Why We Fail at Heart Failure: Lymphatic Insufficiency Is Disregarded

Houck, Philip D.; Dandapantula, Hari Kumar; Hardegree, Evan L.; Massey, Janet M

doi:10.7759/cureus.8930

Cited by 4 publications

(2 citation statements)

References 43 publications

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“…The lymphatic vasculature is an integral circulatory system and crucially influences disease pathophysiology. 7,[51][52][53][54][55][56][57][58][59][60] Lymphedema is the prototypical lymphatic vascular disorder that afflicts nearly 200 million individuals globally with no approved drugs. 61 A better understanding of lymphedema pathobiology can identify much needed therapeutic targets.…”

Section: Discussionmentioning

confidence: 99%

Abnormal Lymphatic Sphingosine-1-Phosphate Signaling Aggravates Lymphatic Dysfunction and Tissue Inflammation

Kim,

Tian,

et al. 2023

Circulation

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BACKGROUND: Lymphedema is a global health problem with no effective drug treatment. Enhanced T-cell immunity and abnormal lymphatic endothelial cell (LEC) signaling are promising therapeutic targets for this condition. Sphingosine-1-phosphate (S1P) mediates a key signaling pathway required for normal LEC function, and altered S1P signaling in LECs could lead to lymphatic disease and pathogenic T-cell activation. Characterizing this biology is relevant for developing much needed therapies. METHODS: Human and mouse lymphedema was studied. Lymphedema was induced in mice by surgically ligating the tail lymphatics. Lymphedematous dermal tissue was assessed for S1P signaling. To verify the role of altered S1P signaling effects in lymphatic cells, LEC-specific S1pr1 -deficient ( S1pr1 LECKO ) mice were generated. Disease progression was quantified by tail-volumetric and -histopathologic measurements over time. LECs from mice and humans, with S1P signaling inhibition, were then cocultured with CD4 T cells, followed by an analysis of CD4 T-cell activation and pathway signaling. Last, animals were treated with a monoclonal antibody specific to P-selectin to assess its efficacy in reducing lymphedema and T-cell activation. RESULTS: Human and experimental lymphedema tissues exhibited decreased LEC S1P signaling through S1P receptor 1 (S1PR1). LEC S1pr1 loss-of-function exacerbated lymphatic vascular insufficiency, tail swelling, and increased CD4 T-cell infiltration in mouse lymphedema. LECs, isolated from S1pr1 LECKO mice and cocultured with CD4 T cells, resulted in augmented lymphocyte differentiation. Inhibiting S1PR1 signaling in human dermal LECs promoted T-helper type 1 and 2 (Th1 and Th2) cell differentiation through direct cell contact with lymphocytes. Human dermal LECs with dampened S1P signaling exhibited enhanced P-selectin, an important cell adhesion molecule expressed on activated vascular cells. In vitro, P-selectin blockade reduced the activation and differentiation of Th cells cocultured with shS1PR1 -treated human dermal LECs. P-selectin–directed antibody treatment improved tail swelling and reduced Th1/Th2 immune responses in mouse lymphedema. CONCLUSION: This study suggests that reduction of the LEC S1P signaling aggravates lymphedema by enhancing LEC adhesion and amplifying pathogenic CD4 T-cell responses. P-selectin inhibitors are suggested as a possible treatment for this pervasive condition.

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Section: Discussionmentioning

confidence: 99%

Abnormal Lymphatic Sphingosine-1-Phosphate Signaling Aggravates Lymphatic Dysfunction and Tissue Inflammation

Kim,

Tian,

et al. 2023

Circulation

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“…Some have argued that the reason we fail at HF is that the definition of HF is too narrow and does not consider the failure of peripheral compensatory mechanisms. 48 The lymphatic system is an important, yet often overlooked, a contributor to maintaining total body volume. HF is characterized by venous congestion, which in turn, results in an increased efflux of fluid out of the vasculature and into the interstitial space at a rate that exceeds the ability of the lymphatic system to remove this fluid.…”

Section: Moving Targets Of the Futurementioning

confidence: 99%

Reflecting on the advancements of HFrEF therapies over the last two decades and predicting what is yet to come

Piña

Gibson

Zieroth

et al. 2022

European Heart Journal Supplements

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What was once considered a topic best avoided, managing heart failure with reduced ejection fraction (HFrEF) has become the focus of many drug and device therapies. While the four pillars of guideline-directed medical therapies have successfully reduced heart failure hospitalizations, and some have even impacted cardiovascular mortality in randomized controlled trials (RCTs), patient-reported outcomes have emerged as important endpoints that merit greater emphasis in future studies. The prospect of an oral inotrope seems more probable now as targets for drug therapies have moved from neurohormonal modulation to intracellular mechanisms and direct cardiac myosin stimulation. While we have come a long way in safely providing durable mechanical circulatory support to patients with advanced HFrEF, several percutaneous device therapies have emerged, and many are under investigation. Biomarkers have shown promise in not only improving our ability to diagnose incident heart failure but also our potential to implicate specific pathophysiological pathways. The once-forgotten concept of discordance between pressure and volume, the forgotten splanchnic venous and lymphatic compartments, have all emerged as promising targets for diagnosing and treating heart failure in the not-so-distant future. The increase in heart failure-related cardiogenic shock (CS) has revived interest in defining optimal perfusion targets and designing RCTs in CS. Rapid developments in remote monitoring, telemedicine, and artificial intelligence promise to change the face of heart failure care. In this state-of-the-art review, we reminisce about the past, highlight the present, and predict what might be the future of HFrEF therapies.

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Abnormal lymphatic S1P signaling aggravates lymphatic dysfunction and tissue inflammation

Kim¹,

Tian²,

Wu³

et al. 2023

Preprint

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BACKGROUND: Lymphedema is a global health problem with no effective drug treatment. Enhanced T cell immunity and abnormal lymphatic endothelial cell (LEC) signaling are promising therapeutic targets for this condition. Sphingosine-1-phosphate (S1P) mediates a key signaling pathway required for normal LEC function, and altered S1P signaling in LECs could lead to lymphatic disease and pathogenic T cell activation. Characterizing this biology is relevant for developing much-needed therapies. METHODS: Human and mouse lymphedema was studied. Lymphedema was induced in mice by surgically ligating the tail lymphatics. Lymphedematous dermal tissue was assessed for S1P signaling. To verify the role of altered S1P signaling effects in lymphatic cells, LEC-specific S1pr1-deficient (S1pr1LECKO) mice were generated. Disease progression was quantified by tail-volumetric and -histopathological measurements over time. LECs from mice and humans, with S1P signaling inhibition, were then co-cultured with CD4 T cells, followed by an analysis of CD4 T cell activation and pathway signaling. Finally, animals were treated with a monoclonal antibody specific to P-selectin to assess its efficacy in reducing lymphedema and T cell activation. RESULTS: Human and experimental lymphedema tissues exhibited decreased LEC S1P signaling through S1PR1. LEC S1pr1 loss-of-function exacerbated lymphatic vascular insufficiency, tail swelling, and increased CD4 T cell infiltration in mouse lymphedema. LECs, isolated from S1pr1LECKO mice and co-cultured with CD4 T cells, resulted in augmented lymphocyte differentiation. Inhibiting S1PR1 signaling in human dermal LECs (HDLECs) promoted T helper type 1 and 2 (Th1 and Th2) cell differentiation through direct cell contact with lymphocytes. HDLECs with dampened S1P signaling exhibited enhanced P-selectin, an important cell adhesion molecule expressed on activated vascular cells. In vitro, P-selectin blockade reduced the activation and differentiation of Th cells co-cultured with shS1PR1-treated HDLECs. P-selectin-directed antibody treatment improved tail swelling and reduced Th1/Th2 immune responses in mouse lymphedema CONCLUSION: This study suggests that reduction of the LEC S1P signaling aggravates lymphedema by enhancing LEC adhesion and amplifying pathogenic CD4 T cell responses. P-selectin inhibitors are suggested as a possible treatment for this pervasive condition.

show abstract

Why We Fail at Heart Failure: Lymphatic Insufficiency Is Disregarded

Cited by 4 publications

References 43 publications

Abnormal Lymphatic Sphingosine-1-Phosphate Signaling Aggravates Lymphatic Dysfunction and Tissue Inflammation

Abnormal Lymphatic Sphingosine-1-Phosphate Signaling Aggravates Lymphatic Dysfunction and Tissue Inflammation

Reflecting on the advancements of HFrEF therapies over the last two decades and predicting what is yet to come

Abnormal lymphatic S1P signaling aggravates lymphatic dysfunction and tissue inflammation

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