Alave, J

Banda, C

Bhuva, A

Culotta, V

Falcon, L

Gonzales, P

Herrey, AS

Mejia, F

Menacho, J

Menacho, K

Moon, JC

Mosto, F

Ntusi, NAB

Putri, A

Ramirez, S

Salazar, D

Seraphim, A

Walker, JM

English

UCL Discovery

1  Myocardial inflammation and edema in People living with Human Immunodeficiency Virus  Running Title: HIV and early myocardium involvement revealed by CMR  Katia Menacho MD1,2, Andreas Seraphim MD1,2, Sara Ramirez MD3, Liana Falcon MD3, Anish Bhuva MD1,2, Jorge Alave MD 4,5 Claudia Banda MD6,7, Fernando Mejia MD6,7, Daniela Salazar MD 6,7, Astrid Putri1, Flavio Mosto3, Pedro Gonzales MD4, Veronica Culotta MD2, Julio Menacho8 MD, Anna S Herrey MD1,2, Ntobeko A. B. Ntusi DPhil9, J Malcolm Walker10 MD1, James C Moon MD1,2  1. Institute of Cardiovascular Science, University College London, United Kingdom 2. Barts Heart Centre, Saint Bartholomew’s Hospital, London, United Kingdom 3. International Clinic, Lima – Peru 4. Asociacion Civil Impacta Salud y Educacion, Lima – Peru 5. Union Peruvian University, Medical School. Lima - Peru 6. Cayetano Heredia University, Lima – Peru 7. Cayetano Heredia Hospital, Lima – Peru.  8. Santiago Antunez de Mayolo University, Huaraz – Ancash. 9. University of Cape Town and Groote Schuur Hospital, Cape Town - South Africa.  10. Hatter Cardiovascular Institute, University College London Hospital  Address for correspondence: Professor James Moon  Barts Heart Centre London EC1A 7BE  E-mail: james.moon@bartshealth.nhs.uk Twitter: @JccmoonMoon Phone number: +44 203 4656114  Fax: +44 203 465 7932  Acknowledgments: Our sincere acknowledgments to Dr Raul Marquina, head of the Advanced Imaging Diagnostic Center in International Clinic,  Lima, Peru, for all the support and approval of the present study; Radiographers: Darwin Gonzales Zelada and Jonathan Infante, and Nurse Ana Graña at Cayetano Heredia Hospital.  Source of Funding: The study was funded by The Peruvian Scientific, Technological Development and Technological Innovation (FONDECYT) and the UK Foreign & Commonwealth Office. AS is supported by a British Heart Foundation Fellowship (FS/18/83/34025). JMW receives support from the National Institute for Health Research University College London Hospitals Biomedical Research Centre and from the UCLH Charity - Greenbaum/ McClean Legacy.    Disclosures: None.  Key Words: HIV Infection, Cardiovascular Disease, Inflammation, Treatment HIV, Cardiac Magnetic Resonance    2   The burden of cardiovascular disease in people living with HIV (PLWH) has tripled over the last 20 years, with cardiac manifestations of disease ranging from coronary disease to heart failure (1). The pathophysiological mechanisms involved in the development of Human immunodeficiency virus (HIV) cardiomyopathy remain elusive. Subclinical structural and functional changes were demonstrated in PLWH, but studies that deployed advanced imaging techniques focused on patients already treated with anti-retroviral therapy (ART), potentially limiting the understanding of cardiac manifestations of HIV. In this study, we evaluated myocardial changes in both treated and untreated PLWH by implementing advanced cardiac magnetic resonance (CMR) with tissue characterization by parametric mapping techniques in an upper-middle income country, Peru. Study participants were prospectively recruited an each provided, written informed consent. The study group consisted of 51 PLWH: 26 were receiving ART, 25 patients were treatment-naïve. Twenty-one healthy controls were selected by frequency matching. No patient had hepatitis C coinfection. Treatment-naïve patients were defined as newly diagnosed patients with HIV, with CMR performed either prior to or within 14 days of initiating ART. Of the ART treated group: 22 (85%) received both nucleoside (NRTIs) and non-nucleoside (NNRTI) reverse transcriptase inhibitors. The average time since the initial diagnosis of HIV was 5 ± 4.4 years. Undetectable viral load was defined as <40copies/ml. All scans were performed with a 3T MRI scanner (Prisma; Siemens). The protocol included cine imaging for volume and function assessment (strain analysis with feature tracking), Modified Look-Locker Inversion Recovery (MOLLI) T1 and T2 mapping. Gadoterate meglumine [0.1 mmol/kg] was administered for late enhancement (LGE) imaging and calculation of the extracellular volume fraction (ECV) was also performed. CMR readers were blinded to patients’ category. 3  There were no significant differences in baseline characteristics and cardiac risk factors between patients and controls. Compared with controls, PLWH had reduced LV function: LVEF 61.4±4.1 vs 64.7±2.4%, p=0.001; Global longitudinal strain (GLS) -17.6±3.3 vs -21.0±3.8%, p=0.002. PLWH had increased native T1 (1294±20 vs 1230±9ms, p<0.001), T2 (41.5±2.4 vs 36.4±1.4ms, p<0.001) and global ECV (28.5±1.5 vs 24.8±0.9%; p<0.001). Amongst PLWH, 39% had LGE vs none of the controls (p<0.001), with the area of LGE being mid or subepicardial in the septal and inferolateral walls. Non-trivial pericardial effusions (≥5mm) were more common among PLWH compared to controls (29 vs 5%, p=0.004). Figure 1A Untreated PLWH had higher global native T1 (1304±20 vs 1285±16ms; p<0.001) and ECV (29.3±0.7 vs 27.7±1.3%; p<0.001) compared to those on ART (Figure 1B). For PLWH, higher ECV was associated with a lower CD4 count, and this was independent of age, gender and LVEF (r=-0.46,p=0.001). Similarly, patients with a detectable viral load had higher ECV (29±1.1 vs 27.5±1.3, p<0.001) and higher native T1 (1300±21.2 vs 1286±16.8, p=0.02) than patients with an undetectable viral load. Figure 1C. Consistent with previous studies (2, 3) this data supports a high prevalence of subclinical myocardial dysfunction and structural changes in PLWH.  However, this is the first study that detected a significant expansion in ECV in PLWH, suggesting a greater myocardial impact of HIV than previously recognized, even in a young patient cohort (mean age 36). The elevation in T1 and T2 mapping values seen in PLWH is consistent with previous studies proposing myocardial inflammation as a component of the pathophysiological mechanism of HIV cardiomyopathy (4). Furthermore,  these structural changes were more prominent in untreated patients (higher native T1 and ECV) compared to patients on ART, and ECV was higher in PLWH with lower CD4 count and higher viral load. These findings support the notion that ART treatment is likely to be offering a 4  protective myocardial effect. The presence of cardiac structural changes in PLWH, particularly the degree of ECV expansion raises several questions with regards to the optimal management of these patients, suggesting the need of prospective studies with serial cardiac evaluation.   5  References: 1. Shah ASV, Stelzle D, et al. Global Burden of Atherosclerotic Cardiovascular Disease in PLWH. Circulation. 2018 Sep 11;138(11):1100–12.  2. Luetkens JA, Doerner Jet al. CMR Reveals Signs of Subclinical Myocardial Inflammation in Asymptomatic HIV-Infected Patients. Circ CVI. 2016 Mar;9(3)  3. Ntusi N, O’Dwyer E, et al. HIV-1-Related Cardiovascular Disease Is Associated With Chronic Inflammation, Frequent Pericardial Effusions, and Probable Myocardial Edema. Circ CVI. 2016 Mar;9(3)  4. Herskowitz A, Wu TC, et al. Myocarditis and cardiotropic viral infection associated with severe left ventricular dysfunction in late-stage infection with human immunodeficiency virus. JACC. 1994 Oct;24(4):1025–32.     6                             Figure 1A: CMR in a PLWH (a) and a control (b) showing increased native T1 mapping and ECV in PLWH (c) Basal antero-septal mid-wall and (d) Infero-lateral sub-epicardial  LGE in PLWH. Figure 1B: ART-naïve PLWH have elevated native T1 and ECV compared to those on ART. Figure 1C: Inverse correlation between (a) ECV with CD4 total count, and (b, c) patients with a detectable viral load >40 copies/ml have higher global ECV and global native T1.  

Myocardial Inflammation and Edema in People Living With Human Immunodeficiency Virus

https://discovery.ucl.ac.uk/10087921/1/19-0444RR_MS_MOD-2%20MERGED.pdf

Myocardial Inflammation and Edema in People Living With Human Immunodeficiency Virus

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