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Grynblat J, Khouri C, Hlavaty A, Jaïs X, Savale L, Chaumais MC, Kularatne M, Jevnikar M, Boucly A, Antigny F, Perros F, Simonneau G, Sitbon O, Humbert M, Montani D. Characteristics and outcomes of patients developing pulmonary hypertension associated with proteasome inhibitors. Eur Respir J 2024; 63:2302158. [PMID: 38697649 DOI: 10.1183/13993003.02158-2023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2023] [Accepted: 04/15/2024] [Indexed: 05/05/2024]
Abstract
BACKGROUND Pulmonary arterial hypertension (PAH) has been described in patients treated with proteasome inhibitors (PIs). Our objective was to evaluate the association between PIs and PAH. METHODS Characteristics of incident PAH cases previously treated with carfilzomib or bortezomib were analysed from the French pulmonary hypertension registry and the VIGIAPATH programme from 2004 to 2023, concurrently with a pharmacovigilance disproportionality analysis using the World Health Organization (WHO) global database (VigiBase) and a meta-analysis of randomised controlled trials. RESULTS 11 incident cases of PI-associated PAH were identified (six with carfilzomib and five with bortezomib) with a female:male ratio of 2.7:1, a median age of 61 years, and a median delay between PI first exposure and PAH of 6 months. Four patients died (two from right heart failure, one from respiratory distress and one from an unknown cause). At diagnosis, six were in New York Heart Association Functional Class III/IV with severe haemodynamic impairment (median mean pulmonary arterial pressure 39 mmHg, cardiac index 2.45 L·min-1·m-2 and pulmonary vascular resistance 7.2 WU). In the WHO pharmacovigilance database, 169 cases of PH associated with PI were reported since 2013 with significant signals of disproportionate reporting (SDR) for carfilzomib, regardless of the definition of cases or control group. However, SDR for bortezomib were inconsistent. The systematic review identified 17 clinical trials, and carfilzomib was associated with a significantly higher risk of dyspnoea, severe dyspnoea and PH compared with bortezomib. CONCLUSION PIs may induce PAH in patients undergoing treatment, with carfilzomib emitting a stronger signal than bortezomib, and these patients should be monitored closely.
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Affiliation(s)
- Julien Grynblat
- INSERM UMR_S 999 "Pulmonary Hypertension: Pathophysiology and Novel Therapies", Hôpital Marie Lannelongue, Le Plessis-Robinson, France
- AP-HP, Department of Respiratory and Intensive Care Medicine, Pulmonary Hypertension National Referral Centre, Bicêtre Hospital, Le Kremlin-Bicêtre, France
- School of Medicine, University of Paris-Saclay, Le Kremlin-Bicêtre, France
- These authors contributed equally to this work
| | - Charles Khouri
- Univ. Grenoble Alpes, HP2 Laboratory, INSERM U 1300, Grenoble, France
- Pharmacovigilance Unit and Clinical Pharmacology Department, Grenoble Alpes University Hospital, Grenoble, France
- These authors contributed equally to this work
| | - Alex Hlavaty
- Univ. Grenoble Alpes, HP2 Laboratory, INSERM U 1300, Grenoble, France
- Pharmacovigilance Unit and Clinical Pharmacology Department, Grenoble Alpes University Hospital, Grenoble, France
| | - Xavier Jaïs
- INSERM UMR_S 999 "Pulmonary Hypertension: Pathophysiology and Novel Therapies", Hôpital Marie Lannelongue, Le Plessis-Robinson, France
- AP-HP, Department of Respiratory and Intensive Care Medicine, Pulmonary Hypertension National Referral Centre, Bicêtre Hospital, Le Kremlin-Bicêtre, France
- School of Medicine, University of Paris-Saclay, Le Kremlin-Bicêtre, France
| | - Laurent Savale
- INSERM UMR_S 999 "Pulmonary Hypertension: Pathophysiology and Novel Therapies", Hôpital Marie Lannelongue, Le Plessis-Robinson, France
- AP-HP, Department of Respiratory and Intensive Care Medicine, Pulmonary Hypertension National Referral Centre, Bicêtre Hospital, Le Kremlin-Bicêtre, France
- School of Medicine, University of Paris-Saclay, Le Kremlin-Bicêtre, France
| | - Marie Camille Chaumais
- INSERM UMR_S 999 "Pulmonary Hypertension: Pathophysiology and Novel Therapies", Hôpital Marie Lannelongue, Le Plessis-Robinson, France
- School of Pharmacy, University of Paris-Saclay, Saclay, France
- AP-HP, Department of Pharmacy, Bicêtre Hospital, Le Kremlin-Bicêtre, France
| | - Mithum Kularatne
- INSERM UMR_S 999 "Pulmonary Hypertension: Pathophysiology and Novel Therapies", Hôpital Marie Lannelongue, Le Plessis-Robinson, France
- AP-HP, Department of Respiratory and Intensive Care Medicine, Pulmonary Hypertension National Referral Centre, Bicêtre Hospital, Le Kremlin-Bicêtre, France
- School of Medicine, University of Paris-Saclay, Le Kremlin-Bicêtre, France
- Division of Respiratory Medicine, Department of Medicine, University of Calgary, Calgary, AB, Canada
| | - Mitja Jevnikar
- INSERM UMR_S 999 "Pulmonary Hypertension: Pathophysiology and Novel Therapies", Hôpital Marie Lannelongue, Le Plessis-Robinson, France
- AP-HP, Department of Respiratory and Intensive Care Medicine, Pulmonary Hypertension National Referral Centre, Bicêtre Hospital, Le Kremlin-Bicêtre, France
- School of Medicine, University of Paris-Saclay, Le Kremlin-Bicêtre, France
| | - Athénaïs Boucly
- INSERM UMR_S 999 "Pulmonary Hypertension: Pathophysiology and Novel Therapies", Hôpital Marie Lannelongue, Le Plessis-Robinson, France
- AP-HP, Department of Respiratory and Intensive Care Medicine, Pulmonary Hypertension National Referral Centre, Bicêtre Hospital, Le Kremlin-Bicêtre, France
- School of Medicine, University of Paris-Saclay, Le Kremlin-Bicêtre, France
| | - Fabrice Antigny
- INSERM UMR_S 999 "Pulmonary Hypertension: Pathophysiology and Novel Therapies", Hôpital Marie Lannelongue, Le Plessis-Robinson, France
- AP-HP, Department of Respiratory and Intensive Care Medicine, Pulmonary Hypertension National Referral Centre, Bicêtre Hospital, Le Kremlin-Bicêtre, France
- School of Medicine, University of Paris-Saclay, Le Kremlin-Bicêtre, France
| | - Frédéric Perros
- INSERM UMR_S 999 "Pulmonary Hypertension: Pathophysiology and Novel Therapies", Hôpital Marie Lannelongue, Le Plessis-Robinson, France
- AP-HP, Department of Respiratory and Intensive Care Medicine, Pulmonary Hypertension National Referral Centre, Bicêtre Hospital, Le Kremlin-Bicêtre, France
- School of Medicine, University of Paris-Saclay, Le Kremlin-Bicêtre, France
- CarMeN Laboratory, INSERM U1060, INRAE U1397, Université Claude Bernard Lyon 1, Pierre-Bénite, France
| | - Gérald Simonneau
- INSERM UMR_S 999 "Pulmonary Hypertension: Pathophysiology and Novel Therapies", Hôpital Marie Lannelongue, Le Plessis-Robinson, France
- AP-HP, Department of Respiratory and Intensive Care Medicine, Pulmonary Hypertension National Referral Centre, Bicêtre Hospital, Le Kremlin-Bicêtre, France
- School of Medicine, University of Paris-Saclay, Le Kremlin-Bicêtre, France
| | - Olivier Sitbon
- INSERM UMR_S 999 "Pulmonary Hypertension: Pathophysiology and Novel Therapies", Hôpital Marie Lannelongue, Le Plessis-Robinson, France
- AP-HP, Department of Respiratory and Intensive Care Medicine, Pulmonary Hypertension National Referral Centre, Bicêtre Hospital, Le Kremlin-Bicêtre, France
- School of Medicine, University of Paris-Saclay, Le Kremlin-Bicêtre, France
| | - Marc Humbert
- INSERM UMR_S 999 "Pulmonary Hypertension: Pathophysiology and Novel Therapies", Hôpital Marie Lannelongue, Le Plessis-Robinson, France
- AP-HP, Department of Respiratory and Intensive Care Medicine, Pulmonary Hypertension National Referral Centre, Bicêtre Hospital, Le Kremlin-Bicêtre, France
- School of Medicine, University of Paris-Saclay, Le Kremlin-Bicêtre, France
| | - David Montani
- INSERM UMR_S 999 "Pulmonary Hypertension: Pathophysiology and Novel Therapies", Hôpital Marie Lannelongue, Le Plessis-Robinson, France
- AP-HP, Department of Respiratory and Intensive Care Medicine, Pulmonary Hypertension National Referral Centre, Bicêtre Hospital, Le Kremlin-Bicêtre, France
- School of Medicine, University of Paris-Saclay, Le Kremlin-Bicêtre, France
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Li M, Tang M, Zhao C, Dang P, Wang X, Liu H, Zhao J, Wang J, He P. Prognostic Potential of Pulmonary Hypertension in Patients with Hematologic Malignancy. Adv Ther 2023; 40:4792-4804. [PMID: 37612564 DOI: 10.1007/s12325-023-02639-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2023] [Accepted: 08/04/2023] [Indexed: 08/25/2023]
Abstract
INTRODUCTION Cardiovascular diseases present a great burden for survivors of hematologic malignancy (HM). However, the effect of pulmonary hypertension (PH) on the clinical outcome of patients with HM remains unknown. This study aims to evaluate the prognostic potential of PH in patients with HM and explore the related clinical determinants. METHODS This retrospective study included 220 patients with HM and PH and 220 controls without PH, the case-matching cohort analysis was performed based on age, sex, the year of diagnosis and disease type. The baseline characteristics and overall survival (OS) of the patients with HM with or without PH were compared. The cumulative overall survival was analyzed using the Kaplan-Meier curves and the log-rank test. Multivariate Cox proportional hazard models were conducted to identify the predictors of OS. RESULTS PH was found in 11.98% (302/2520) of the patients with HM. The PH group had lower levels of hemoglobin, platelet, albumin, fibrinogen and B cell count; whereas the levels of lactate dehydrogenase, N terminal pro B type natriuretic peptide, D-dimer, fibrinogen degradation products and C-reactive protein were higher. Additionally, the PH group had a higher prevalence of atrial fibrillation. Survival analysis revealed that the PH group had an inferior OS compared to the non-PH group (16.9 vs. 37.6 months, p = 0.002). Further subgroup analysis revealed that the severe PH group had the worst OS, followed by the moderate and the mild PH groups (8.7 vs. 14.7 vs. 23.7 months, p < 0.001). Multivariate analysis showed that PH was an independent predictor for unfavorable clinical outcomes. CONCLUSIONS Coexisting PH was associated with inferior clinical outcomes in patients with HM, and the severe PH group had the worst prognosis. The study may provide additional risk stratification for patients with HM.
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Affiliation(s)
- Miaojing Li
- Department of Hematology, The First Affiliated Hospital of Xi'an Jiaotong University, 277 Yanta West Road, Xi'an, 710061, Shaanxi, China
| | - Manyun Tang
- Key Laboratory of Surgical Critical Care and Life Support, Xi'an Jiaotong University, Ministry of Education, Xi'an, 710061, Shaanxi, China
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, Shaanxi, China
| | - Changying Zhao
- Department of Cardiovascular Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, Shaanxi, China
| | - Peizhu Dang
- Department of Cardiovascular Medicine, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, Shaanxi, China
| | - Xindi Wang
- Department of Clinical Medicine, School of Medicine, Xi'an Jiaotong University, Xi'an, 710061, Shaanxi, China
| | - Hui Liu
- The Biobank of the First Affiliated Hospital of Xian Jiaotong University, Xi'an, 710061, Shaanxi, China
| | - Juan Zhao
- Department of Hematology, The First Affiliated Hospital of Xi'an Jiaotong University, 277 Yanta West Road, Xi'an, 710061, Shaanxi, China
| | - Jie Wang
- Department of Hematology, The First Affiliated Hospital of Xi'an Jiaotong University, 277 Yanta West Road, Xi'an, 710061, Shaanxi, China
| | - Pengcheng He
- Department of Hematology, The First Affiliated Hospital of Xi'an Jiaotong University, 277 Yanta West Road, Xi'an, 710061, Shaanxi, China.
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Gao M, Zhang WH, Zhang ZG, Yang N, Tong Q, Chen LP. Cardiac amyloidosis presenting as pulmonary arterial hypertension: A case report. World J Clin Cases 2023; 11:2780-2787. [PMID: 37214585 PMCID: PMC10198101 DOI: 10.12998/wjcc.v11.i12.2780] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/13/2023] [Revised: 02/22/2023] [Accepted: 03/30/2023] [Indexed: 04/25/2023] Open
Abstract
BACKGROUND Pulmonary hypertension is a rare cardiopulmonary disease, with an insidious onset that usually worsens rapidly. Amyloid light chain (AL) amyloidosis is a rare systemic disease caused by extracellular deposition of pathologic, insoluble, and proteinaceous fibrils in organs and tissues; however, it is difficult to diagnose given its varied and nonspecific symptoms. To date, rare cases of amyloidosis with pulmonary hypertension have been reported. Of note, the optimal treatments for cardiac amyloidosis complicated with pulmonary hypertension remain unclear.
CASE SUMMARY We report a case of a 51-year-old woman who presented with progressively worsening dyspnea. Transthoracic echocardiography indicated severe pulmonary hypertension. Twenty-seven months after first admission, the patient returned with symptoms of progressive heart failure. A myocardial tissue sample stained with Congo red was positive, and the patient was ultimately diagnosed with AL amyloidosis with cardiac involvement.
CONCLUSION Although pulmonary hypertension may be idiopathic, it is frequently associated with other conditions. In rare cases, pulmonary hypertension can be a complication of AL amyloidosis, which should be seriously considered in any adult presenting with nonspecific signs or symptoms of cardiac distress.
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Affiliation(s)
- Ming Gao
- Department of Cardiology, The First Hospital of Jilin University, Changchun 130021, Jilin Province, China
| | - Wei-Hua Zhang
- Department of Cardiology, The First Hospital of Jilin University, Changchun 130021, Jilin Province, China
| | - Zhi-Guo Zhang
- Department of Cardiology, The First Hospital of Jilin University, Changchun 130021, Jilin Province, China
| | - Na Yang
- Department of Cardiology, The First Hospital of Jilin University, Changchun 130021, Jilin Province, China
| | - Qian Tong
- Department of Cardiology, The First Hospital of Jilin University, Changchun 130021, Jilin Province, China
| | - Li-Ping Chen
- Department of Echocardiography, Center of Cardiovascular Disease, The First Hospital of Jilin University, Changchun 130021, Jilin Province, China
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Maddipati V, Sankhyan P, Goswami DP, Mahajan A. Pulmonary hypertension in patients with multiple myeloma: A comprehensive review. Pulm Circ 2023; 13:e12210. [PMID: 37063748 PMCID: PMC10098295 DOI: 10.1002/pul2.12210] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/06/2022] [Revised: 02/02/2023] [Accepted: 03/08/2023] [Indexed: 04/18/2023] Open
Abstract
Multiple myeloma (MM) is a common hematological malignancy resulting from clonal proliferation of plasma cells and is defined by criteria set forth by the international myeloma working group. Pulmonary hypertension (PH) is defined by an elevated mean pulmonary artery pressure >20 mmHg measured during right heart catheterization. Echocardiography-diagnosed PH is relatively common in patients with MM and has been associated with increased mortality, morbidity, and poor stem cell transplant outcomes. PH in patients with MM (PH-MM) is usually multifactorial in origin. MM disease-specific factors, host comorbidities, and treatment-related adverse effects are the key factors for the development of PH-MM. Pragmatically, patients with PH-MM can be grouped into either (i) PH in patients with a new diagnosis of MM or (ii) PH that develops or worsens along the way of MM treatment. In the latter group, drug-induced PH, venous thromboembolism, pulmonary veno occlusive disease, and cardiotoxicity should be considered as possible causes. PH-MM should be evaluated and managed in a multidisciplinary setting. Select individuals with PH-MM could be considered for pulmonary vasodilators at PH-specialized centers.
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Affiliation(s)
- Veeranna Maddipati
- Division of Pulmonary and Critical Care Medicine, Pulmonary Vascular MedicineEast Carolina UniversityGreenvilleNorth CarolinaUSA
| | - Pratyaksha Sankhyan
- Division of Pulmonary and Critical Care MedicineEast Carolina UniversityGreenvilleNorth CarolinaUSA
| | - Durga P. Goswami
- Department of Internal MedicineEast Carolina UniversityGreenvilleNorth CarolinaUSA
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Etiology of pulmonary hypertension in multiple myeloma: A case series and literature review. Respir Med 2023; 206:107071. [PMID: 36508985 DOI: 10.1016/j.rmed.2022.107071] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/15/2022] [Revised: 10/25/2022] [Accepted: 12/01/2022] [Indexed: 12/12/2022]
Abstract
BACKGROUND Multiple myeloma is often complicated by pulmonary hypertension through a variety of mechanisms. These mechanisms include pulmonary hypertension (PH) due to concomitant cardiac amyloid, high output heart failure due to anemia or lytic bone lesions, chronic thromboembolic pulmonary hypertension (CTEPH), toxicity from medications to treat multiple myeloma, and congestive heart failure. This case series highlights the various mechanisms through which multiple myeloma patients develop pulmonary hypertension. OBJECTIVES To identify the etiologies of pulmonary hypertension and their management among multiple myeloma patients treated at University of California San Diego. METHODS A retrospective chart review was performed to identify patients with multiple myeloma and pulmonary hypertension who were evaluated at the University of California San Diego between July 2013 and July 2021. Patients also required a right heart catheterization to be included. Demographics, comorbidities, clinical course, and etiology of pulmonary hypertension were obtained from chart review. RESULTS There were 11 patients included. Of the 11 patients described, two had PH due to cardiac amyloid, one had PH due to high output heart failure, one had PH due to CTEPH, two had pulmonary arterial hypertension due to medications (carfilzomib), and five had PH due to congestive heart failure. The right heart catheterization and echocardiogram findings of the various mechanisms of PH in multiple myeloma are described. CONCLUSIONS Pulmonary hypertension in multiple myeloma is a common finding that necessitates further evaluation. The initial evaluation should include an echocardiogram and thorough medication review. Further diagnostic testing should be guided by the patient's history and can include right heart catheterization, cardiac biopsy, ventilation-perfusion scan, and bone scan.
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Qaiser KN, Sahay S, Tonelli AR. Pulmonary hypertension due to high cardiac output. Respir Med 2023; 206:107034. [PMID: 36511685 DOI: 10.1016/j.rmed.2022.107034] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/26/2022] [Revised: 10/12/2022] [Accepted: 10/26/2022] [Indexed: 12/24/2022]
Abstract
Pulmonary hypertension (PH) is usually associated with a normal or decreased cardiac output (CO). Less commonly, PH can occur in the context of a hyperdynamic circulation, characterized by high CO (>8 L/min) and/or cardiac index ≥4 L/min/m2 in the setting of a decreased systemic vascular resistance. PH due to high CO can occur due to multiple conditions and in general remains understudied. In this review article we describe the pathophysiology, etiology, diagnosis, hemodynamic characteristics, and management of PH in the setting of high CO. It is important to recognize this distinct entity as PH tends to improve with treatment of the underlying etiology and PH specific therapies may worsen the hemodynamic state.
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Affiliation(s)
- Kanza N Qaiser
- Department of Hospital Medicine, Cleveland Clinic, Cleveland, OH, USA.
| | - Sandeep Sahay
- Houston Methodist Lung Center, Division of Pulmonary, Critical Care & Sleep Medicine, Houston Methodist Hospital, Houston, TX, USA.
| | - Adriano R Tonelli
- Department of Pulmonary, Allergy and Critical Care Medicine, Respiratory Institute, Cleveland Clinic, Cleveland, OH, USA.
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Jian Y, Zhou H, Wang Y, Zhang Z, Yang G, Geng C, Tian Y, Gao W, Chen W. Echocardiography-defined pulmonary hypertension is an adverse prognostic factor for newly diagnosed multiple myeloma patients. Cancer Med 2022; 11:4182-4192. [PMID: 35466549 DOI: 10.1002/cam4.4770] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2022] [Revised: 03/23/2022] [Accepted: 04/09/2022] [Indexed: 12/15/2022] Open
Abstract
BACKGROUND Pulmonary hypertension (PH) is a common but rarely recognized comorbidity of multiple myeloma (MM) patients, while its prognostic significance for MM has been rarely reported. METHODS We retrospectively analyzed the clinical characteristics and prognostic value of baseline echocardiography-defined PH in 426 newly diagnosed MM (NDMM) patients. RESULTS Echocardiograph-defined PH was found in 12.7% (54/426) of NDMM patients, associated with older age, anemia, and renal insufficiency, as well as severe diastolic dysfunction and higher BNP and NT-pro-BNP levels. Patients with PH presented with a higher prevalence of atrial fibrillation, while with a similar incidence of thrombosis compared with those without PH. Based on similar treatment regimens and autologous stem cell transplantation (ASCT) rates, patients without PH have deeper and better responses than those with PH (p = 0.002). With the remission of MM, 81.5% of PH was reversible, accompanied by improvement of right ventricular dysfunction and normalization of BNP/NT-pro-BNP levels, while could reoccur at MM relapse. Survival analysis revealed that PH was an adverse prognostic factor, associated with reduced progression-free survival (PFS) (21 vs. 50 months, p < 0.001) and overall survival (OS) (45 vs. 90 months, p = 0.014). Multivariate analysis further verified that baseline PH was an independent predictor for shorter PFS and OS. CONCLUSION In conclusion, echocardiography-defined PH is an adverse prognostic indicator for MM patients and should be routinely evaluated in MM patients at diagnosis to make a precise prognosis.
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Affiliation(s)
- Yuan Jian
- Department of Hematology, Myeloma Research Center of Beijing, Beijing Chaoyang Hospital, Capital Medical University, Beijing, China
| | - Huixing Zhou
- Department of Hematology, Myeloma Research Center of Beijing, Beijing Chaoyang Hospital, Capital Medical University, Beijing, China
| | - Yidan Wang
- Department of Cardiology, Beijing Chaoyang Hospital, Capital Medical University, Beijing, China
| | - Zhiyao Zhang
- Department of Hematology, Myeloma Research Center of Beijing, Beijing Chaoyang Hospital, Capital Medical University, Beijing, China
| | - Guangzhong Yang
- Department of Hematology, Myeloma Research Center of Beijing, Beijing Chaoyang Hospital, Capital Medical University, Beijing, China
| | - Chuanying Geng
- Department of Hematology, Myeloma Research Center of Beijing, Beijing Chaoyang Hospital, Capital Medical University, Beijing, China
| | - Ying Tian
- Department of Hematology, Myeloma Research Center of Beijing, Beijing Chaoyang Hospital, Capital Medical University, Beijing, China
| | - Wen Gao
- Department of Hematology, Myeloma Research Center of Beijing, Beijing Chaoyang Hospital, Capital Medical University, Beijing, China
| | - Wenming Chen
- Department of Hematology, Myeloma Research Center of Beijing, Beijing Chaoyang Hospital, Capital Medical University, Beijing, China
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Yang JZ, Buckstaff T, Narezkina A, Fernandes TM. Carfilzomib-associated pulmonary arterial hypertension in multiple myeloma. Pulm Circ 2021; 11:20458940211049300. [PMID: 34603687 PMCID: PMC8485285 DOI: 10.1177/20458940211049300] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/16/2021] [Accepted: 09/07/2021] [Indexed: 11/15/2022] Open
Abstract
Drug-induced pulmonary arterial hypertension (PAH) is constantly evolving as new drugs are developed. Carfilzomib is a recently approved therapy for relapsed and refractory multiple myeloma. While it has been associated with cardiovascular adverse events, such as ischemic heart disease and heart failure, PAH has not been a well-described side effect. We present two patients who developed PAH associated with initiation of carfilzomib. They both initially presented with severe dyspnea, had elevated right ventricular systolic pressure on transthoracic echocardiography and ultimately underwent right heart catheterization. With discontinuation of carfilzomib, both patients had improvement in hemodynamics. However, one patient required initiation of PAH-targeted therapies and has had worsening right ventricular function again despite permanent discontinuation of carfilzomib. It is important to recognize the association between carfilzomib and PAH. Echocardiography can be an important initial screening tool. PAH from carfilzomib therapy may be reversible, especially if diagnosed early; however, extended follow-up is essential.
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Affiliation(s)
- Jenny Z Yang
- Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, University of California San Diego, La Jolla, CA, USA
| | - Taylor Buckstaff
- Department of Medicine, University of California San Diego, La Jolla, CA, USA
| | - Anna Narezkina
- Division of Cardiovascular Medicine, Department of Medicine, University of California San Diego, La Jolla, CA, USA
| | - Timothy M Fernandes
- Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, University of California San Diego, La Jolla, CA, USA
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Ramirez RL, Pienkos SM, de Jesus Perez V, Zamanian RT. Pulmonary Arterial Hypertension Secondary to Drugs and Toxins. Clin Chest Med 2021; 42:19-38. [PMID: 33541612 DOI: 10.1016/j.ccm.2020.11.008] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
Pulmonary arterial hypertension secondary to drugs and toxins is an important subgroup of group 1 pulmonary hypertension associated with significant morbidity and mortality. Many drugs and toxins have emerged as risk factors for pulmonary arterial hypertension, which include anorexigens, illicit agents, and several US Food and Drug Administration-approved therapeutic medications. Drugs and toxins are classified as possible or definite risk factors for pulmonary arterial hypertension. This article reviews agents that have been implicated in the development of pulmonary arterial hypertension, their pathologic mechanisms, and methods to prevent the next deadly outbreak of drug- and toxin-induced pulmonary arterial hypertension.
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Affiliation(s)
- Ramon L Ramirez
- Division of Pulmonary, Allergy and Critical Care, Stanford University School of Medicine, 300 Pasteur Drive, Room S102, Stanford, CA 94305, USA
| | - Shaun M Pienkos
- Department of Medicine, Stanford University School of Medicine, 300 Pasteur Drive, Room S102, Stanford, CA 94305, USA
| | - Vinicio de Jesus Perez
- Division of Pulmonary, Allergy and Critical Care, Stanford University School of Medicine, 300 Pasteur Drive, Room S102, Stanford, CA 94305, USA; Vera Moulton Wall Center for Pulmonary Vascular Disease, Stanford, CA, USA
| | - Roham T Zamanian
- Division of Pulmonary, Allergy and Critical Care, Stanford University School of Medicine, 300 Pasteur Drive, Room S102, Stanford, CA 94305, USA; Vera Moulton Wall Center for Pulmonary Vascular Disease, Stanford, CA, USA.
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Shibata S, Fukunaga A. Gamma heavy chain disease complicated by pulmonary hypertension, which was successfully treated with lenalidomide. BMJ Case Rep 2020; 13:13/11/e236162. [PMID: 33257362 PMCID: PMC7705367 DOI: 10.1136/bcr-2020-236162] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022] Open
Abstract
Heavy chain disease (HCD) is a rare B-cell proliferative neoplasm that is characterised by the production of truncated monoclonal immunoglobulin heavy chains without light chains. Gamma HCD is a subgroup of HCD. A 67-year-old man was admitted to our hospital with dyspnoea and lower leg oedema. Based on the results of heart catheterisation, he was diagnosed with pulmonary hypertension. Laboratory tests revealed an elevated level of IgG, and serum immunoelectrophoresis showed that IgG was a monoclonal gamma heavy chain without light chains. Finally, he was diagnosed with gamma HCD complicated by pulmonary hypertension. Bortezomib and dexamethasone therapy was initiated, but became refractory within 8 months. Therefore, the treatment was switched to lenalidomide and dexamethasone therapy, and the disease has been stably controlled for more than 2 years. To the best of our knowledge, this is the first case of gamma HCD being successfully treated by lenalidomide and dexamethasone therapy.
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Affiliation(s)
- Sho Shibata
- Hematology, Tazuke Kofukai, Medical Research Institute, Kitano Hospital, Osaka, Japan
| | - Akiko Fukunaga
- Hematology, Tazuke Kofukai, Medical Research Institute, Kitano Hospital, Osaka, Japan
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Abstract
Pulmonary hypertension (PH) has been described in myeloproliferative disorders; monoclonal plasma cell disorder such as polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes syndrome; and plasma cell dyscrasias such as multiple myeloma and amyloidosis. We describe 4 cases of PH likely due to pulmonary vascular involvement and myocardial deposition from light chain deposition disease, amyloidosis, and multiple myeloma. On the basis of our clinical experience and literature review, we propose screening for plasma cell dyscrasia in patients with heart failure with preserved ejection fraction, unexplained PH, and hematological abnormalities. We also recommend inclusion of cardiopulmonary screening in patients with monoclonal gammopathy of undetermined significance.
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Key Words
- AL, amyloid light chain
- ASCT, autologous stem cell transplant
- BMB, bone marrow biopsy
- CKD, chronic kidney disease
- CT, computed tomography
- FLC, free light chain
- HIV, human immunodeficiency virus
- ILD, interstitial lung disease
- LC-MGUS, light chain monoclonal gammopathy of undetermined significance
- LCDD, light chain deposition disease
- LV, left ventricular
- MGUS, monoclonal gammopathy of undetermined significance
- MM, multiple myeloma
- MRI, magnetic resonance imaging
- PAP, pulmonary artery pressure
- PH, pulmonary hypertension
- RA, right atrial
- RHC, right heart catheterization
- RV, right ventricle/ventricular
- TTE, transthoracic echocardiography
- WHO, World Health Organization
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Carfilzomib-Induced Pulmonary Hypertension. Am J Ther 2020; 27:e693-e694. [PMID: 31724976 DOI: 10.1097/mjt.0000000000001051] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
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Kreidy M, Al-Hilli A, Yachoui R, Resnick J. Severe but reversible pulmonary hypertension in scleromyxedema and multiple myeloma: a case report. BMC Pulm Med 2020; 20:8. [PMID: 31918690 PMCID: PMC6953266 DOI: 10.1186/s12890-019-1020-6] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2019] [Accepted: 12/06/2019] [Indexed: 12/20/2022] Open
Abstract
BACKGROUND Scleromyxedema is a progressive, systemic connective tissue disorder characterized by fibro-mucous skin lesions and increased serum monoclonal immunoglobulin levels. Pulmonary involvement occurs in a subset of patients, though the overall prevalence of pulmonary lesions in scleromyxedema is unknown. Since pulmonary hypertension presumably occurs in these patients due to disease progression and development of additional conditions, treatment of the underlying plasma cell dyscrasia and connective tissue disorder may improve pulmonary hypertension symptoms. CASE PRESENTATION An elderly patient with scleromyxedema developed pulmonary hypertension refractory to vasodilator and diuretic therapy and subsequently multiple myeloma that responded to a combination therapy of bortezomib, cyclophosphamide, and dexamethasone treatment. CONCLUSIONS Treatment of the underlying disease(s) that contributed to pulmonary hypertension development with anti-neoplastic agents like bortezomib may improve cardiopulmonary symptoms secondary to reducing abnormal blood cell counts and paraprotein levels.
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Affiliation(s)
- Mazen Kreidy
- Department of Pulmonary and Critical Care Medicine, Marshfield Clinic, Marshfield, WI USA
- Present affiliation: Christiana Care Health System, PO Box 1668, Wilmington, DE 19899 USA
| | - Ali Al-Hilli
- Department of Internal Medicine, Marshfield Clinic, Marshfield, WI USA
| | - Ralph Yachoui
- Department of Rheumatology, Ronald Reagan UCLA Medical Center, Santa Monica, California, USA
| | - Jeffrey Resnick
- Department of Pathology, Marshfield Clinic, Marshfield, WI USA
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Sargsyan LA, Faiz SA. Pulmonary Hypertension in an Oncologic Intensive Care Unit. ONCOLOGIC CRITICAL CARE 2020. [PMCID: PMC7123640 DOI: 10.1007/978-3-319-74588-6_47] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/04/2022]
Abstract
Pulmonary hypertension (PH) is the condition of elevated pressures in the pulmonary circulation. PH can develop acutely in patients with critical illness such as acute respiratory distress syndrome, sepsis, massive pulmonary embolism, left ventricular dysfunction, or after surgery. In a cancer patient, unique etiologies such as myeloproliferative disorders, tyrosine kinase inhibitors, or tumor emboli may result in PH. Early recognition and treatment of the causative condition may reverse acute PH or return chronic PH to its baseline status. Progression of the disease or its decompensation due to infection, a thromboembolic event, or other triggers can lead to admission to an intensive care unit. Regardless of etiology, the development or worsening of PH may precipitate hypoxemia, hemodynamic instability, or right ventricular failure, which can be challenging to manage or even fatal. In select cases, rapid institution of advanced treatment modalities may be warranted. This chapter reviews the etiology, epidemiology, pathophysiology, clinical features, diagnosis, and prognosis of PH and presents a comprehensive analysis of PH and right heart failure management strategies in the critical care setting. In particular, a unique perspective on oncologically relevant PH is provided.
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McGee M, Whitehead N, Martin J, Collins N. Drug-associated pulmonary arterial hypertension. Clin Toxicol (Phila) 2018; 56:801-809. [PMID: 29508628 DOI: 10.1080/15563650.2018.1447119] [Citation(s) in RCA: 42] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/17/2022]
Abstract
INTRODUCTION While pulmonary arterial hypertension remains an uncommon diagnosis, various therapeutic agents are recognized as important associations. These agents are typically categorized into "definite", "likely", "possible", or "unlikely" to cause pulmonary arterial hypertension, based on the strength of evidence. OBJECTIVE This review will focus on those therapeutic agents where there is sufficient literature to adequately comment on the role of the agent in the pathogenesis of pulmonary arterial hypertension. METHODS A systematic search was conducted using PubMed covering the period September 1970- 2017. The search term utilized was "drug induced pulmonary hypertension". This resulted in the identification of 853 peer-reviewed articles including case reports. Each paper was then reviewed by the authors for its relevance. The majority of these papers (599) were excluded as they related to systemic hypertension, chronic obstructive pulmonary disease, human immunodeficiency virus, pulmonary fibrosis, alternate differential diagnosis, treatment, basic science, adverse effects of treatment, and pulmonary hypertension secondary to pulmonary embolism. Agents affecting serotonin metabolism (and related anorexigens): Anorexigens, such as aminorex, fenfluramine, benfluorex, phenylpropanolamine, and dexfenfluramine were the first class of medications recognized to cause pulmonary arterial hypertension. Although most of these medications have now been withdrawn worldwide, they remain important not only from a historical perspective, but because their impact on serotonin metabolism remains relevant. Selective serotonin reuptake inhibitors, tryptophan, and lithium, which affect serotonin metabolism, have also been implicated in the development of pulmonary arterial hypertension. Interferon and related medications: Interferon alfa and sofosbuvir have been linked to the development of pulmonary arterial hypertension in patients with other risk factors, such as human immunodeficiency virus co-infection. Antiviral therapies: Sofosbuvir has been associated with two cases of pulmonary artery hypertension in patients with multiple risk factors for its development. Its role in pathogenesis remains unclear. Small molecule tyrosine kinase inhibitors: Small molecule tyrosine kinase inhibitors represent a relatively new class of medications. Of these dasatinib has the strongest evidence in drug-induced pulmonary arterial hypertension, considered a recognized cause. Nilotinib, ponatinib, carfilzomib, and ruxolitinib are newer agents, which paradoxically have been linked to both cause and treatment for pulmonary arterial hypertension. Monoclonal antibodies and immune regulating medications: Several case reports have linked some monoclonal antibodies and immune modulating therapies to pulmonary arterial hypertension. There are no large series documenting an increased prevalence of pulmonary arterial hypertension complicating these agents; nonetheless, trastuzumab emtansine, rituximab, bevacizumab, cyclosporine, and leflunomide have all been implicated in case reports. Opioids and substances of abuse: Buprenorphine and cocaine have been identified as potential causes of pulmonary arterial hypertension. The mechanism by which this occurs is unclear. Tramadol has been demonstrated to cause severe, transient, and reversible pulmonary hypertension. Chemotherapeutic agents: Alkylating and alkylating-like agents, such as bleomycin, cyclophosphamide, and mitomycin have increased the risk of pulmonary veno-occlusive disease, which may be clinically indistinct from pulmonary arterial hypertension. Thalidomide and paclitaxel have also been implicated as potential causes. Miscellaneous medications: Protamine appears to be able to cause acute, reversible pulmonary hypertension when bound to heparin. Amiodarone is also capable of causing pulmonary hypertension by way of recognized side effects. CONCLUSIONS Pulmonary arterial hypertension remains a rare diagnosis, with drug-induced causes even more uncommon, accounting for only 10.5% of cases in large registry series. Despite several agents being implicated in the development of PAH, the supportive evidence is typically limited, based on case series and observational data. Furthermore, even in the drugs with relatively strong associations, factors that predispose an individual to PAH have yet to be elucidated.
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Affiliation(s)
- Michael McGee
- a Cardiovascular Department , John Hunter Hospital , Newcastle , Australia
| | - Nicholas Whitehead
- a Cardiovascular Department , John Hunter Hospital , Newcastle , Australia
| | - Jennifer Martin
- b Clinical Pharmacology, School of Medicine and Public Health , University of Newcastle , Newcastle , Australia
| | - Nicholas Collins
- a Cardiovascular Department , John Hunter Hospital , Newcastle , Australia
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