All Publications


  • Body Composition, Natriuretic Peptides, and Adverse Outcomes in Heart Failure With Preserved and Reduced Ejection Fraction. JACC. Cardiovascular imaging Selvaraj, S., Kim, J., Ansari, B. A., Zhao, L., Cvijic, M. E., Fronheiser, M., Mohan-Rao Vanjarapu, J., Kumar, A. A., Suri, A., Yenigalla, S., Satija, V., Ans, A. H., Narvaez-Guerra, O., Herrera-Enriquez, K., Obeid, M. J., Lee, J. J., Jehangir, Q., Seiffert, D. A., Car, B. D., Gordon, D. A., Chirinos, J. A. 2021; 14 (1): 203–15

    Abstract

    The purpose of this study was to determine the relationship between body composition, N-terminal B-type natriuretic peptide (NT-proBNP) levels, and heart failure (HF) phenotypes and outcomes.Abnormalities in body composition can influence metabolic dysfunction and HF severity; however, data assessing fat distribution and skeletal muscle (SM) size in HF with reduced (HFrEF) and preserved EF (HFpEF) are limited. Further, whether NPs relate more closely to axial muscle mass than measures of adiposity is not well studied.We studied 572 adults without HF (n = 367), with HFrEF (n = 113), or with HFpEF (n = 92). Cardiac magnetic resonance was used to assess subcutaneous and visceral abdominal fat, paracardial fat, and axial SM size. We measured NT-proBNP in 334 participants. We used Cox regression to analyze the relationship between body composition and mortality.Compared with controls, pericardial and subcutaneous fat thickness were significantly increased in HFpEF, whereas patients with HFrEF had reduced axial SM size after adjusting for age, sex, race, and body height (p < 0.05 for comparisons). Lower axial SM size, but not fat, was significantly predictive of death in unadjusted (standardized hazard ratio: 0.63; p < 0.0001) and multivariable-adjusted analyses (standardized hazard ratio = 0.72; p = 0.0007). NT-proBNP levels more closely related to lower axial SM rather than fat distribution or body mass index (BMI) in network analysis, and when simultaneously assessed, only SM (p = 0.0002) but not BMI (p = 0.18) was associated with NT-proBNP. However, both NT-proBNP and axial SM mass were independently predictive of death (p < 0.05).HFpEF and HFrEF have distinct abnormalities in body composition. Reduced axial SM, but not fat, independently predicts mortality. Greater axial SM more closely associates with lower NT-proBNP rather than adiposity. Lower NT-proBNP levels in HFpEF compared with HFrEF relate more closely to muscle mass rather than obesity.

    View details for DOI 10.1016/j.jcmg.2020.07.022

    View details for PubMedID 32950445

    View details for PubMedCentralID PMC7796896

  • Serum Albumin Is a Marker of Myocardial Fibrosis, Adverse Pulsatile Aortic Hemodynamics, and Prognosis in Heart Failure With Preserved Ejection Fraction. Journal of the American Heart Association Prenner, S. B., Pillutla, R., Yenigalla, S., Gaddam, S., Lee, J., Obeid, M. J., Ans, A. H., Jehangir, Q., Kim, J., Zamani, P., Mazurek, J. A., Akers, S. R., Chirinos, J. A. 2020; 9 (3): e014716

    Abstract

    Background Data regarding the phenotypic correlates and prognostic value of albumin in heart failure with preserved ejection fraction (HFpEF) are scarce. The goal of the current study is to determine phenotypic correlates (myocardial hypertrophy, myocardial fibrosis, detailed pulsatile hemodynamics, and skeletal muscle mass) and prognostic implications of serum albumin in HFpEF. Methods and Results We studied 118 adults with HFpEF. All-cause death or heart-failure-related hospitalization was ascertained over a median follow-up of 57.6 months. We measured left ventricular mass, myocardial extracellular volume, and axial muscle areas using magnetic resonance imaging. Pulsatile arterial hemodynamics were assessed with a combination of arterial tonometry and phase-contrast magnetic resonance imaging. Subjects with lower serum albumin exhibited a higher body mass index, and a greater proportion of black ethnicity and diabetes mellitus. A low serum albumin was associated with higher myocardial extracellular volume (52.3 versus 57.4 versus 39.3 mL in lowest to highest albumin tertile, respectively; P=0.0023) and greater N-terminal pro B-type natriuretic peptide levels, but not with a higher myocardial cellular volume (123 versus 114 versus 102 mL; P=0.13). Lower serum albumin was also associated with an increased forward wave amplitude and markedly increased pulsatile power in the aorta. Serum albumin was a strong predictor of death or heart failure hospitalization even after adjustment for N-terminal pro B-type natriuretic peptide levels and the Meta-Analysis Global Group in Chronic Heart Failure (MAGGIC) risk score (adjusted standardized hazard ratio=0.56; 95% CI=0.37-0.83; P<0.0001). Conclusions Serum albumin is associated with myocardial fibrosis, adverse pulsatile aortic hemodynamics, and prognosis in HFpEF. This readily available clinical biomarker can enhance risk stratification in HFpEF and identifies a subgroup with specific pathophysiological abnormalities.

    View details for DOI 10.1161/JAHA.119.014716

    View details for PubMedID 32009529

    View details for PubMedCentralID PMC7033884

  • Mechanism of pulsus bisferiens in thoracoabdominal thoracic aneurysms: Insights from wave intensity analysis. Journal of clinical hypertension (Greenwich, Conn.) Chirinos, J. A., Lee, J., Segers, P. 2020

    Abstract

    Aortic pulsatile hemodynamics are important in various clinical conditions. Whereas the importance of wave reflections of the closed type in pulsatile hemodynamics has been extensively studied, less is known about the impact of reflections of the open type, in which reflected waves changes both direction and type (compression vs suction) compared to the incident wave. In this report, we present careful pulsatile hemodynamic analyses of a case in which prominent reflections of the open type occur in a patient with a thoracoabdominal aortic aneurysm, causing a highly abnormal proximal aortic and peripheral arterial hemodynamic pattern, known as pulsus bisferiens. Wave intensity analysis of central pressure-flow data demonstrated an early systolic forward-traveling compression wave followed by a prominent late systolic forward-traveling expansion wave, along with an abnormal prominent late systolic/early diastolic backward-traveling compression wave which produced a sharp rise in diastolic pressure, and was responsible for the pulsus bisferiens pattern.

    View details for DOI 10.1111/jch.14100

    View details for PubMedID 33216447

  • Usefulness of Left Ventricular Strain by Cardiac Magnetic Resonance Feature-Tracking to Predict Cardiovascular Events in Patients With and Without Heart Failure. The American journal of cardiology Sardana, M., Konda, P., Hashmath, Z., Oldland, G., Gaddam, S., Miller, R., Satija, V., Ansari, B., Lee, J., Mustafa, A., Akers, S. R., Chirinos, J. A. 2019; 123 (8): 1301–8

    Abstract

    There is controversy regarding the utility of left ventricular (LV) mechanics assessed by feature-tracking steady-state free-precession (FT-SSFP), a readily implementable technique in clinical practice. In particular, whether LV mechanics assessed by FT-SSFP predicts outcomes in subjects with heart failure (HF) with reduced ejection fraction (HFrEF), with preserved ejection fraction (HFpEF), or without HF is unknown. We aimed to assess whether LV mechanics measured with FT-SSFP cine magnetic resonance imaging (MRI) predicts adverse outcomes. We prospectively enrolled 612 adults without HF (n = 402), with HF with reduced ejection fraction (HFrEF; n = 113), or HFpEF (n = 97) and assessed LV strain using FT-SSFP cine MRI. Over a median follow-up of 39.5 months, 75 participants had an HF admission, and 85 died. In Cox proportional hazards models, lower global longitudinal (Standardized hazard ratio 1.56, 95% confidence interval [CI] 1.22 to 2.00, p = 0.0004), circumferential (Standardized HR 1.46, 95% CI 1.08 to 1.95, p = 0.0123), and radial strain (Standardized HR 0.59, 95% CI 0.43 to 0.83, p = 0.0019) were independently associated with the composite endpoint, after adjustment for HF status, LV ejection fraction (LVEF), age, sex, ethnicity, body mass index, systolic and diastolic blood pressure, hypertension, diabetes, coronary artery disease, and glomerular filtration rate. Furthermore, global longitudinal strain stratified the risk of adverse outcomes across tertiles better than LVEF. In analyses that included only participants with a preserved LVEF, systolic radial, circumferential and longitudinal strain were independently predictive of adverse outcomes. We conclude that LV longitudinal, circumferential and radial strain measured using FT-SSFP cine MRI (a readily implementable technique in clinical practice) predict the risk of adverse events, independently of LVEF.

    View details for DOI 10.1016/j.amjcard.2019.01.025

    View details for PubMedID 30717885

    View details for PubMedCentralID PMC6435378

  • Vitamin K Status, Warfarin Use, and Arterial Stiffness in Heart Failure. Hypertension (Dallas, Tex. : 1979) Hashmath, Z., Lee, J., Gaddam, S., Ansari, B., Oldland, G., Javaid, K., Mustafa, A., Vasim, I., Akers, S., Chirinos, J. A. 2019; 73 (2): 364–70

    Abstract

    Large artery stiffening contributes to the pathophysiology of heart failure (HF) and associated comorbidities. MGP (matrix Gla-protein) is a potent inhibitor of vascular calcification. MGP activation is vitamin K-dependent. We aimed (1) to compare dp-ucMGP (dephospho-uncarboxylated MGP) levels between subjects with HF with preserved ejection fraction (HFpEF) and HF with reduced ejection fraction (HFrEF) and subjects without HF; (2) to assess the relationship between dp-ucMGP levels and arterial stiffness; and (3) to assess the relationship between warfarin use, dp-ucMGP levels, and arterial stiffness in HF. We enrolled 348 subjects with HFpEF (n=96), HFrEF (n=53), or no HF (n=199). Carotid-femoral pulse wave velocity, a measure of large artery stiffness, was measured with arterial tonometry. Dp-ucMGP was measured with ELISA. Dp-ucMGP levels were greater in both HFrEF (582 pmol/L; 95% CI, 444-721 pmol/L) and HFpEF (549 pmol/L; 95% CI, 455-643 pmol/L) compared with controls (426 pmol/L; 95% CI, 377-475 pmol/L; ANCOVA P=0.0067). Levels of dp-ucMGP were positively associated with carotid-femoral pulse wave velocity (standardized β, 0.31; 95% CI, 0.19-0.42; P<0.0001), which was also true in analyses restricted to patients with HF (standardized β, 0.34; 95% CI, 0.16-0.52; P=0.0002). Warfarin use was significantly associated with carotid-femoral pulse wave velocity (standardized β, 0.13; 95% CI, 0.004-0.26; P=0.043), but this relationship was eliminated after adjustment for dp-ucMGP. In conclusion, levels of dp-ucMGP are increased in HFpEF and HFrEF and are independently associated with arterial stiffness. Future studies should investigate whether vitamin K supplementation represents a suitable therapeutic strategy to prevent or reduce arterial stiffness in HFpEF and HFrEF.

    View details for DOI 10.1161/HYPERTENSIONAHA.118.12157

    View details for PubMedID 30580682

    View details for PubMedCentralID PMC6326852

  • Axial Muscle Size as a Strong Predictor of Death in Subjects With and Without Heart Failure. Journal of the American Heart Association Kumar, A., Ansari, B. A., Kim, J., Suri, A., Gaddam, S., Yenigalla, S., Vanjarapu, J. M., Selvaraj, S., Tamvada, D., Lee, J., Akers, S. R., Chirinos, J. A. 2019; 8 (4): e010554

    Abstract

    Background The impact of skeletal muscle size, quantified using simple noninvasive images routinely obtained during cardiac magnetic resonance imaging studies on mortality in the heart failure ( HF ) population is currently unknown. Methods and Results We prospectively enrolled 567 subjects without HF (n=364), with HF with reduced ejection fraction (n=111), or with HF with preserved ejection fraction (n=92), who underwent a cardiac magnetic resonance imaging. Skeletal muscle cross-sectional area was assessed with manual tracing of major thoracic muscle groups on axial chest magnetic resonance images. Factor analysis was used to identify a latent factor underlying the shared variability in thoracic muscle cross-sectional area. Cox regression was used to assess the relationship between these measurements and all-cause mortality (median follow up, 36.4 months). A higher overall thoracic muscle area factor assessed with principal component analysis was independently associated with lower mortality (standardized hazard ratio, 0.51; P<0.0001). The thoracic muscle area factor was predictive of death in subjects with HF with preserved ejection fraction, HF with reduced ejection fraction, and those without HF . Among all muscle groups, the pectoralis major cross-sectional area was the most representative of overall muscle area and was also the most robust predictor of death. A higher pectoralis major cross-sectional area predicted a lower mortality (standardized hazard ratio, 0.49; P<0.0001), which persisted after adjustment for various confounders (standardized hazard ratio, 0.55; P=0.0017). Conclusions Axial muscle size, and in particular smaller size of the pectoralis major, is independently associated with higher risk of mortality in patients with and without HF . Further work should clarify the role of muscle wasting as a therapeutic target in patients with HF .

    View details for DOI 10.1161/JAHA.118.010554

    View details for PubMedID 30755074

    View details for PubMedCentralID PMC6405649

  • Arterial Properties as Determinants of Left Ventricular Mass and Fibrosis in Severe Aortic Stenosis: Findings From ACRIN PA 4008. Journal of the American Heart Association Chirinos, J. A., Akers, S. R., Schelbert, E., Snyder, B. S., Witschey, W. R., Jacob, R. M., Jamis-Dow, C., Ansari, B., Lee, J., Segers, P., Schnall, M., Cavalcante, J. L. 2019; 8 (1): e03742

    Abstract

    Background The role of arterial load in severe aortic stenosis is increasingly recognized. However, patterns of pulsatile load and their implications in this population are unknown. We aimed to assess the relationship between the arterial properties and both (1) left ventricular remodeling and fibrosis and (2) the clinical course of patients with severe aortic stenosis undergoing aortic valve replacement ( AVR ). Methods and Results We enrolled 38 participants with symptomatic severe aortic stenosis scheduled to undergo surgical AVR . Aortic root characteristic impedance, wave reflections parameters (reflection magnitude, reflected wave transit time), and myocardial extracellular mass were measured with cardiac magnetic resonance imaging and arterial tonometry Cardiac magnetic resonance imaging was repeated at 6 months in 30 participants. A reduction in cellular mass (133.6 versus 113.9 g; P=0.002) but not extracellular mass (42.3 versus 40.6 g; P=0.67) was seen after AVR . Participants with higher extracellular mass exhibited greater reflection magnitude (0.68 versus 0.54; P=0.006) and lower aortic root characteristic impedance (56.3 versus 96.9 dynes/s per cm5; P=0.006). Reflection magnitude was a significant predictor of smaller improvement in the quality of life (Kansas City Cardiomyopathy Questionnaire score) after AVR ( R=-0.51; P=0.0026). The 6-minute walk distance at 6 months after AVR was positively correlated with the reflected wave transit time ( R=0.52; P=0.01). Conclusions Consistent with animal studies, arterial wave reflections are associated with interstitial volume expansion in severe aortic stenosis and predict a smaller improvement in quality of life following AVR . Future trials should assess whether wave reflections represent a potential therapeutic target to mitigate myocardial interstitial remodeling and to improve the clinical status of this patient population.

    View details for DOI 10.1161/JAHA.118.010271

    View details for PubMedID 30590991

    View details for PubMedCentralID PMC6405727

  • Association of arginine vasopressin with low atrial natriuretic peptide levels, left ventricular remodelling, and outcomes in adults with and without heart failure. ESC heart failure Chirinos, J. A., Sardana, M., Oldland, G., Ansari, B., Lee, J., Hussain, A., Mustafa, A., Akers, S. R., Wei, W., Lakatta, E. G., Fedorova, O. V. 2018; 5 (5): 911–19

    Abstract

    The arginine vasopressin (AVP) pathway has been extensively studied in heart failure (HF) with reduced ejection fraction (HFrEF), but less is known about AVP in HF with preserved EF (HFpEF). Furthermore, the association between AVP and atrial natriuretic peptide (ANP, a well-known inhibitor of AVP secretion) in HF is unknown.We studied subjects with HFpEF (n = 28) and HFrEF (n = 25) and without HF (n = 71). Left ventricular (LV) mass and left atrial (LA) volumes were measured with cardiac magnetic resonance imaging. Arginine vasopressin and ANP were measured with enzyme-linked immunosorbent assay. Arginine vasopressin levels were significantly greater in HFpEF [0.96 pg/mL; 95% confidence interval (CI) = 0.83-1.1 pg/mL] compared with subjects without HF (0.69 pg/mL; 95% CI = 0.6-0.77 pg/mL; P = 0.0002). Heart failure with preserved ejection fraction (but not HFrEF) was a significant predictor of higher AVP after adjustment for potential confounders. Arginine vasopressin levels were independently associated with a greater LA volume and also paradoxically, with lower ANP levels. Key independent correlates of higher AVP were the presence of HFpEF (standardized β = 0.32; 95% CI = 0.09-0.56; P = 0.0073) and the ANP/LA volume ratio (standardized β = -0.23; 95% CI = -0.42 to -0.04; P = 0.0196). Arginine vasopressin levels were independently associated with LV mass (β = 0.26; 95% CI = 0.09-0.43; P = 0.003) and with an increased risk of death or HF admissions during follow-up (hazard ratio = 1.61; 95% CI = 1.13-2.29; P = 0.008).Arginine vasopressin is increased in HFpEF and is associated with LV hypertrophy and poor outcomes. Higher AVP is associated with the combination of LA enlargement and paradoxically low ANP levels. These findings may indicate that a relative deficiency of ANP (an inhibitor of AVP secretion) in the setting of chronically increased LA pressure may contribute to AVP excess.

    View details for DOI 10.1002/ehf2.12319

    View details for PubMedID 29969536

    View details for PubMedCentralID PMC6165935

  • Left Atrial Phasic Function by Cardiac Magnetic Resonance Feature Tracking Is a Strong Predictor of Incident Cardiovascular Events. Circulation. Cardiovascular imaging Chirinos, J. A., Sardana, M., Ansari, B., Satija, V., Kuriakose, D., Edelstein, I., Oldland, G., Miller, R., Gaddam, S., Lee, J., Suri, A., Akers, S. R. 2018; 11 (12): e007512

    Abstract

    The prognostic importance of left atrial (LA) dysfunction is increasingly recognized. Magnetic resonance imaging can provide excellent visualization of the LA wall. We aimed to study the association of LA dysfunction measured using feature-tracking magnetic resonance imaging with incident adverse cardiovascular events among subjects with or without heart failure (HF) at baseline.We prospectively studied 640 adults without HF (n=419), HF with preserved ejection fraction (n=101), or HF with reduced ejection fraction (n=120). We measured phasic LA function by volumetric and feature-tracking methods to derive longitudinal strain. The composite outcome of incident HF hospitalization or death was adjudicated during a median follow-up of 37.1 months. Measures of LA phasic function were more prominently impaired in subjects with HF with reduced ejection fraction than among subjects with HF with preserved ejection fraction. In unadjusted Cox proportional hazards models, all measures of phasic LA function and volumes (maximum, minimum, and diastatic) were associated with the composite outcome. However, in analyses that adjusted for clinical risk factors, HF status, maximum LA volume, left ventricular mass, and left ventricular ejection fraction, measures of conduit and reservoir LA function, but not booster-pump function, were associated with the composite outcome. The strongest associations were observed for conduit longitudinal strain (standardized hazard ratio, 0.66; 95% CI, 0.49-0.88; P=0.004), conduit strain rate (standardized hazard ratio, 1.59; 95% CI, 1.16-2.16; P=0.0035), and reservoir strain (standardized hazard ratio, 0.68; 95% CI, 0.52-0.89; P=0.0055).Phasic LA function measured using magnetic resonance imaging feature tracking is independently predictive of the risk of incident HF admission or death, even after adjusting for LA volume and left ventricular remodeling.

    View details for DOI 10.1161/CIRCIMAGING.117.007512

    View details for PubMedID 30562112

    View details for PubMedCentralID PMC6301081

  • Circulating Dephospho-Uncarboxylated Matrix Gla-Protein Is Associated With Kidney Dysfunction and Arterial Stiffness. American journal of hypertension Puzantian, H., Akers, S. R., Oldland, G., Javaid, K., Miller, R., Ge, Y., Ansari, B., Lee, J., Suri, A., Hasmath, Z., Townsend, R., Chirinos, J. A. 2018; 31 (9): 988–94

    Abstract

    Large artery stiffening is increased in advanced chronic kidney disease (CKD) but likely develops progressively in earlier stages of CKD. Active matrix Gla-protein (MGP) is a potent vitamin K-dependent inhibitor of vascular calcification. A recent animal model demonstrated intrinsic abnormalities in vitamin K metabolism even in early CKD, but whether early human CKD is associated with vascular vitamin K deficiency is unknown.We enrolled 137 adults without HF with varying degrees of renal function: normal estimated glomerular filtration rate (eGFR; >90 ml/min; n = 59), mildly reduced eGFR (stage 2 CKD: eGFR = 60-89 ml/min; n = 53) or at least moderately reduced eGFR (stage 3-5 CKD; eGFR < 60 ml/min; n = 25). Carotid-femoral pulse wave velocity (CF-PWV) was measured with carotid and femoral tonometry. Dephospho-uncarboxylated matrix gla-protein (dp-ucMGP) was measured with enzyme-linked immunosorbent assay (ELISA) (VitaK; Maastricht University; The Netherlands).Dp-ucMGP levels were progressively increased with decreasing renal function (eGFR ≥ 90: 247 pmol/l; eGFR 60-89: 488 pmol/l; eGFR < 60: 953 pmol/l; P < 0.0001). These differences persisted after adjustment for multiple potential confounders (eGFR ≥ 90: 314 pmol/l; eGFR 60-89: 414 pmol/l; eGFR < 60: 770 pmol/l; P < 0.0001). In a multivariable model adjusted for various confounders, dp-ucMGP was a significant independent predictor of CF-PWV (β = 0.21; P = 0.019). In formal mediation analyses, dp-ucMGP mediated a significant relationship between eGFR and higher CF-PWV (β = -0.16; P = 0.005), whereas no significant dp-ucMGP-independent relationship was present (β = -0.02; P = 0.80).CKD is associated with increased (inactive) dp-ucMGP, a vitamin K-dependent inhibitor of vascular calcification, which correlates with large artery stiffness. Further studies are needed to assess whether vitamin K2 supplementation represents a suitable therapeutic strategy to prevent or reduce arterial stiffening in CKD.

    View details for DOI 10.1093/ajh/hpy079

    View details for PubMedID 29788226

    View details for PubMedCentralID PMC6077812

  • Right Atrial Phasic Function in Heart Failure With Preserved and Reduced Ejection Fraction. JACC. Cardiovascular imaging Jain, S., Kuriakose, D., Edelstein, I., Ansari, B., Oldland, G., Gaddam, S., Javaid, K., Manaktala, P., Lee, J., Miller, R., Akers, S. R., Chirinos, J. A. 2018

    Abstract

    This study researched right atrial (RA) deformation indexes and their association with all-cause mortality among subjects with or without heart failure (HF).Although left atrial dysfunction is well described in HF, patterns of RA dysfunction and their prognostic implications are unclear. Cardiac magnetic resonance (CMR) imaging can provide excellent visualization of the RA. We used CMR to characterize RA phasic function in HF and to assess its prognostic implications.This study prospectively examined 608 adults without HF (n = 407), as well as adults with HF with a reduced ejection fraction (HFrEF) (n = 105) or with HF with a preserved ejection fraction (HFpEF) (n = 96). Phasic RA function was measured via volume measurements and feature-tracking methods to derive longitudinal strain. All-cause death was ascertained over a median follow-up of 38.9 months. Standardized hazard ratios (HRs) were computed via Cox regression.Measures of RA phasic function were more prominently impaired in subjects with HFrEF than those in subjects with HFpEF. In analyses that adjusted for demographic factors, HF status, left ventricular ejection fraction, right ventricular end-diastolic volume index, and right ventricular ejection fraction, RA reservoir strain (HR: 0.66; 95% confidence interval [CI]: 0.47 to 0.92; p = 0.0154), RA expansion index (HR: 0.53; 95% CI: 0.31 to 0.91; p = 0.0116), RA conduit strain (HR: 0.58; 95% CI: 0.40 to 0.84; p = 0.0039), and RA conduit strain rate (HR: 1.51; 95% CI: 1.02 to 2.220; p = 0.0373) independently predicted all-cause mortality. In contrast, RA booster pump function and RA volume index did not independently predict the risk of death.Phasic RA function is predictive of the risk of all-cause death in a diverse group of subjects with and without HF. RA conduit and reservoir function are independent predictors of mortality.

    View details for DOI 10.1016/j.jcmg.2018.08.020

    View details for PubMedID 30343071

    View details for PubMedCentralID PMC6461533