Pulling Out All the Stops: A Case of Progressive Dyspnea.

HomeCirculationVol. 147, No. 8Pulling Out All the Stops: A Case of Progressive Dyspnea Free AccessCase ReportPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessCase ReportPDF/EPUBPulling Out All the Stops: A Case of Progressive Dyspnea John W. Ostrominski, Deepak L. Bhatt and Benjamin M. Scirica John W. OstrominskiJohn W. Ostrominski Correspondence to: John W. Ostrominski, MD, Brigham and Women’s Hospital, Harvard Medical School, 75 Francis Street, Boston, MA 02115. Email E-mail Address: [email protected] https://orcid.org/0000-0002-2866-9414 Division of Cardiovascular Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA. Search for more papers by this author , Deepak L. BhattDeepak L. Bhatt https://orcid.org/0000-0002-1278-6245 Division of Cardiovascular Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA. Search for more papers by this author and Benjamin M. SciricaBenjamin M. Scirica https://orcid.org/0000-0002-7093-7048 Division of Cardiovascular Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA. Search for more papers by this author Originally published20 Feb 2023https://doi.org/10.1161/CIRCULATIONAHA.122.062753Circulation. 2023;147:688–693Information about a real patient is presented in stages (boldface type) to an expert clinician (Dr Scirica), who responds to the information, sharing his reasoning with the reader (regular type). A discussion by the authors follows.Patient presentation: A 63-year-old woman presented to the emergency department with 3 weeks of progressive nonproductive cough, nasal congestion, and exercise intolerance, preceded by 2 months of worsening fatigue. Previously able to climb multiple flights of stairs, in the days before presentation she had been unable to walk for short distances on a flat surface because of severe exertional dyspnea. She denied chest discomfort, extremity swelling, orthopnea, palpitations, fevers, and chills.Dr Scirica: Although cough and exertional dyspnea individually engender broad initial differential diagnoses, their combination is most supportive of cardiopulmonary pathology. The preceding months of fatigue may allude to a single unifying condition with rapid progression (ie, Occam razor) or alternatively subacute worsening of an underlying chronic condition triggered by superimposed illness (ie, Hickam dictum). Single disease processes with these symptoms and temporal pattern include pneumonia and endocarditis (eg, with progressive valvular or electrical sequelae), but are less likely in the absence of fever. An evolving cancer with associated pulmonary embolism or pericardial effusion may also provide a parsimonious explanation. The nonproductive cough and nasal congestion may instead suggest a viral respiratory illness leading to exercise intolerance by way of exacerbation of obstructive pulmonary disease, chronic heart failure, or established neuromuscular disease (eg, myasthenia gravis).Patient presentation (continued): Her medical history included hypertension, type 2 diabetes, severe obesity, and obstructive sleep apnea treated with nocturnal continuous positive airway pressure. Fourteen years earlier, she received a diagnosis of ER+/GATA3+ breast cancer and underwent neoadjuvant anthracycline-based chemotherapy with subsequent left-sided lumpectomy, axillary lymph node dissection, and adjuvant chest radiotherapy, chemotherapy, and hormonal therapy, as well. She achieved remission. She owned a local business and had never used tobacco, alcohol, or other drugs. Her medications were amlodipine, atorvastatin, hydrochlorothiazide, lisinopril, and metformin. Family history included hypertension in multiple first-degree relatives, without other forms of cardiopulmonary disease.Dr Scirica: The patient’s cardiometabolic risk factors further raise the possibility of heart failure, arrhythmia (eg, atrial fibrillation with evolving tachyarrhythmia-mediated cardiomyopathy), and kidney dysfunction. The history of breast cancer additionally highlights potential complications of previous radiotherapy, including radiation-induced coronary artery disease, pericardial constriction, and valvular dysfunction. Heart failure attributable to anthracycline-mediated cardiomyopathy would be unusual because, in general, this presents within 3 years of exposure. Cancer, whether recurrent primary carcinoma or secondary to previous anticancer therapies (eg, therapy-related acute myeloid leukemia with pulmonary leukostasis), is also a possibility.Patient presentation (continued): On physical examination, the temperature was 36.2 °C, blood pressure 110/75 mm Hg, heart rate 97 beats per minute, respiratory rate 26 breaths per minute, oxygen saturation of 88% on ambient air improving to 95% with 5 L/min oxygen through nasal cannula. She was in mild distress with increased respiratory effort. There was no parasternal heave or apical displacement. The heart rate and rhythm were normal and regular, respectively. The S2 was crisp and physiologically split, and P2 could be appreciated out to the apex. A 2/6 holosystolic murmur was noted at the left lower sternal border, augmenting with inspiration. The jugular venous pulsation was seen at 12 cm H2O, demonstrating sustained hepatojugular reflux and a Kussmaul sign. The lungs were clear to auscultation and the extremities were warm with trace edema. There was no hepatosplenomegaly or abdominal tenderness. The musculoskeletal, neurological, and skin examinations were normal.Dr Scirica: Physical examination reveals evidence of respiratory distress in the context of hypoxemia and elevated right atrial pressure (elevated jugular venous pulsation). Appreciation of P2 at the left ventricular apex additionally suggests markedly elevated pulmonary arterial pressures, implying a level of chronicity. The Kussmaul sign (paradoxical elevation or stasis of the jugular venous pulsation with inspiration) is consistent with impaired right ventricular compliance attributable to pericardial tamponade or constriction, restrictive cardiomyopathy, ischemia, or cor pulmonale. The prominent P2 argues against significant constriction or restriction, and the crisp heart sounds and preserved pulse pressure would additionally not support pericardial tamponade. Significant anatomic (eg, atrial septal defect) or physiological shunt is unlikely to be the principal driver of hypoxemia given the responsiveness to supplemental oxygen. In view of normal lung auscultation and absence of other signs/symptoms of left heart failure (eg, rales and orthopnea), these findings are collectively most suggestive of pulmonary vascular pathology.Patient presentation (continued): The white-cell count was 4230/μL with a normal differential, the hematocrit was 29.4% with 4.8% reticulocytes, and the platelet count was 29 000/μL. A basic metabolic panel was within normal range. Alanine and aspartate aminotransferase levels were 133 U/L (normal range, 10–50) and 152 U/L (normal range, 10–50), respectively. The alkaline phosphatase level was 442 U/L (normal range, 35–130). Total bilirubin was 1.1 mg/dL (normal range, ≤1.0). Levels of total protein, albumin, and fibrinogen were normal. Coagulation studies were normal. The D-dimer level was 1.12 μg/mL (normal range, ≤0.49). Lactate dehydrogenase and haptoglobin levels were 1572 IU/L (normal range, 98–192) and <14 mg/dL (normal range, 30–200), respectively. The high-sensitivity cardiac troponin T level was 11 ng/L (normal range, ≤9) and the N-terminal pro-B-type natriuretic peptide level was 1317 pg/mL (normal range, <900). Peripheral smear showed numerous nucleated red blood cells and reticulocytes, occasional dacrocytes and schistocytes, and few platelets with normal size and morphology. A 12-lead ECG showed normal sinus rhythm with an S1Q3T3 pattern, diffuse T-wave inversions, and early precordial transition with low voltages (Figure 1).Download figureDownload PowerPointFigure 1. 12-Lead ECG on presentation. Presentation ECG findings included an S1Q3T3 pattern, diffuse T-wave inversions, and inferior, anterior, and lateral downsloping ST-segment depressions with subtle ST-segment elevation in aVR, as well. Precordial leads otherwise exhibited low voltages and early transition. These were collectively consistent with right ventricular strain and superimposed diffuse subendocardial ischemia.Dr Scirica: Laboratory assessment reveals liver injury and marked hematologic derangements. Elevated liver enzymes can be seen with hepatic congestion (eg, attributable to right heart failure), but thrombocytopenia attributable to associated chronic portal hypertension is rarely severe. Dacrocytes (ie, teardrop cells) and pancytopenia usually signify primary marrow failure or fibrosis (less likely given the intact reticulocytotic response) but can also be seen with myelophthisic cancer. The hepatocellular injury could additionally be attributable to concomitant hepatic parenchymal infiltration, with the elevated alkaline phosphatase of either hepatobiliary or bone origin. Instead, profound thrombocytopenia, when coupled with evidence of end-organ dysfunction, microangiopathic hemolytic anemia (eg, markedly elevated lactate dehydrogenase, low haptoglobin, and schistocytes), and normal coagulation studies raises suspicion for thrombotic microangiopathy. A secondary thrombotic microangiopathy (eg, attributable to metastatic cancer) is most likely given the other features of this case and absence of findings suggestive of a primary thrombotic microangiopathy syndrome (eg, renal dysfunction). The modestly elevated natriuretic peptides and cardiac troponin are otherwise consistent with the physical examination and electrocardiographic evidence of right ventricular strain. At this stage, the overall clinical presentation and initial laboratory findings are concerning for a progressive systemic cancer, and associated pulmonary embolism is the most likely explanation for the relatively acute respiratory presentation.Patient presentation (continued): Computed tomography angiography of the chest showed few small nodules, dilation of the main pulmonary artery, and diffuse vertebral osteosclerosis (Figure 2A-2C). There was no pulmonary embolism, lymphadenopathy, pleural pathology, interlobular septal thickening, or other parenchymal abnormality. Transthoracic echocardiography disclosed moderate dilation of the right ventricle with moderate systolic dysfunction, and moderate tricuspid regurgitation with a maximal regurgitant jet velocity of 4.0 m/s (Figure 3). The structure and function of the left ventricle and other valves was normal. Heterogeneous hepatic parenchyma was appreciated on abdominal ultrasound, with innumerable hypoechoic lesions.Download figureDownload PowerPointFigure 2. Imaging studies. Computed tomography pulmonary angiography demonstrated dilation of the main pulmonary artery (asterisk), measuring 3.3 cm before its bifurcation (A), interventricular septal flattening with subtle leftward inversion (arrow), consistent with right ventricular strain (B), and diffuse vertebral osteosclerosis and signal heterogeneity, consistent with osteoblastic metastases (C). 99mTc lung perfusion scintigraphy disclosed multiple peripheral perfusion defects (arrows) in the background of otherwise heterogeneous perfusion bilaterally (D). The study additionally suggests a central to peripheral perfusion gradient, with relatively reduced perfusion peripherally, possibly indicative of more diffuse dropout of the pulmonary microvasculature. LAO indicates left anterior oblique; LPO, left posterior oblique; RAO, right anterior oblique; and RPO, right posterior oblique.Download figureDownload PowerPointFigure 3. Selected transthoracic echocardiography images. A, Parasternal short-axis image obtained at end-diastole revealed intraventricular septal flattening and leftward inversion, consistent with right ventricular volume overload. A small pericardial effusion was predominantly localized to the inferolateral wall (arrow). B, Apical 4-chamber view additionally demonstrated severe right ventricular dilation and right atrial enlargement. LA indicates left atrium; LV, left ventricle; RA, right atrium; and RV, right ventricle.Dr Scirica: Tricuspid regurgitation with a maximal regurgitant jet velocity of >3.4 m/s is associated with a high probability of pulmonary hypertension (PH), especially with concomitant right ventricle and pulmonary artery dilation, as seen in this case. In the context of normal left ventricle structure/function and absence of pulmonary edema on cross-sectional imaging, these findings are most supportive of precapillary PH. There is no evidence of explanatory parenchymal lung disease, and the absence of intralobular septal thickening argues against pulmonary vaso-occlusive disease. The diffuse vertebral osteosclerosis and hepatic lesions strongly suggest widespread osteoblastic metastatic disease, such as recrudescent breast cancer. Although there is no evidence of acute or chronic pulmonary embolism, computed tomography angiography cannot exclude chronic thromboembolic PH because of the limited evaluation of the distal subsegmental pulmonary vessels. As such, ventilation/perfusion imaging should be considered. Although exceedingly rare, pulmonary tumor thrombotic microangiopathy, a rapidly progressive form of PH caused by tumor microembolization to the distal pulmonary vasculature, would provide a unifying diagnosis. Extensive hepatic metastasis may be an important precursor, enabling rapid hematogenous spread into the inferior vena cava and downstream pulmonary circulation.Patient presentation (continued): She was transferred to the cardiac intensive care unit because of progressive hypoxemia and hypotension, initially stabilized with oxygen therapy through high-flow nasal cannula and vasopressin, respectively. Lung perfusion scintigraphy revealed a heterogeneous pattern with numerous peripheral perfusion defects (Figure 2D). Ventilation images were not obtained. Right heart catheterization demonstrated a right atrial pressure of 12 mm Hg with right ventricle pressure 72/16 mm Hg, pulmonary artery pressure 72/40 mm Hg (mean, 51 mm Hg), pulmonary capillary wedge pressure 6 mm Hg, pulmonary vascular resistance 775 dynes/sec-cm5, and cardiac index of 2.0 L/min by Fick method. The ratio of pulmonary to systemic blood flow was 1.Dr Scirica: Invasive hemodynamic assessment confirms the presence of elevated right-sided filling pressures, severe precapillary PH, low cardiac output, and the absence of significant shunt. Although ventilation imaging should be routinely performed to ensure that observed perfusion defects are not attributable to ventilation defects, the absence of significant structural lung disease on computed tomography angiography is reassuring against a ventilation abnormality. Hence, the abnormal perfusion pattern may be consistent with obstruction of the distal subsegmental vessels either by pulmonary embolism or tumor microemboli. The images additionally suggest a decremental gradient of central to peripheral perfusion, perhaps attributable to more global dropout of the pulmonary microvasculature. These data, along with the patient’s history of cancer, rapid clinical decline, and hematologic abnormalities are collectively most concerning for pulmonary tumor thrombotic microangiopathy (PTTM). PTTM is usually rapidly fatal, with early diagnosis and initiation of anticancer therapies representing the greatest opportunity for life prolongation. Expeditious tissue diagnosis is therefore imperative, but gold-standard lung biopsy or wedge resection are often precluded by critical illness, as in this case. Otherwise, cytological analysis of an aspirate obtained from a wedged pulmonary artery catheter is a less invasive and often high-yield approach.Patient presentation (continued): A pulmonary capillary wedge blood aspirate was sent for cytology, revealing clusters of neoplastic cells positive for GATA3 on immunohistochemical analysis (Figure 4), consistent with PTTM associated with recurrent breast carcinoma. The patient’s subsequent course was notable for refractory hypoxemic respiratory failure and shock despite escalation of oxygen therapy and addition of inhaled epoprostenol and milrinone. Systemic glucocorticoids were administered for empirical treatment of PTTM, but the extent of clinical deterioration precluded candidacy for chemotherapy. In the setting of refractory shock and hypoxemia, she was transitioned to comfort measures only, ultimately experiencing a bradycardic pulseless electrical activity arrest on hospital day 8. Autopsy was declined.Download figureDownload PowerPointFigure 4. Cytopathological analysis of the pulmonary capillary wedge blood aspirate. A, ThinPrep showing a representative cluster of atypical cells (arrows) exhibiting cytologic features of malignancy, consistent with pulmonary tumor microembolism. Clusters of malignant cells were redemonstrated on hematoxylin and eosin staining of cell block sections (B), and further analysis revealed that the lesional cells were positive for GATA3 (C), consistent with the immunohistochemical profile of the patient’s index breast carcinoma.DiscussionAlthough the patient’s presenting syndrome engendered a broad initial differential diagnosis, incremental investigation revealed cor pulmonale attributable to a rapidly progressive form of PH, which when coupled with evidence of metastatic cancer, thrombotic microangiopathy, and ultimately pulmonary microembolization of tumor cells, culminated in a unifying diagnosis of PTTM. PTTM is an exceedingly rare but likely underrecognized cause of PH, with a reported prevalence of 1% to 3% in autopsy series.1 Gastric (59%), breast (10%), and lung (6%) carcinomas are most implicated,2 and PTTM may emerge as part of a presenting cancer syndrome or in the setting of established metastatic disease.3 The median survival from symptom onset is 3 to 4 weeks.1,2 PTTM is postulated to arise from hematogenous or lymphatic spread of tumor cells, or both, to the pulmonary microvasculature, where subsequent endothelial damage and coagulation cascade activation in addition to proinflammatory, proangiogenic, and profibrotic cytokine release results in fibrointimal proliferation, microvascular occlusion, and resultant PH.1,3 As in this case, concurrent microangiopathic hemolytic anemia and severe thrombocytopenia, possibly resulting from formation of platelet-rich vascular microthrombi with subsequent intravascular shearing of red blood cells, provides an additional clue to the diagnosis.Because of the challenges of early identification, PTTM is overwhelmingly a postmortem diagnosis. Lung biopsy remains the gold standard for diagnosis but is usually precluded by prohibitively severe illness.1 Otherwise, in addition to a comprehensive hemodynamic characterization of suspected PH, right heart catheterization provides a unique and important opportunity to “pull out the stops,” therein enabling early diagnosis and therapy. On the basis of small case series of patients with known pulmonary involvement by systemic cancer, pulmonary capillary wedge cytology has been shown to be safe with sensitivity and specificity as high as 80% to 88% and 82% to 94%, respectively,1,3–5 but yield may be lower in less advanced cases. Despite a favorable profile of risk/benefit, pulmonary capillary wedge cytology is rarely performed because of the limited clinical suspicion for PTTM. Low procedural familiarity may also affect utilization and yield. Once a pulmonary arterial catheter is confirmed to be in wedge position (eg, by pressure waveform and oxygen saturation of aspirated blood), the first 10 mL, representing the column of blood proximal to the pulmonary microvasculature, should be withdrawn and discarded. Between 5 and 10 mL should then be slowly aspirated into a heparin-treated tube and sent for cytology. Repositioning the catheter may be needed to optimize yield. The presence of megakaryocytes, normal residents of the pulmonary microvasculature, signifies a satisfactory microvascular sample, but care must be taken to avoid misidentification of these cells as malignant.4,5 Overall, pulmonary microvascular cytology should be considered for all patients with new PH and either previous, suspected, or known carcinoma.Early empirical or targeted systemic chemotherapy remains the only disease-modifying approach but is typically precluded by poor performance status at the time of diagnosis.1,2 Otherwise, therapy involves supportive care with supplemental oxygen, vasoactive medications to support impaired right ventricle function, and pulmonary vasodilators. Systemic glucocorticoids and anticoagulation are also recommended, but benefit is limited in late disease.1 Limited data additionally support the use of antineoplastic agents that antagonize putative causal pathways of PH in PTTM, including imatinib and bevacizumab.1ConclusionTaken together, this case highlights several unique diagnostic challenges and opportunities in PTTM, including the rare instance of PTTM diagnosis aided by pulmonary capillary wedge cytology, reinforcing the multidimensional role of right heart catheterization in this underrecognized and devastating clinical entity.Article InformationSources of FundingNone.Disclosures Dr Bhatt discloses the following relationships: Advisory Board: AngioWave, Bayer, Boehringer Ingelheim, Cardax, CellProthera, Cereno Scientific, Elsevier Practice Update Cardiology, High Enroll, Janssen, Level Ex, McKinsey, Medscape Cardiology, Merck, MyoKardia, NirvaMed, Novo Nordisk, PhaseBio, PLx Pharma, Regado Biosciences, Stasys; Board of Directors: AngioWave (stock options), Boston VA Research Institute, Bristol Myers Squibb (stock), DRS.LINQ (stock options), High Enroll (stock), Society of Cardiovascular Patient Care, TobeSoft; Chair: Inaugural Chair, American Heart Association Quality Oversight Committee; Consultant: Broadview Ventures; Data Monitoring Committees: Acesion Pharma, Assistance Publique-Hôpitaux de Paris, Baim Institute for Clinical Research (formerly Harvard Clinical Research Institute, for the PORTICO trial (Portico Re-sheathable Transcatheter Aortic Valve System US IDE Trial), funded by St. Jude Medical, now Abbott), Boston Scientific (Chair, PEITHO trial [PEITHO Pulmonary Embolism Thrombolysis Study]), Cleveland Clinic (including for the ExCEED trial [CENTERA THV System in Intermediate Risk Patients Who Have Symptomatic, Severe, Calcific, Aortic Stenosis], funded by Edwards), Contego Medical (Chair, PERFORMANCE 2 [Protection Against Emboli During Carotid Artery Stenting Using the Neuroguard IEP System]), Duke Clinical Research Institute, Mayo Clinic, Mount Sinai School of Medicine (for the ENVISAGE trial [Edoxaban Compared to Standard Care After Heart Valve Replacement Using a Catheter in Patients With Atrial Fibrillation], funded by Daiichi Sankyo; for the ABILITY-DM trial [ABILITY Diabetes Global], funded by Concept Medical), Novartis, Population Health Research Institute; Rutgers University (for the National Institutes of Health–funded MINT Trial [Myocardial Ischemia and Transfusion]); Honoraria: American College of Cardiology (Senior Associate Editor, Clinical Trials and News, ACC.org; Chair, ACC Accreditation Oversight Committee), Arnold and Porter law firm (work related to Sanofi/Bristol-Myers Squibb clopidogrel litigation), Baim Institute for Clinical Research (formerly Harvard Clinical Research Institute; RE-DUAL PCI (Evaluation of Dual Therapy With Dabigatran vs. Triple Therapy With Warfarin in Patients With AF That Undergo a PCI With Stenting) clinical trial steering committee funded by Boehringer Ingelheim; AEGIS-II (Study to Investigate CSL112 in Subjects With Acute Coronary Syndrome) executive committee funded by CSL Behring), Belvoir Publications (Editor in Chief, Harvard Heart Letter), Canadian Medical and Surgical Knowledge Translation Research Group (clinical trial steering committees), Cowen and Company, Duke Clinical Research Institute (clinical trial steering committees, including for the PRONOUNCE trial (A Trial Comparing Cardiovascular Safety of Degarelix Versus Leuprolide in Patients With Advanced Prostate Cancer and Cardiovascular Disease), funded by Ferring Pharmaceuticals), HMP Global (Editor in Chief, Journal of Invasive Cardiology), Journal of the American College of Cardiology (Guest Editor; Associate Editor), K2P (Co-Chair, interdisciplinary curriculum), Level Ex, Medtelligence/ReachMD (Continuing Medical Education [CME] steering committees), MJH Life Sciences, Oakstone CME (Course Director, Comprehensive Review of Interventional Cardiology), Piper Sandler, Population Health Research Institute (for the COMPASS (Cardiovascular Outcomes for People Using Anticoagulation Strategies) operations committee, publications committee, steering committee, and USA national co-leader, funded by Bayer), Slack Publications (Chief Medical Editor, Cardiology Today’s Intervention), Society of Cardiovascular Patient Care (Secretary/Treasurer), WebMD (CME steering committees), Wiley (steering committee); Other: Clinical Cardiology (Deputy Editor), NCDR-ACTION Registry Steering Committee (Chair), VA CART Research and Publications Committee (Chair); Patent: Sotagliflozin (named on a patent for sotagliflozin assigned to Brigham and Women’s Hospital who assigned to Lexicon; neither I nor Brigham and Women’s Hospital receive any income from this patent); Research Funding: Abbott, Acesion Pharma, Afimmune, Aker Biomarine, Amarin, Amgen, AstraZeneca, Bayer, Beren, Boehringer Ingelheim, Boston Scientific, Bristol-Myers Squibb, Cardax, CellProthera, Cereno Scientific, Chiesi, CinCor, CSL Behring, Eisai, Ethicon, Faraday Pharmaceuticals, Ferring Pharmaceuticals, Forest Laboratories, Fractyl, Garmin, HLS Therapeutics, Idorsia, Ironwood, Ischemix, Janssen, Javelin, Lexicon, Lilly, Medtronic, Merck, Moderna, MyoKardia, NirvaMed, Novartis, Novo Nordisk, Owkin, Pfizer, PhaseBio, PLx Pharma, Recardio, Regeneron, Reid Hoffman Foundation, Roche, Sanofi, Stasys, Synaptic, The Medicines Company, Youngene, 89Bio; Royalties: Elsevier (Editor, Braunwald’s Heart Disease); Site Co-Investigator: Abbott, Biotronik, Boston Scientific, CSI, Endotronix, St. Jude Medical (now Abbott), Philips, SpectraWAVE, Svelte, Vascular Solutions; Trustee: American College of Cardiology; Unfunded Research: FlowCo, Takeda. Dr Scirica reports institutional research grants to Brigham and Women’s Hospital from Better Therapeutics, Merck, NovoNordisk, and Pfizer, and consulting fees, as well, from Allergan, Boehringer Ingelheim, Better Therapeutics, Elsevier Practice Update Cardiology, Esperion, Hanmi, Lexicon, NovoNordisk, and equity in Health [at] Scale and Doximity. All other authors report no disclosures.FootnotesFor Sources of Funding and Disclosures, see page 693.Circulation is available at www.ahajournals.org/journal/circCorrespondence to: John W. Ostrominski, MD, Brigham and Women’s Hospital, Harvard Medical School, 75 Francis Street, Boston, MA 02115. Email jostrominski@bwh.harvard.eduReferences1. Price LC, Seckl MJ, Dorfmüller P, Wort SJ. Tumoral pulmonary hypertension.Eur Respir Rev. 2019; 28:180065. doi: 10.1183/16000617.0065-2018CrossrefMedlineGoogle Scholar2. Godbole RH, Saggar R, Kamangar N. Pulmonary tumor thrombotic microangiopathy: a systematic review.Pulm Circ. 2019; 9:1–13. doi: 10.1177/2045894019851000CrossrefGoogle Scholar3. D’Silva K, Cockrill B, Anderson WJ, Miller AL, Loscalzo J. A rapid change in pressure.N Engl J Med. 2020; 382:563–570. doi: 10.1056/nejmcps1814993CrossrefMedlineGoogle Scholar4. Abati A, Landucci D, Danner RL, Solomon D. Diagnosis of pulmonary microvascular metastases by cytologic evaluation of pulmonary artery catheter-derived blood specimens.Hum Pathol. 1994; 25:257–262. doi: 10.1016/0046-8177(94)90197-xCrossrefMedlineGoogle Scholar5. Masson RG, Krikorian J, Lukl P, Evans GL, McGrath J. Pulmonary microvascular cytology in the diagnosis of lymphangitic carcinomatosis.N Engl J Med. 1989; 321:71–76. doi: 10.1056/nejm198907133210202CrossrefMedlineGoogle Scholar eLetters(0)eLetters should relate to an article recently published in the journal and are not a forum for providing unpublished data. 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