak LV twist and peak untwisting rate increased significantly in the 3rd trimester of normal pregnancy (13.48 ± 2.90°, 13.12 ± 3.30°, 16.83 ± 3.61°, P < 0.001; and -111.52 ± 23.54°/sec, -107.40 ± 26.58°/sec, -144.30 ± 45.14°/sec, P < 0.001; in the 1st, 2nd, and 3rd trimester, respectively). Global longitudinal and circumferential strain of the apex decreased significantly from the 2nd trimester. An independent association was found between the change in LV twist and the change in LV end-systolic volume between the 1st and 3rd trimester. Peak untwisting rate at the 3rd trimester correlated significantly with peak twist and LV end-diastolic volume. CONCLUSIONS: During normal pregnancy, LV twist and peak untwisting rate increase in the 3rd trimester and correlate with end-systolic and end-diastolic volume, respectively. Circumferential strain of the apex and global longitudinal strain decrease from the 2nd trimester.

Severe aortic valve regurgitation in patient with Takayasu arteritis: a case report.

Background: Takayasu arteritis (TAK) is a systemic non-inflammatory vasculitis that primarily affects large- and medium-sized arteries. Case summary: We report the case of a 57-year-old woman with a history of coronary artery bypass grafting (CABG) 7 years prior, who was referred for a stress echo due to chest pain. Transthoracic echocardiography revealed the left ventricle at the upper limits of normal with preserved contractility, as well as circumferential thickening of the aortic root, causing severe aortic regurgitation (AR). Cardiac computed tomography and angiography demonstrated diffuse thickening of the aortic wall from the aortic root to the descending thoracic aorta, extending to the left carotid artery and significant stenosis of the left subclavian artery. Coronary angiography showed severe narrowing of the left main coronary ostium with ostial stenosis and total occlusion of the right coronary and left internal mammary arteries. Magnetic angiography highlighted thickening of the aortic wall, while no active inflammation was detected on positron emission tomography. These findings suggested Takayasu aortitis with chronic inflammation. Discussion: In young patients, particularly women, who present with angina and coronary ostial stenosis, Takayasu arteritis should be considered in the differential diagnosis. Aortic regurgitation (AR) is a serious complication, and its surgical management can be challenging.

Association Between Chronic Diseases and Frailty in a Sample of Older Greek Inpatients.

INTRODUCTION: Previous reports have associated frailty with the existence of various chronic diseases. Especially for cardiovascular diseases, this relationship seems to be bidirectional as common pathophysiological mechanisms lead to the progression of both diseases and frailty. The study aimed to examine the relationship between chronic diseases and frailty in a sample of older Greek inpatients Methodology: In 457 consecutively admitted older patients (226, 49.5% females), the median age was 82 years (interquartile range [IQR] 75-89), and demographic factors, medical history, cause of admission, and the degree of frailty assessed with the Clinical Frailty Scale were recorded. The level of frailty was calculated for the pre-hospital status of the patients. Parametric tests and logistic regression analysis were applied to identify diseases independently associated with frailty. RESULTS: Using the scale, 277 patients (60.6%) were classified as frail and 180 as non-frail (39.4%). In univariate analysis, frail patients were more likely to have respiratory disease, dementia, Parkinson's disease, chronic kidney disease (CKD), atrial fibrillation (AFIB), neoplastic disease, depression, stroke, heart failure (HF), and coronary artery disease. In binomial regression analysis, the diseases that were statistically significantly associated with frailty were respiratory diseases (P = 0.009, odds ratio [OR] = 2.081, 95% confidence interval [CI] 1.198-3.615), dementia (P ≤ 0.001, OR = 20.326, 95% CI 8.354-49.459), Parkinson's disease (P = 0.049, OR = 3.920, 95% CI 1.005-15.295), CKD (P = 0.018, OR = 2.542, 95% CI 1.172-5.512), AFIB (P = 0.017, OR = 1.863, 95% CI 1.118-3.103), HF (P = 0.002, OR = 2.411, 95% CI 1.389-4.185), and coronary artery disease (P = 0.004, OR = 2.434, 95% CI 1.324-4.475). CONCLUSIONS: Among diseases independently associated with frailty, chronic diseases such as respiratory diseases, dementia, Parkinson's disease, CKD, and cardiovascular diseases (AFIB, HF, and coronary heart disease) have an important role. Recognizing the diseases that are highly related to frailty may contribute, by their optimal management, to delaying the progression or even reversing frailty in a large proportion of the elderly.

Posterior Mitral Valve Annulus Vegetation in the Presence of Mitral Annulus Calcification: A Case Report.

The evaluation of patients who present at the emergency department with fever and a history of cardiac valve replacement should be thorough, and the possibility of endocarditis must be high in the differential diagnosis. The modified Duke's criteria are recommended for the diagnosis of endocarditis, and the role of positron emission tomography-computed tomography (PET-CT) scan is highlighted in the presence of bioprosthetic valves among the recent guidelines. Here, we describe a challenging case of endocarditis in a patient with severe mitral annulus calcification and bioprosthetic aortic valve replacement. Transesophageal echocardiography revealed an echogenic mass on the posterior mitral annulus, which was confirmed to be a vegetation on the PET-CT scan. Despite adequate antibiotic therapy and no indication for emergency cardiac surgery, in the fourth week of treatment, an embolic event in the ophthalmic artery occurred, and the patient was admitted for surgery. Intraoperatively, the presence of vegetation was confirmed. Because severe mitral annulus calcification may act as a nidus for infective endocarditis, special attention must be paid to these patients. Additional studies are required in patients with residual vegetation at the end of antibiotic treatment, especially if they have increased dimensions, to accurately formulate the optimal management plan.

Primary treatment of light-chain amyloidosis with bortezomib, lenalidomide, and dexamethasone.

Bortezomib and dexamethasone with cyclophosphamide (CyBorD) or melphalan (BMDex) are commonly used primary treatments for light-chain (AL) amyloidosis, but limited data exist on bortezomib with immunomodulatory drug combinations. We report our experience with primary therapy with a bortezomib, lenalidomide, and dexamethasone (VRD) "light" regimen in 34 consecutive patients with AL amyloidosis. The majority (79%) had cardiac involvement, 15% and 23% were Mayo stage 3A and 3B, respectively, and 54% had renal involvement. After the first VRD cycle, 71% of patients achieved a hematologic response (44% at least very good partial response [VGPR]). On intent to treat, 11 (32%) achieved a complete response (of whom 5 of 11 were minimal residual disease [MRD] negative at 10-5), 17 (50%) a VGPR, and 2 (7%) a partial response. The 12-month survival was 73%. Starting lenalidomide dose was 5 mg in 86% of patients. Hematologic toxicity was mild; nonhematologic toxicities included rash (grade 3/4 [16%]), infections (grade ≥3 [12%]), constipation (grade ≥3 [9%]), and peripheral neuropathy (grade 2 [20%]); 37.5% of patients required lenalidomide dose reduction, 27% discontinued lenalidomide, 38% required bortezomib dose reduction, and 12% discontinued bortezomib. We compared VRD to CyBorD in 68 patients matched for Mayo stage and baseline difference between involved minus uninvolved serum free light chain levels, and observed a trend for deeper response at 3 and 6 months with VRD. In conclusion, VRD can be an active regimen for newly diagnosed patients with AL amyloidosis able to induce very deep hematologic responses at the expense of increased toxicity.

Propranolol Versus Metoprolol for Treatment of Electrical Storm in Patients With Implantable Cardioverter-Defibrillator.

BACKGROUND: Electrical storm (ES), characterized by unrelenting recurrences of ventricular arrhythmias, is observed in approximately 30% of patients with implantable cardioverter-defibrillators (ICDs) and is associated with high mortality rates. OBJECTIVES: Sympathetic blockade with ß-blockers, usually in combination with intravenous (IV) amiodarone, have proved highly effective in the suppression of ES. In this study, we compared the efficacy of a nonselective ß-blocker (propranolol) versus a ß1-selective blocker (metoprolol) in the management of ES. METHODS: Between 2011 and 2016, 60 ICD patients (45 men, mean age 65.0 ± 8.5 years) with ES developed within 24 h from admission were randomly assigned to therapy with either propranolol (160 mg/24 h, Group A) or metoprolol (200 mg/24 h, Group B), combined with IV amiodarone for 48 h. RESULTS: Patients under propranolol therapy in comparison with metoprolol-treated individuals presented a 2.67 times decreased incidence rate (incidence rate ratio: 0.375; 95% confidence interval: 0.207 to 0.678; p = 0.001) of ventricular arrhythmic events (tachycardia or fibrillation) and a 2.34 times decreased rate of ICD discharges (incidence rate ratio: 0.428; 95% CI: 0.227 to 0.892; p = 0.004) during the intensive care unit (ICU) stay, after adjusting for age, sex, ejection fraction, New York Heart Association functional class, heart failure type, arrhythmia type, and arrhythmic events before ICU admission. At the end of the first 24-h treatment period, 27 of 30 (90.0%) patients in group A, while only 16 of 30 (53.3%) patients in group B were free of arrhythmic events (p = 0.03). The termination of arrhythmic events was 77.5% less likely in Group B compared with Group A (hazard ratio: 0.225; 95% CI: 0.112 to 0.453; p < 0.001). Time to arrhythmia termination and length of hospital stay were significantly shorter in the propranolol group (p < 0.05 for both). CONCLUSIONS: The combination of IV amiodarone and oral propranolol is safe, effective, and superior to the combination of IV amiodarone and oral metoprolol in the management of ES in ICD patients.

Efficacy of lenalidomide as salvage therapy for patients with AL amyloidosis.

We retrospectively evaluated 55 consecutive patients who received at least one dose of lenalidomide for relapsed/refractory AL amyloidosis. Their median age was 63 years; 72% had heart and 75% kidney involvement and 13% were on dialysis; while 20%, 46% and 34% had Mayo stage -1, -2 and -3 disease, respectively. Median time from start of primary therapy to lenalidomide was 15 months (range 2-100) and median number of prior therapies was 1 (range 1-4); 73% of the patients had prior bortezomib and 42% were bortezomib-refractory. On intent to treat, haematologic response rate was 51% (5.5% CRs, 20% VGPRs) and was 56% versus 40% for patients with and without prior bortezomib and 47% versus 62.5% for bortezomib refractory versus non-refractory patients (p = .351). Organ response was achieved by 16% of evaluable patients (22% renal, 7% liver and 3% cardiac); however, 10 (21%) patients progressed to dialysis. Median survival post lenalidomide was 25 months. Bortezomib-refractory patients had worse outcome (median survival of 10.5 versus 25 months for bortezomib-sensitive patients versus not reached for bortezomib-naive patients, p = .011). Median lenalidomide dose was 10 mg and no patient received the 25 mg dose; however, in 60% a dose reduction was required. Median duration of lenalidomide therapy was 7.2 months and 46% discontinued lenalidomide before completion of planned therapy, mainly due to toxicity (26%) or disease progression/no response (13%). We conclude that although lenalidomide is a major salvage option for patients with relapsed/refractory AL amyloidosis, its toxicity in patients with AL amyloidosis is significant and doses should be adjusted for optimal tolerability.

Cardiac and renal complications of carfilzomib in patients with multiple myeloma.

Clinical trials with carfilzomib have indicated a low but reproducible incidence of cardiovascular and renal toxicities. Among 60 consecutive myeloma patients treated with carfilzomib-based regimens who were thoroughly evaluated for cardiovascular risk factors, 12% (95% confidence interval, 3.8%-20%) experienced a reversible reduction of left ventricular ejection fraction (LVEF) by ≥20%, an objective measure of cardiac dysfunction. The incidence of LVEF reduction was 5% at 3 months, 8% at 6 months, 10% at 12 months, and 12% at 15 months, whereas the respective carfilzomib discontinuation rate unrelated to toxicity was 17%, 35%, 41%, and 49%. The presence of any previously known cardiovascular disease was associated with an increased incidence of cardiac events (23.5% vs 7%; P = .07), but there was no association with the dose of carfilzomib or the duration of infusion. Re-treatment with carfilzomib at lower doses was possible. Carfilzomib was commonly associated with a transient reduction of estimated glomerular filtration rate (eGFR) but also improved renal function in 55% of patients with baseline eGFR <60 mL/min/1.73 m2. Further investigation is needed to elucidate the underlying mechanisms of carfilzomib-related cardiorenal toxicity.

Effect of left ventricular pacing mode and site on hemodynamic, torsional and strain indices.

INTRODUCTION: Several reports have indicated that left ventricular (LV) lead placement at an optimal pacing site is an important determinant of short- and long-term outcome. This study investigated the effect of pacing mode (atrioventricular [AV] or ventricular) and site (LV apical or lateral) outside the ischemic region on the LV hemodynamic, torsional and strain indices in the ischemic myocardium. METHODS: Experiments were conducted in anesthetized open-chest pigs (n = 15) 30 min after LAD ligation to investigate the hemodynamic effects of temporary epicardial AV and ventricular LV pacing at the LV apical (outside the ischemic region) or lateral wall. LV hemodynamic data were recorded (ejection fraction, stroke volume, dP/dtmax, systolic pressure, cardiac output and e/e΄ ratio) and torsional (twist, rotation), as well as deformation (radial and circumferential strain), indices of LV function were assessed using two-dimensional speckle tracking imaging. RESULTS: The LV function was highly dependent on the pacing mode and site. LV dP/dtmax, systolic pressure and twist decreased significantly during LV pacing in comparison to sinus rhythm (p = 0.004, p<0.001, p = 0.002, respectively). Torsion in sinus rhythm decreased significantly during AV-pacing at the lateral wall (0.11±0.04°/mm vs. 0.06±0.02°/mm, p = 0.005) but did not change significantly during AV-pacing at the apex (0.07±0.05°/mm). CONCLUSIONS: LV pacing at the apical or lateral wall, in the ischemic myocardium, leads to a suboptimal response in comparison to sinus rhythm. LV pacing at the apex outside the ischemic area exhibits a better response than pacing at the lateral wall, possibly because pacing from this site leads to a more physiological propagation of electrical conduction.

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.

Myocardial performance index suggests optimal fluid loss during hemodialysis.

BACKGROUND: Patients on long-term maintenance hemodialysis (HD) are at high risk of developing cardiovascular disease and suffering various cardiovascular complications during HD. HYPOTHESIS: The purpose of this study was to evaluate the influence of changing loading conditions on the myocardial performance index (MPI) in patients on long-term HD and to specify an optimal level of fluid loss during HD that would maintain stable global cardiac function. METHODS: The study consisted of 52 patients with end-stage renal failure (ESRF), mean age 56±11.7 y, range: 25-80 y, on regular HD. For each patient a complete echocardiographic-Doppler examination was performed before and after HD. Systolic and diastolic parameters of left ventricular function were measured, and the myocardial performance index (MPI) was calculated. RESULTS: The MPI was significantly prolonged after HD (0.47±0.15 before HD versus 0.59±0.16 after HD, p < 0.001). Mean change in body weight during HD was 2.1±0.86 kg. The MPI did not change significantly in patients with intradialytic weight loss up to 1.75 kg. CONCLUSIONS: The MPI value seems to be independent of acute preload changes only when fluid loss is less than 1.75 kg. A 1.75-kg fluid loss during HD seems to be the optimal goal. In ESRF patients on HD, the MPI seems to be a good indicator of global left ventricular function and potentially a valuable aid in the effort to maintain optimal fluid balance.