Right Heart Changes Impact on Clinical Phenotype of Amyloid Cardiac Involvement: A Single Centre Study

Amyloidosis is due to deposition of an excessive amount of protein in many parenchymal tissues, including myocardium. The onset of cardiac Amyloidosis (CA) is an inauspicious prognostic factor, which can lead to sudden death. We retrospectively analyzed 135 patients with systemic amyloidosis, admitted to our ward between 1981 and 2019. Among them, 54 patients (46.30% F/53.70% M, aged 63.95 ± 12.82) presented CA at baseline. In 53 patients, it was associated with a multiorgan involvement, while in one there was a primary myocardial deposition. As a control group, we enrolled 81 patients (49.30% F/50.70% M, aged 58.33 ± 15.65) who did not meet the criteria for CA. In 44/54 of patients CA was associated with AL, 5/54 with AA and 3/54 of patients with ATTR, and in 1/54 AL was related to hemodialysis and in 1/54 to Gel-Amyloidosis. The most common AL type was IgG (28/44); less frequent forms were either IgA (7/44) or IgD (2/44), while seven patients had a λ free light chain form. The 32 AL with complete Ig were 31 λ-chain and just one k-chain. CA patients presented normal BP (SBP 118.0 ± 8.4 mmHg; DBP 73.8 ± 4.9 mmHg), while those with nCA had an increased proteinuria (p = 0.02). TnI and NT-proBNP were significantly increased compared to nCA (p = 0.031 and p = 0.047, respectively). In CA patients we found an increased LDH compared to nCA (p = 0.0011). CA patients were also found to have an increased interventricular septum thickness compared to nCA (p = 0.002), a decreased Ejection Fraction % (p = 0.0018) and Doppler velocity E/e’ ratio (p = 0.0095). Moreover, CA patients had an enhanced right atrium area (p = 0.0179), right ventricle basal diameter (p = 0.0112) and wall thickness (p = 0.0471) compared to nCA, and an increased inferior cava vein diameter (p = 0.0495) as well. TAPSE was the method chosen to evaluate systolic function of the right heart. In CA subjects very poor TAPSE levels were found compared to nCA patients (p = 0.0495). Additionally, we found a significant positive correlation between TAPSE and lymphocyte count (r = 0.47; p = 0.031) as well as Gamma globulins (r = 0.43, p = 0.033), Monoclonal components (r = 0.72; p = 0.047) and IgG values (r = 0.62, p = 0.018). Conversely, a significant negative correlation with LDH (r = −0.57, p = 0.005), IVS (r = −0.51, p = 0.008) and diastolic function evaluated as E/e’ (r = −0.60, p = 0.003) were verified. CA patients had very poor survival rates compared to controls (30 vs. 66 months in CA vs. nCA, respectively, p = 0.15). Mean survival of CA individuals was worse also when stratified according to NT-proBNP levels, using 2500 pg/mL as class boundary (174 vs. 5.5 months, for patients with lower vs. higher values than the median, respectively p = 0.013). In much the same way, a decreased right heart systolic function was correlated with a worse prognosis (18.0 months median survival, not reached in subjects with lower values than 18 mm, p = 0.0186). Finally, our data highlight the potential prognostic and predictive value of right heart alterations characterizing amyloidosis, as a novel clinical parameter correlated to increased LDH and immunoglobulins levels. Overall, we confirm the clinical relevance of cardiac involvement suggests that right heart evaluation may be considered as a new marker for clinical risk stratification in patients with amyloidosis.

[1]  M. Weigand,et al.  Preoperative neutrophil to lymphocyte ratio and platelet to lymphocyte ratio are associated with major adverse cardiovascular and cerebrovascular events in coronary heart disease patients undergoing non-cardiac surgery , 2020, BMC Cardiovascular Disorders.

[2]  H. Daida,et al.  Neutrophil to Lymphocyte Ratio and Long-Term Cardiovascular Outcomes in Coronary Artery Disease Patients with Low High-Sensitivity C-Reactive Protein Level. , 2020, International heart journal.

[3]  M. Picken The Pathology of Amyloidosis in Classification: A Review , 2020, Acta Haematologica.

[4]  G. Cenini,et al.  Oxidative Stress and Mitochondrial Damage in Neurodegenerative Diseases: From Molecular Mechanisms to Targeted Therapies , 2020, Oxidative medicine and cellular longevity.

[5]  T. Rassaf,et al.  Diagnosing cardiac amyloidosis in every-day practice: A practical guide for the cardiologist , 2020, International journal of cardiology. Heart & vasculature.

[6]  Asif Khan,et al.  Utilization of Ultrasound to Assess Volume Status in Heart Failure , 2020, Journal of clinical medicine research.

[7]  James A. White,et al.  Determinants and Prognostic Significance of Serial Right Heart Function Changes in Patients With Cardiac Amyloidosis. , 2020, Canadian Journal of Cardiology.

[8]  P. Colonna,et al.  Early echocardiographic detection of left ventricular diastolic dysfunction in patients with systemic lupus erythematosus asymptomatic for cardiovascular disease , 2019, Clinical and Experimental Medicine.

[9]  H. Einsele,et al.  CIC Mutation as a Molecular Mechanism of Acquired Resistance to Combined BRAF-MEK Inhibition in Extramedullary Multiple Myeloma with Central Nervous System Involvement. , 2019, The oncologist.

[10]  Y. Takeishi,et al.  Utility of B-Type Natriuretic Peptide for Detecting Cardiac Involvement in Immunoglobulin Amyloidosis. , 2019, International heart journal.

[11]  C. Hagemeyer,et al.  Shear-Dependent Platelet Aggregation: Mechanisms and Therapeutic Opportunities , 2019, Front. Cardiovasc. Med..

[12]  N. Mahmud,et al.  Combined immune score of lymphocyte to monocyte ratio and immunoglobulin levels predicts treatment-free survival of multiple myeloma patients after autologous stem cell transplant , 2019, Bone Marrow Transplantation.

[13]  H. Einsele,et al.  High-Risk Multiple Myeloma: Integrated Clinical and Omics Approach Dissects the Neoplastic Clone and the Tumor Microenvironment , 2019, Journal of clinical medicine.

[14]  A. Vacca,et al.  Suspected Pericardial Tuberculosis Revealed as an Amyloid Pericardial Mass , 2018, Case reports in hematology.

[15]  M. Henein,et al.  Right ventricular involvement in transthyretin amyloidosis , 2018, Amyloid : the international journal of experimental and clinical investigation : the official journal of the International Society of Amyloidosis.

[16]  P. Milani,et al.  Management of the elderly patient with AL amyloidosis. , 2018, European journal of internal medicine.

[17]  M. Dimopoulos,et al.  Growth differentiation factor-15 is a new biomarker for survival and renal outcomes in light chain amyloidosis. , 2018, Blood.

[18]  D. Dingli,et al.  Clinical presentation and outcomes in light chain amyloidosis patients with non-evaluable serum free light chains , 2018, Leukemia.

[19]  Christos G Mihos,et al.  A Focused Review on the Pathophysiology, Diagnosis, and Management of Cardiac Amyloidosis. , 2017, Reviews in cardiovascular medicine.

[20]  G. Merlini AL amyloidosis: from molecular mechanisms to targeted therapies. , 2017, Hematology. American Society of Hematology. Education Program.

[21]  M. Hanna,et al.  Cardiac amyloidosis: An update on diagnosis and treatment , 2017, Cleveland Clinic Journal of Medicine.

[22]  P. Milani,et al.  Proteotoxicity in cardiac amyloidosis: amyloidogenic light chains affect the levels of intracellular proteins in human heart cells , 2017, Scientific Reports.

[23]  F. Dammacco,et al.  Subcutaneous immunoglobulins in patients with multiple myeloma and secondary hypogammaglobulinemia: a randomized trial. , 2017, Clinical immunology.

[24]  O. Berlanga,et al.  Immunoparesis defined by heavy+light chain suppression is a novel marker of long‐term outcomes in cardiac AL amyloidosis , 2017, British journal of haematology.

[25]  D. Dingli,et al.  Elevation of serum lactate dehydrogenase in AL amyloidosis reflects tissue damage and is an adverse prognostic marker in patients not eligible for stem cell transplantation , 2017, British journal of haematology.

[26]  M. Nöthen,et al.  Genome-wide association study of immunoglobulin light chain amyloidosis in three patient cohorts: comparison with myeloma , 2017, Leukemia.

[27]  H. Agis News in AL Amyloidosis ASH 2016 , 2017, memo - Magazine of European Medical Oncology.

[28]  Roman M. Ženka,et al.  Clarifying immunoglobulin gene usage in systemic and localized immunoglobulin light-chain amyloidosis by mass spectrometry. , 2017, Blood.

[29]  M. Dimopoulos,et al.  Clinical and prognostic significance of serum levels of von Willebrand factor and ADAMTS-13 antigens in AL amyloidosis. , 2016, Blood.

[30]  P. Schirmacher,et al.  Cardiac Amyloid Load: A Prognostic and Predictive Biomarker in Patients With Light-Chain Amyloidosis. , 2016, Journal of the American College of Cardiology.

[31]  J. Deux,et al.  Prognostic value of right ventricular systolic function in cardiac amyloidosis , 2016, Amyloid : the international journal of experimental and clinical investigation : the official journal of the International Society of Amyloidosis.

[32]  D. Dingli,et al.  Immunoparesis in newly diagnosed AL amyloidosis is a marker for response and survival , 2016, Amyloid : the international journal of experimental and clinical investigation : the official journal of the International Society of Amyloidosis.

[33]  S. Yusuf,et al.  Use of Noninvasive Imaging in Cardiac Amyloidosis , 2016, Current Treatment Options in Cardiovascular Medicine.

[34]  G. Spadaro,et al.  Intravenous versus subcutaneous immunoglobulin replacement in secondary hypogammaglobulinemia. , 2016, Clinical immunology.

[35]  G. Palladini,et al.  Novel mitochondrial protein interactors of immunoglobulin light chains causing heart amyloidosis , 2015, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[36]  A. Jaffe,et al.  Soluble suppression of tumorigenicity 2 (sST2), but not galactin‐3, adds to prognostication in patients with systemic AL amyloidosis independent of NT‐proBNP and troponin T , 2015, American journal of hematology.

[37]  G. Gensini,et al.  Echocardiographic and Biohumoral Characteristics in Patients With AL and TTR Amyloidosis at Diagnosis , 2015, Clinical cardiology.

[38]  A. Foli,et al.  A staging system for renal outcome and early markers of renal response to chemotherapy in AL amyloidosis. , 2014, Blood.

[39]  W. Edwards,et al.  Left ventricular amyloid deposition in patients with heart failure and preserved ejection fraction. , 2014, JACC. Heart failure.

[40]  D. Dingli,et al.  Coexistent multiple myeloma or increased bone marrow plasma cells define equally high-risk populations in patients with immunoglobulin light chain amyloidosis. , 2013, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[41]  G. Merlini,et al.  Systemic light chain amyloidosis: an update for treating physicians. , 2013, Blood.

[42]  G. Merlini,et al.  Differential diagnosis of monoclonal gammopathy of undetermined significance. , 2012, Hematology. American Society of Hematology. Education Program.

[43]  B. Fernandez,et al.  AL Amyloidosis , 2012, Orphanet Journal of Rare Diseases.

[44]  L. Padeletti,et al.  Right ventricular function in AL amyloidosis: characteristics and prognostic implication. , 2012, European heart journal cardiovascular Imaging.

[45]  R. Falk,et al.  Current perspectives on cardiac amyloidosis. , 2012, American journal of physiology. Heart and circulatory physiology.

[46]  G. Merlini,et al.  The repertoire of λ light chains causing predominant amyloid heart involvement and identification of a preferentially involved germline gene, IGLV1-44. , 2012, Blood.

[47]  M. Rosenzweig,et al.  Light chain (AL) amyloidosis: update on diagnosis and management , 2011, Journal of hematology & oncology.

[48]  D. Seldin,et al.  Amyloidotic cardiomyopathy: multidisciplinary approach to diagnosis and treatment. , 2011, Heart failure clinics.

[49]  R. Rokey,et al.  Stiff Heart Syndrome , 2011, Clinical Medicine & Research.

[50]  J. Rysä,et al.  Distinct regulation of B-type natriuretic peptide transcription by p38 MAPK isoforms , 2011, Molecular and Cellular Endocrinology.

[51]  W. Aronow,et al.  A Novel Two‐Dimensional Echocardiographic Finding in Cardiac Amyloidosis , 2010, Echocardiography.

[52]  M. Benson,et al.  Amyloid fibril protein nomenclature: 2010 recommendations from the nomenclature committee of the International Society of Amyloidosis , 2010, Amyloid : the international journal of experimental and clinical investigation : the official journal of the International Society of Amyloidosis.

[53]  G. Dotti Blocking PD-1 in cancer immunotherapy. , 2009, Blood.

[54]  C. Schmid,et al.  A new equation to estimate glomerular filtration rate. , 2009, Annals of internal medicine.

[55]  W. Manning,et al.  Diagnostic and prognostic utility of cardiovascular magnetic resonance imaging in light-chain cardiac amyloidosis. , 2009, The American journal of cardiology.

[56]  D. Pennell,et al.  Cardiovascular Magnetic Resonance and prognosis in cardiac amyloidosis , 2008, Journal of cardiovascular magnetic resonance : official journal of the Society for Cardiovascular Magnetic Resonance.

[57]  R. Rivera,et al.  Cardiac manifestations of amyloid disease. , 2008, Boletin de la Asociacion Medica de Puerto Rico.

[58]  Keyur B Shah,et al.  Amyloidosis and the heart: a comprehensive review. , 2006, Archives of internal medicine.

[59]  R. Falk,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 , 2005, American journal of hematology.

[60]  A. Balduini,et al.  Serum N-Terminal Pro–Brain Natriuretic Peptide Is a Sensitive Marker of Myocardial Dysfunction in AL Amyloidosis , 2003, Circulation.

[61]  C. Martínez,et al.  The tropism of organ involvement in primary systemic amyloidosis: contributions of Ig V(L) germ line gene use and clonal plasma cell burden. , 2001, Blood.

[62]  Victor Mor-Avi,et al.  Recommendations for cardiac chamber quantification by echocardiography in adults: an update from the American Society of Echocardiography and the European Association of Cardiovascular Imaging. , 2015, Journal of the American Society of Echocardiography : official publication of the American Society of Echocardiography.

[63]  M. Terol,et al.  High-risk cytogenetics and persistent minimal residual disease by multiparameter flow cytometry predict unsustained complete response after autologous stem cell transplantation in multiple myeloma. , 2012, Blood.

[64]  S. Cicco,et al.  The influence of oxygen supply, hemorheology and microcirculation in the heart and vascular systems. , 2010, Advances in experimental medicine and biology.

[65]  M. Iacoviello,et al.  Could dilated cardiomyopathy alter the peripheral microcirculation and blood rheology? , 2010, Advances in experimental medicine and biology.

[66]  H. Drexler,et al.  Endothelial dysfunction in human disease. , 1999, Journal of molecular and cellular cardiology.