Degree Of Cardiac Involvement Research Articles

#2757 Clinical course and prognostic factors in amyloidosis

Abstract Background and Aims Early diagnosis and specific therapy are crucial for the prognosis of patients with systemic amyloidosis. The aim of this single-center retrospective study was to evaluate the clinical course and identify prognostic factors associated with survival in a large cohort of patients from the Regional Reference Center “Gemelli Isola” in Rome, Italy. Method A total of 244 patients with amyloidosis were studied, including 100 with AL (63 M, 37 F, mean age 64 ± 13 yrs), 18 with AA (3 M, 15 F, mean age 57 ± 21 yrs), 9 with amyloidosis due to myeloma (MM) (5 M, 4 F, mean age 65 ± 15 yrs), 69 with ATTR mutant (38 M, 31 F, mean age 63 ± 15 yrs), 33 with ATTR wild-type (31 M, 2 F, mean age of 70 ± 10 yrs) 2 with Apolipoprotein (1 M, 1 F, mean age 60 yrs), and 15 unclassified amyloidosis (AX) (9 M, 6 F, mean age 63 ± 9 yrs). We considered several parameters, comprising gender, age, type of amyloidosis, time interval between disease onset and diagnosis, clinical signs and symptoms at onset and diagnosis, biochemical parameters, score of renal involvement (RI) (absent, proteinuria, nephrotic syndrome, and eGFR < 60 ml/min), score of cardiac involvement (CI) (absent, hypertrophic cardiopathy, dilated cardiopathy, arrhythmias and heart failure) at onset, diagnosis, and follow-up (FU). Renal outcome was defined as renal replacement therapy (RRT) initiation. The diagnosis of amyloidosis was histologically confirmed in all patients by Congo red stain, immunohistochemical classification and specific diagnostic criteria. Data were collected at diagnosis and retrieved dating back to the clinical onset. The impact of treatment was evaluated, in terms of clinical course and prognosis. Results Regardless of the amyloidosis type, between the onset and diagnosis clinical signs and symptoms significantly worsened and the involvement of affected organs increased. The median time from disease onset to diagnosis was 12 months for AL, AX, and MM, and 36 and 37 months for AA and ATTR. RI increased in all patients, from 47% at onset to 65% at diagnosis, and 71% during FU (p < 0.001). In the AL subgroup an eGFR < 60 ml/min was identified in 16% of patients at onset, 37% at diagnosis and 51% at FU (p < 0.001). As expected, in the mutant ATTR group RI was identified in only a small proportion of patients and an eGFR < 60 ml/min was found only in 2% of patients at onset and at diagnosis and in 6% at FU. CI was observed in 77% of all patients at onset, 88% at diagnosis and 98% at FU (p < 0.001). In the AL subgroup, at onset there was a high prevalence of hypertrophic cardiopathy (65%), while at FU there was a significant increase in the prevalence of heart failure (51%) (p < 0.001). In the mutant ATTR group, at onset, hypertrophic cardiopathy was present in 80% of patients while, at FU, heart failure was present in 64%. The median global survival time was 8 years (IC 95%, 7-12 yrs). RRT was started in 28% of patients. Survival curves according to renal and cardiac scores are shown in Fig. 1. Mortality at 6 years was statistically significative in patients with RI (p < 0.005). Survival curve according to renal or cardiac vs RI and CI is shown in Fig. 2. The univariate analysis demonstrated that progressive cardiac impairment from onset to FU, the number of organs involved, serum creatinine, albumin and eGFR had a significant impact on survival (HR of 18.46, CI 95% = 2.57-132.79; HR = 1.33, CI 95% = 1.09-1.62; HR = 1.47, CI 95% = 1.05-2.05; HR = 0.37, CI 95% = 0.24-0.56; HR = 0.99, CI 95% = 0.98-0.99). The multivariate analysis was based on the ‘forward stepwise’ method to select the significant predictors of mortality. The number of organs involved, age at onset, CI at onset, albumin and progressive worsening of CI from onset to FU, significantly impacted on survival (HR = 1.30, CI 95% = 1.02-1.65, p = 0.031, HR = 1.03, CI 95% = 1.01-1.05; HR = 2.08, CI 95% = 1.20-3.60; HR = 0.33, CI 95% = 0.21-0.53; HR = 21.40, CI 95% = 2.95-155.14). Conclusion The diagnosis of amyloidosis is often delayed. Prognosis is significantly influenced by the degree of CI and RI, serum albumin, age at onset and the number of organs involved. Better diagnostic accuracy and the availability of novel therapies have however significantly improved survival rates.

Heterogeneity of right ventricular echocardiographic parameters in systemic lupus erythematosus among four clinical subgroups, as stratified by clinical organ involvement in observational cohort

BackgroundSystemic lupus erythematosus (SLE) is a heterogeneous autoimmune disease. Cardiac involvement in SLE is rare but plays an important prognostic role. The degree of cardiac involvement according to SLE subsets...

Kawasaki disease versus Multisystem Inflammatory Syndrome COVID-19 with Kawasaki disease phenotype. Single-center experience

to compare the clinical presentation, laboratory testing, and evolution of KD with PIMS Kawasaki phenotype (PIMS-KD) in patients hospitalized before the pandemic, compared with the pandemic period. Cross-sectional study in two groups of patients at the Hospital Exequiel González Cortés: typical KD (group 1) and PIMS-KD (group 2). Data on demographic, clinical, and biochemical details were collected, as well as echocardiogram, treatment, and evolution records. IgG and IgM serology for SARS-CoV-2 was performed in both groups. In the KD group and the PIMS-KD group, 20 and 33 patients were analyzed, respectively. There were differences in age, days of fever, count of leukocytes, lymphocytes, and platelets, erythrocyte sedimentation rate (ESR), and hospital stay. In 25% of the KD group, there were alterations in the echocardiogram and, in the PIMS-K group, all patients received corticosteroids and 25 patients received intravenous immunoglobulin (IVIG). In both groups, a favorable clinical evolution was observed, characterized by the absence of complications and mortality. Based on the data obtained in our study, the importance of the epidemiological link is emphasized as an essential factor in differentiating between both pathologies, highlighting the need to consider factors such as age, duration of fever, count of leukocytes, lymphocytes, and platelets, and degree of cardiac involvement, for a differential evaluation between patients with PIMS-KD versus KD.

The Impact of Melphalan Conditioning Schedule on Post-Transplant Outcomes in AL Amyloidosis: A Multicenter Study with 1718 Patients

Introduction: High dose chemotherapy and autologous stem cell transplantation (ASCT) is one of the most effective therapies in light chain (AL) amyloidosis. It is associated with a high hematologic response rate and leads to durable remissions. High dose melphalan is the most frequently used conditioning chemotherapy, as has been used in multiple myeloma (MM). Melphalan dose is based on renal function, age, degree of cardiac involvement and patients' frailty and is predictive of outcomes. While studies that assessed the conditioning schedule have been conducted in MM, with variable results, no such studies were done in AL amyloidosis. Methods: In this retrospective study, we explored the impact of the conditioning schedule on post-transplant outcomes in a large multicenter study. Patients with AL amyloidosis who underwent ASCT for the primary diagnosis of AL amyloidosis between January 1, 2003, and December 31, 2020, were included in this study. Results: One thousand seven hundred and eighteen (n=1718) patients from 9 centers are included. The median age was 58 years, and 61% were male. Most patients had one (43%) or two (33%) involved organs, with the most involved organs were the kidneys (69%) followed by the heart (52%). Induction therapy was given to 52% of patients. The conditioning regimen was almost exclusively melphalan (99.2%), with 65% receiving full dose melphalan (≥170 mg/m 2). Melphalan was given over two days in most patients (80%). A rest day between conditioning and stem cell infusion was provided in 53% of patients, mostly in those who received melphalan on a single day rather than over 2 days (87% vs 44%, P<0.001). Post-transplant hematologic response was available for 1569 patients (91% of patients) and were assessed from baseline. Complete response (CR) and very good partial responses (VGPR) were achieved post-ASCT in 33.7% of patients each. Low dFLC-partial response (PR) was achieved in 2.7% and PR in 18% of patients. Altogether, satisfactory post-ASCT response (CR, VGPR, or low-dFLC PR combined) was achieved in 70% of patients. Compared to no induction, less than a PR to induction was associated with a lower probability of achieving satisfactory post-ASCT response, while PR or better to induction had higher chances of satisfactory post-ASCT response (65% vs 46% vs 84%, P<0.001). A single day of melphalan conditioning was associated with a higher probability of satisfactory post-ASCT response compared to two days of conditioning (82% vs 67%, P<0.001). Omitting a day of rest between conditioning and stem cell infusion was also associated with higher satisfactory post-ASCT response compared to having a rest day (76% vs 65%, P<0.001). The Table lists other predictors for a post-ASCT satisfactory hematologic response. In a nominal multivariate logistic regression analysis, independent predictors for higher post-ASCT satisfactory hematological response rate included: PR or better to induction therapy, female gender, kappa light chain isotype, lower dFLC at baseline, and kidney and liver involvement. In addition, full dose melphalan, conditioning given over a single day and having no rest day between conditioning and stem cell infusion were also associated with a higher likelihood of satisfactory post-ASCT response. Post-ASCT hematologic CR rate was higher in those receiving full dose conditioning (36% vs 28%, P<0.001), in those having no rest day (40% vs 28%, P<0.001) but not in those who received one day of conditioning versus two days (35% vs 33%, P=0.5). The rate of ICU admission was higher in those receiving no day rest (17.7% vs 12.6%), P=0.003) and among those who received reduced dose melphalan (18.1% vs 13.3%, P=0.008) but not based on number of conditioning days (P=0.56). Day 100 mortality was significantly higher in the no rest day group (5.6% vs 3.2%, P=0.01) and among those receiving reduced dose melphalan (6.8% vs 3.1%, P=0.004) compared to their counterparts, but not based on the number of days of conditioning (P=0.89). The median follow-up in the entire cohort was 104 months (95% CI 98-110). In a multivariate analysis for overall survival (OS), the conditioning dose but not the conditioning schedule was independently associated with OS. Conclusions: This study is the first to demonstrate the effect of melphalan conditioning schedule on post-transplant response. This study supports a single day melphalan conditioning in AL amyloidosis to improve post-ASCT response.

Heterogeneity of echocardiographic variables in systemic lupus erythematosus among clinical subgroups according to non-cardiac organ involvement

Systemic lupus erythematosus (SLE) is a heterogeneous autoimmune disease. Cardiac involvement is rare but plays an important prognostic role. The degree of cardiac involvement according to SLE subsets defined by non-cardiac manifestations is unknown. The objective of this study was to identify differences in TTE parameters associated with different SLE subgroups. One hundred and eighty-one patients fulfilling the ACR/EULAR 2019 classification criteria for SLE and had a TTE were included in this cross-sectional study. We defined four subsets of SLE based on the predominant clinical manifestations. A multivariate multinomial regression analysis was performed to determine whether TTE parameters differ between the subsets. The first subset (n = 37) of patients showed features of mixed connective tissue disease (MCTD); the second subset (n = 76) had primarily cutaneous involvement; the third subset (n = 18) exhibited serositis and the last subset (n = 50) had severe disease with significant organ involvement, including renal involvement. Forty TTE parameters were assessed in each patient. Using a multivariate multinomial regression analysis, 3 parameters differed between groups: early diastolic tricuspid annular velocity (RV-E′, P < 0.0001), RV-S′ (RV-pulse DTI systolic peak wave, P = 0.0031), and RV end-diastole diameter (P = 0.0419). The degree of RV dysfunction was lowest in patients with primarily cutaneous involvement. Four distinct clinical subsets based on clinical manifestations differed in terms of TTE parameters of right heart function and diastolic dysfunction. This could help to tailor the cardiac follow-up required by the different clinical subsets of SLE.

Different profiles of lipoprotein particles associate various degrees of cardiac involvement in adolescents with morbid obesity.

Dyslipidemia secondary to obesity is a risk factor related to cardiovascular disease events, however a pathological conventional lipid profile (CLP) is infrequently found in obese children. The objective is to evaluate the advanced lipoprotein testing (ALT) and its relationship with cardiac changes, metabolic syndrome (MS) and inflammatory markers in a population of morbidly obese adolescents with normal CLP and without type 2 diabetes mellitus, the most common scenario in obese adolescents. Prospective case-control research of 42 morbidly obese adolescents and 25 normal-weight adolescents, whose left ventricle (LV) morphology and function had been assessed. The ALT was obtained by proton nuclear magnetic resonance spectroscopy, and the results were compared according to the degree of cardiac involvement - normal heart, mild LV changes, and severe LV changes (specifically LV remodeling and systolic dysfunction) - and related to inflammation markers [highly-sensitive C-reactive protein and glycoprotein A (GlycA)] and insulin-resistance [homeostatic model assessment for insulin-resistance (HOMA-IR)]. A second analysis was performed to compare our results with the predominant ALT when only body mass index and metabolic syndrome criteria were considered. The three cardiac involvement groups showed significant increases in HOMA-IR, inflammatory markers and ALT ratio LDL-P/HDL-P (40.0 vs. 43.9 vs. 47.1, p 0.012). When only cardiac change groups were considered, differences in small LDL-P (565.0 vs. 625.1 nmol/L, p 0.070), VLDL size and GlycA demonstrated better utility than just traditional risk factors to predict which subjects could present severe LV changes [AUC: 0.79 (95% CI: 0.54-1)]. In the second analysis, an atherosclerotic ALT was detected in morbidly obese subjects, characterized by a significant increase in large VLDL-P, small LDL-P, ratio LDL-P/HDL-P and ratio HDL-TG/HDL-C. Subjects with criteria for MS presented overall worse ALT (specially in triglyceride-enriched particles) and remnant cholesterol values. ALT parameters and GlycA appear to be more reliable indicators of cardiac change severity than traditional CV risk factors. Particularly, the overage of LDL-P compared to HDL-P and the increase in small LDL-P with cholesterol-depleted LDL particles appear to be the key ALT's parameters involved in LV changes. Morbidly obese adolescents show an atherosclerotic ALT and those with MS present worse ALT values.

Transthyretin cardiac amyloidosis.

Transthyretin cardiac amyloidosis (ATTR-CA) is an increasingly recognized cause of heart failure (HF) and mortality worldwide. Advances in non-invasive diagnosis, coupled with the development of effective treatments, have shifted ATTR-CA from a rare and untreatable disease to a relatively prevalent condition that clinicians should consider on a daily basis. Amyloid fibril formation results from age-related failure of homoeostatic mechanisms in wild-type ATTR (ATTRwt) amyloidosis (non-hereditary form) or destabilizing mutations in variant ATTR (ATTRv) amyloidosis (hereditary form). Longitudinal large-scale studies in the United States suggest an incidence of cardiac amyloidosis in the contemporary era of 17 per 100 000, which has increased from a previous estimate of 0.5 per 100 000, which was almost certainly due to misdiagnosis and underestimated. The presence and degree of cardiac involvement is the leading cause of mortality both in ATTRwt and ATTRv amyloidosis, and can be identified in up to 15% of patients hospitalized for HF with preserved ejection fraction. Associated features, such as carpal tunnel syndrome, can preceed by several years the development of symptomatic HF and may serve as early disease markers. Echocardiography and cardiac magnetic resonance raise suspicion of disease and might offer markers of treatment response at a myocardial level, such as extracellular volume quantification. Radionuclide scintigraphy with 'bone' tracers coupled with biochemical tests may differentiate ATTR from light chain amyloidosis. Therapies able to slow or halt ATTR-CA progression and increase survival are now available. In this evolving scenario, early disease recognition is paramount to derive the greatest benefit from treatment.

RELATIONSHIP OF CARDIAC INVOLVEMENT WITH DISEASE SEVERITY IN PATIENTS OF SYSTEMIC SCLEROSIS

Objectives: Systemic Sclerosis (SSc) is an autoimmune condition with underlying pathology in the connective tissue and can affect almost any organ system mainly skin, joints, lungs, heart and the abdomen. It usually follows a chronic course of disease. The objective of this study was to determine the relationship of cardiac involvement with the severity of disease course in patients with systemic sclerosis. Methodology: Two hundred patients with a diagnosis of Systemic Sclerosis (SSc) were evaluated for cardiac involvement via history, examination, electrocardiogram and echocardiography. Cardiac involvement was compared across genders, age, duration of disease, and relationship with American College of Rheumatology (ACR) scores. Results: Cardiac abnormalities were detected in 16% of these patients. Mean age of the study population was 38.67 ± 12.73 years including 55.5% males and 44.5% females. The mean ACR score of the study population was 12.8 ± 3. A significant relationship was observed between the degree of cardiac involvement and ACR scores (p=0.001) while that between cardiac abnormality and other confounding factors was non-significant i.e., gender (p=0.630), age groups (p=0.287) and duration since diagnosis (p=0.801). Conclusion: There is a potential association of cardiac dysfunction with how severe the systemic sclerosis is, without a noteworthy impact of age, gender and disease duration.

Multimodality Imaging in the Evaluation and Prognostication of Cardiac Amyloidosis.

Cardiac amyloidosis (CA) is an infiltrative cardiomyopathy resulting from deposition of misfolded immunoglobulin light chains (AL-CA) or transthyretin (ATTR-CA) proteins in the myocardium. Survival varies between the different subtypes of amyloidosis and degree of cardiac involvement, but accurate diagnosis is essential to ensure initiation of therapeutic interventions that may slow or potentially prevent morbidity and mortality in these patients. As there are now effective treatment options for CA, identifying underlying disease pathogenesis is crucial and can be guided by multimodality imaging techniques such as echocardiography, magnetic resonance imaging, and nuclear scanning modalities. However, as use of cardiac imaging is becoming more widespread, understanding optimal applications and potential shortcomings is increasingly important. Additionally, certain imaging modalities can provide prognostic information and may affect treatment planning. In patients whom imaging remains non-diagnostic, tissue biopsy, specifically endomyocardial biopsy, continues to play an essential role and can facilitate accurate and timely diagnosis such that appropriate treatment can be started. In this review, we examine the multimodality imaging approach to the diagnosis of CA with particular emphasis on the prognostic utility and limitations of each imaging modality. We also discuss how imaging can guide the decision to pursue tissue biopsy for timely diagnosis of CA.

Cardiac Remodeling According to the Nocturnal Fall of Blood Pressure in Hypertensive Subjects: The Whole Assessment of Cardiac Abnormalities in Non-Dipper Subjects with Arterial Hypertension (Wacanda) Study.

Objective: Several epidemiological studies suggest that the preservation of the physiological circadian rhythm of blood pressure or its disruption affects the extent of the organ damage developed by the patient. If we classify the circadian rhythm of blood pressure into four nocturnal profiles, significant differences emerge in terms of organ damage burden and prognosis: reverse dippers have the worst prognosis while dippers and mild dippers fall into an intermediate risk range. The risk profile of extreme dippers is still debated, and the available data are very conflicting and inconclusive. Starting from this gap of knowledge, we aimed to evaluate, retrospectively, in a cohort of hypertensive subjects, the degree of cardiac involvement in relation to the different nocturnal blood pressure profiles. Methods: We retrospectively evaluated 900 patients with essential hypertension, of whom 510 met our study criteria. We graded the 510 patients in relation to the percentage of reduction in mean systolic blood pressure (SBP) at night-time compared with day-time, considering this as a continuous variable, and then compared the extreme quintiles with each other and with the middle quintile (considered as reference). Results: Patients with less (or no) reduction in nocturnal SBP (reverse dipper) showed a higher level of organ damage and comorbidities. With regard to echocardiographic indexes, patients with maximum nocturnal pressure reduction (extreme dipper) showed a lower level of remodeling and/or impairment of E/e’ ratio, Right Atrium Area, Basal Right Ventricular Diameter, Inferior Vena Cava Average Diameter, and Tricuspidal Anular Plane Systolic Excursion compared also with hypertensive patients with a physiological nocturnal pressure reduction, even after correction for the main confounders. Conclusions: These data suggest that extreme dippers may constitute the subgroup of hypertensive patients with the lowest 24-h pressure load and, therefore, less cardiac remodeling.

AVOIDING ANCHORING BIAS: DIAGNOSIS OF AL-AMYLOIDOSIS IN WORSENING HEART FAILURE AFTER CORONARY ARTERY BYPASS GRAFTING

TOPIC: Cardiovascular Disease TYPE: Medical Student/Resident Case Reports INTRODUCTION: Amyloidosis is a systemic disease caused by deposition of misfolded protein in various tissues and organs. Early recognition of amyloidosis is necessary as cardiac dysfunction is the major determinant of survival(1). The diagnosis is often delayed given the non-specific symptoms at onset. Prognosis in amyloidosis is primarily dependent on the degree of cardiac involvement and, in AL amyloidosis, on circulating light-chain levels(2). CASE PRESENTATION: The patient is a 68-year-old male referred to our institution for assessment of worsening heart failure (HF). Four months prior, he began to experience exertional dyspnea along with jaw pain. Subsequent evaluation included lab work, chest X-ray and electrocardiogram demonstrating troponin elevation, pulmonary edema and complete heart block respectively. An echocardiogram(ECHO) demonstrated a severely reduced ejection fraction(EF). Temporary pacemaker was placed and a subsequent angiogram showed severe multi-vessel coronary artery disease(CAD). He underwent coronary artery bypass graft surgery. Post-operatively EF improved to 45%. Implantable loop recorder was placed due to concerns for post-operative atrial fibrillation. Three months later, he experienced a syncopal event attributed to ventricular tachycardia, and CRT-D was placed. ECHO revealed reduction of his EF (30%) with moderate concentric left ventricular hypertrophy(LVH). A repeat angiogram demonstrated patency of his bypass grafts. After referral to our institution, a repeat ECHO demonstrated findings concerning amyloidosis. Protein electrophoresis revealed monoclonal IgG gammopathy, and fat pad aspirate confirmed the diagnosis of AL amyloidosis. DISCUSSION: Although CAD is the most common cause of HF with reduced EF, other etiologies must be considered when symptoms cannot be explained solely by ischemia. Cardiac amyloidosis was suspected based on a constellation of clinical symptoms as well as suggestive ECHO findings(Biventricular concentric hypertrophy, restrictive filling pattern, Bull's eye appearance on LV strain). The diagnosis should be suspected in patients with HF who have unexplained LVH with no prior history of hypertension(3). Patients also present with syncopal events caused by conduction blocks, bradyarrhythmia, or in the case of our patient, ventricular tachyarrhythmias. Early diagnosis is important given the emerging therapies that can halt cardiac damage, potentially reducing the risk of mortality and allowing amyloid clearance and improved cardiac function. CONCLUSIONS: Anchoring bias is the tendency to stick with initial impressions even as new information becomes available. Clinicians must avoid this and consider alternative diagnoses when patients do not experience the anticipated outcome to a particular treatment. REFERENCE #1: 1. Fontana M. Banypersad SM. Treibel TA, et al. Differential myocyte responses in patients with cardiac transthyretin amyloidosis and light-chain amyloidosis: a cardiac MR imaging study. Radiology. 2015;277:388–97 REFERENCE #2: 2. Kumar S, Dispenzieri A, Lacy MQ, et al. Revised prognostic staging system for light chain amyloidosis incorporating cardiac biomarkers and serum free light chain measurements. J Clin Oncol 2012;30:989-95 REFERENCE #3: 3. Gertz MA. Comenzo R. Falk RH, et al. Definition of organ involvement and treatment response in immunoglobulin light chain amyloidosis (AL): a consensus opinion from the 10th International Symposium on Amyloid and Amyloidosis, Tours, France, 18-22 April 2004. Am J Hematol. 2005;79:319–28 DISCLOSURES: no disclosure on file for Brian Hardaway; No relevant relationships by Michael Liu, source=Web Response No relevant relationships by Amith Reddy Seri, source=Web Response

Diagnosis and Treatment of Cardiac Amyloidosis Related to Plasma Cell Dyscrasias.

Light chain amyloidosis is a deadly disease in which a monoclonal plasma cell dyscrasia produces misfolded immunoglobulin light chains (AL) that aggregate and form rigid amyloid fibrils. The amyloid deposits infiltrate one or more organs, leading to injury and severe dysfunction. The degree of cardiac involvement is a major driver of morbidity and mortality. Early diagnosis and treatment are crucial to prevent irreversible end-organ damage and improve overall survival. Treatment of AL cardiac amyloidosis involves eliminating the underlying plasma cell dyscrasia with chemotherapy and pursuing supportive heart failure management.

Therapies for cardiac light chain amyloidosis: An update

Light-chain (AL) amyloidosis is the most common type of systemic amyloidosis, affecting around 10 people per million per year. This serious disorder is characterized by the presence of a clone of bone marrow plasma cells that produces monoclonal light chains (LCs) of the κ or predominantly λ type. These amyloidogenic LCs undergo extracellular misfolding and aggregation into proteotoxic soluble oligomers and amyloid fibrils that deposit within tissues. The lethal consequences of AL amyloidosis are due to the toxic products (the LCs) and not to the malignant behaviour of the plasma cell clone. Almost 80% of patients with AL amyloidosis have some degree of cardiac involvement, manifesting as heart failure (HF), and carrying a particularly poor prognosis.The past decade has seen major advances in the treatment of AL amyloidosis, and a rapidly fatal disease has become a treatable and possibly curable condition. The number of therapeutic options is rapidly expanding, offering hope to address currently unmet needs (most notably, the treatment of frail patients). The treatment of AL amyloidosis consists in a combination of agents targeting multiple steps of the amyloid cascade, associated with effective HF management, and there is ground for hope for dramatically improving the outcome in the near future.In the present review we will summarize our current knowledge on therapy for cardiac AL amyloidosis, targeting clinical cardiologists involved in the care of this serious disorder.

Renal Outcomes in Patients with AL Amyloidosis: Evaluation of Prognostic Factors and Impact of Therapy with Novel Agents

Kidney is involved in about 70% of patients with AL amyloidosis. End stage renal disease requiring dialysis has deleterious impact on the life of the patients. Recently, Palladini et al proposed that eGFR < 60 ml/min and proteinuria > 5gr/d at diagnosis were able to identify patients with low, intermediate or high probability of progression to dialysis. Also, achievement of at least hemVGPR was associated with favorable renal outcomes. The aim of our study was to validate the above prognostic criteria in a different population and to assess the role of primary therapy with novel agents (bortezomib or lenalidomide) in the renal outcomes of patients with AL amyloidosis. We analyzed 101 consecutive patients with newly diagnosed AL and kidney involvement, which were treated and followed in a single center (Department of Clinical Therapeutics, University of Athens). Because the prognosis of patients with AL is dominated by the degree of cardiac involvement and because many patients die to cardiac complications before reaching dialysis, our analysis was based on competing risk models (proposed by Fine & Gray), in which death without dialysis was treated as competing event.Median age was 65 years (range 40-84), 54% had also cardiac involvement, 27% were Mayo stage 1, 46% stage 2 and 27% stage 3. Median eGFR at the time of diagnosis was 57.5 ml/min; 52% had eGFR <60 ml/min, 29% had eGFR < 30 ml/min and 56% had proteinuria >5 gr/d. Nine (9%) patients who required dialysis at the time of diagnosis were excluded from further analysis. Primary therapy was bortezomib based (mainly VD) in 51%, lenalidomide-based in 29%, MDex in 11%, VAD in 5% and MP in 3%. After a median follow up of 4 years, 28% of the patients required dialysis, 33% died off-dialysis while 40% patients remain alive off-dialysis. One- and 3-year dialysis rates were 14% and 21%, while the incidence of death off-dialysis was 20% and 31% respectively. Thus, even among patients with renal involvement cardiac amyloidosis dominates their prognosis (Figure 1a).We then evaluated the staging system proposed by Palladini et al. One- and 3-year rate of dialysis for patients with eGFR < 60 ml/min was 20% & 34% vs 9% & 12% for those with eGFR ≥ 60 ml/min (p=0.009); there was no difference in the incidence of death off-dialysis (p=0.345). For patients with proteinuria > 5 gr/d vs those with ≤ 5 gr/d, the respective 1- and 3-year dialysis rate was 23% & 30% vs 5% & 15% (p=0.02) with similar incidence of death off dialysis (p=0.59). Thus, in patients with 0, 1 & 2 risk factors, the 1-year rate of dialysis was 0% vs 13% vs 28% and the 3-year rate was 0% vs 24% vs 37% (p<0.001) (figure 1b). We then evaluated the impact of different types of primary therapy with novel agents (bortezomib or lenalidomide) in renal outcomes. There was no difference in the baseline characteristics of patients who were treated with bortezomib-based vs lenalidomide-based regimens. In univariate analysis bortezomib-based was associated with a longer time to dialysis than lenalidomide-based therapy: 1- and 3- year rate of dialysis was 11.5% vs 26% and 17% vs 37% (p=0.03). There was no difference in the death rates off-dialysis for bortezomib- vs lenalidomide-based therapy (p=0.53). In multivariate analysis, bortezomib-based therapy remained independently associated with a lower probability of progression to dialysis compared to lenalidomide-based therapy (HR: 0.74, 95% CI 0.15-0.95, p=0.039). Hematologic response was associated with renal response as well as longer overall survival. The quality of hematologic response was also associated lower probability of dialysis: 3-year dialysis rate of patients with hemVGPR or hemCR was 10% vs 22% for hemPR vs 28% for patients with no hematologic response to primary therapy (p=0.023). Reduction of proteinuria >20% was associated with excellent renal outcomes: at 3 years no patient who achieved a renal response required dialysis vs. 39% of non renal responders (p<0.001), but death rates off-dialysis were 29% and 36% respectively.In conclusion, our data confirm previous observations that AL patients with renal involvement who present before severe renal damage occurs (i.e. when eGFR ≥ 60 ml/min and proteinuria ≤ 5gr/d) and which initiate therapy with effective agents, targeting at least hemVGPR, have excellent renal outcomes. In this regard, our data indicate that primary bortezomib-based therapy may be more effective than lenalidomide-based therapy. [Display omitted] DisclosuresDimopoulos:Celgene: Consultancy, Honoraria.

Thoraco-omphalopagus asymmetric conjoined twins: Report of a case and complete review of the literature

Thoraco-omphalopagus asymmetric conjoined twinning is a rare condition in which a grossly defective foetus (the parasite) is attached to the thorax and upper abdomen of the main foetus (the autosite). We describe a case of thoraco-omphalopagus asymmetric conjoined twins in which the autosite had an associated large-diameter omphalocoele that was successfully separated at our institution. Reconstruction of the resulting abdominal-wall defect was performed using a flap from the gluteal region and the proximal portion of the inferior limb of the parasite, which is demonstrated. In addition, a review of all previously published cases is presented, showing that overall positive results can be obtained in treating this condition and that the presence and degree of cardiac involvement have a major influence on the prognosis.

Current Trends in Diagnosis and Management of Cardiac Amyloidosis

Amyloidosis is a rare disease in which insoluble extracellular protein fibrils in β-pleated sheets infiltrate multiple organs, causing organ dysfunction and failure. Amyloidoses are generally classified into light chain or primary systemic amyloidosis, hereditary amyloidosis (most commonly, transthyretin amyloidosis), senile systemic amyloidosis, secondary amyloidosis, and isolated atrial amyloidosis. At least 100 different amyloidogenic proteins have been identified in humans and can be differentiated by mass spectroscopy after laser capture microdissection and genetic testing. Organ involvement can include kidneys, skin, blood vessels, central and peripheral nervous systems, lungs, liver, intestines, and heart. Developments in noninvasive techniques are facilitating earlier and more accurate diagnosis. Management depends on the specific disease type, thus early and accurate diagnosis is imperative. Prognosis generally correlates with degree of cardiac involvement but varies widely with specific amyloid protein type. New treatment strategies involving chemotherapy and organ transplantation are improving survival, but prognosis is guarded.

Differential clinical characteristics and outcome predictors of acute heart failure in elderly patients

ObjectiveWe determined the clinical-epidemiological characteristics and prognostic factors of early mortality and re-consultation in an elderly population attending the hospital emergency department (HED) for acute heart failure (AHF). Patients and methodsA prospective, observational, non interventional study including all the patients with AHF attended in the Spanish's HED. Two groups were defined: elderly (≥80years) and controls (<80years). Variables: demographic characteristics, comorbidity, degree of cardiac involvement, previous treatment, symptoms and signs of the AHF episode, precipitating factors, treatment in the HED and outcome. Outcome variables: mortality and re-consultation within 30days. ResultsOf the 942 patients included, 455 of whom were elderly (48.3%). In this elderly population female sex, auricular fibrillation and a history of ictus and a poor functional status predominated. The type of ventricular dysfunction was unknown in 70%. No main differences in the presentation of AHF were found between the two groups. Mortality and re-consultation to the HED within 30days were similar in both groups. While several factors were identified to be related to mortality or re-consultation in control group, in the elderly group it was more difficult to identify patients who will die or re-consult to the HED within the following 30days. Only respiratory insufficiency on arrival to the HED was found to predict a greater probability of death (OR 3.55; CI95% 1.39–9.11). ConclusionsAHF in elderly patients presents some differential characteristics and, most importantly, it is more difficult to identify which of these patients will die or re-consult in the short-term.

Dilated Cardiomyopathy With Conduction Disease and Arrhythmia

case presentation: A 48-year-old woman presents with exertional dyspnea and recurrent syncope. One year earlier, a permanent pacemaker was placed after she complained of fatigue and was found to have high-grade atrioventricular block. Now, she has echocardiographic evidence of moderate to severe left ventricular (LV) systolic dysfunction with regional wall-motion abnormalities. Nuclear imaging is notable for heterogeneous myocardial uptake of technetium Tc99m sestamibi, and coronary angiography reveals widely patent epicardial vessels. Multiple episodes of nonsustained ventricular tachycardia (VT) are documented on continuous ECG monitoring. What are the diagnostic considerations for this patient, and what further evaluations are indicated? This patient presents with dilated cardiomyopathy (DCM) with electric instability (DCM+E), which we define as conduction disease and arrhythmia out of proportion to the severity of LV systolic dysfunction. Diverse causes can result in DCM+E and fall into general categories of inflammatory, infectious, hereditary, and infiltrative processes. Cardiac presentation associated with these conditions is distinct from more common causes of DCM such as ischemic heart disease, viral myocarditis, valvular dysfunction, pregnancy, or substance abuse. Clinical features that are suggestive of DCM+E include supraventricular arrhythmias or conduction disease that precedes cardiomyopathy, multiple VT morphologies, and features suggestive of ischemic heart disease (Q waves, regional wall-motion abnormalities, perfusion defects, ventricular aneurysm) in the absence of epicardial stenoses. In this Clinician Update, we focus on the diagnostic approach to patients with DCM+E. Emphasis is placed on diagnoses that are relatively common or for which the clinical management would be impacted significantly by recognition of the underlying cause. Ischemic heart disease may present with conduction disease and a high burden of arrhythmia, especially in the setting of acute myocardial ischemia/infarction. The exclusion of obstructive coronary artery disease is strongly recommended in patients with DCM+E because atherosclerosis is so prevalent, evidence-based treatment is readily available, and the …

A Novel Prognostic Staging System for Light Chain Amyloidosis (AL) Incorporating Markers of Plasma Cell Burden and Organ Involvement.

Abstract 2797Poster Board II-773 Background:Primary systemic amyloidosis (AL) is characterized by deposition of light chain derived amyloid fibrils in multiple organs leading to varying degree of dysfunction. Cardiac involvement is a common feature of AL, and when significant is highly predictive of poor outcome. The currently used prognostic classification is based on cardiac biomarkers troponin-T (cTnT) and N-terminal pro B-type Natriuretic peptide (NT-ProBNP) and is effective at predicting outcome in patients with AL. However, this is driven primarily by the degree of cardiac involvement and does not take into account the degree of plasma cell burden and its impact on the disease course. It is possible that some of the heterogeneity in outcome can be explained by the plasma cell characteristics rather than the degree of the end organ damage. Methods:We examined the baseline clinical and laboratory data from 2119 patients with AL who were seen at our institution with in 90 days of their diagnosis. The data were collected from a prospectively maintained data base, and additional testing was done for free light chain levels (FLC) on stored sera from patients seen before the routine introduction of FLC testing. Cox proportional hazards analysis was performed to estimate the prognostic values of different variables. Results:We first examined the impact of plasma cell clone related characteristics namely, difference between involved and uninvolved FLC (FLC-Diff), bone marrow plasma cell (BMPC) %, plasma cell labeling index (PCLI), beta 2 microglobulin (B2M), and presence of circulating plasma cells, on overall survival (OS) from diagnosis. All variables were dichotomized into high and low based on their median value (FLC-diff: 20 mg/dL, BMPC: 10%, PCLI as a continuous variable, B2M: 3 mg/dL and circulating cells: absent or present). While all were found to be prognostic for OS in univariate analysis; in a multivariate analysis incorporating a stepwise selection only B2M and FLC-diff were significant. We then used these two variables along with the cTnT and NT-ProBNP that are used in the current model to develop a staging system. The median values for all four variables were used for developing the scores. Patients were assigned a score of 1 for presence of each characteristic (FLC difference > 20 mg/dL, troponin-T > 0.02, NT-ProBNP > 1000, and B2M > 3) or 0 if the value was at or below the cutoff. The scores were added to obtain a composite prognostic score that grouped the 370 patients (who had all the variables available for analysis) into 5 groups with very different OS (4.4, 9.3, 24.4, 43, and not reached for stages 4, 3, 2, 1, and 0 respectively; Figure A). However, since the NT-ProBNP did not have independent impact on survival in a multivariable model incorporating all the four variables, we also examined a system that only included FLC-diff, cTnT and B2M. This system again allowed grouping of patients (n=450 with all three variables available) into four distinct groups with divergent outcome with OS of 4.6, 10.5, 36.8, and not reached for stages 3, 2, 1, and 0 respectively; (Figure B). Conclusion:Incorporation of plasma cell related measurements into the existing staging system using cardiac biomarkers allows better risk stratification of patients with AL amyloidosis. The system using FLC, B2M and troponin has the advantage of easily available laboratory values and can be widely adopted. Addition of NT-ProBNP into the system allows better refinement of the intermediate risk groups. This system will allow upfront risk stratification and development of risk-adapted therapies for patients with AL. [Display omitted] Disclosures:Gertz:Genzyme: Research Funding.

Multiple myeloma-associated AL amyloidosis: is a distinctive therapeutic approach warranted?

The natural history of multiple myeloma (MM) was revolutionized by the introduction of haematopoietic stem cell transplantation to the treatment armamentarium of this disease. Defined subgroups of MM patients (such as the elderly or dialysis-dependent) have required an individualized approach in order to minimize the transplant-related mortality. Little, however, is known about the management of 12-30% of MM patients with coexistent AL amyloidosis as the amyloidopathy is often overlooked and when recognized these patients commonly are excluded from clinical trials. While occult amyloidosis appears to have no impact on the toxicity and outcome of MM patients, the presence of symptomatic amyloidopathy clearly worsens their prognosis. Use of induction chemotherapy drugs that can cause further damage to the heart (Adriamycin), nervous system (Vincristine) or kidneys should be avoided as should lengthy delays in proceeding to autograft. Further, refining the transplant eligibility criteria for this subgroup of patients with co-existent amyloidopathy to include the number of organs involved and the degree of cardiac involvement (NYHA class, Troponins and NT-pro-BNP levels) along with melphalan dose-adjustment will minimize the treatment-related toxicity and mortality and possibly allow a reversal of the organ damage induced by the amyloidogenic light chain.