Pathways Case Report: Blood Finds a Way

A 30-year-old woman with injection drug use, hepatitis C, cirrhosis, and tricuspid valve endocarditis with two prior surgical valve replacements, was admitted to the hospital with progressive dyspnea (labored breathing) and low blood oxygen levels. The patient's first injection drug use-associated infection of her native tricuspid valve occurred approximately six years ago, at which time she was treated with antibiotics and subsequently with a surgical valve repair. A few months later, in the context of ongoing injection drug use, the patient's endocarditis recurred, and her prosthetic tricuspid valve was replaced. Around five years later, the patient was admitted with suspected tricuspid valve endocarditis, but at this time was not a candidate for surgery. She was treated with antibiotics and a follow-up echocardiogram demonstrated resolution of her valvular vegetations, but severe tricuspid valve stenosis (narrowing). Over the ensuing months, the patient developed progressive shortness of breath and ultimately was hospitalized for dyspnea and hypoxemia, refractory to diuresis requiring supplemental oxygen. A repeat echocardiogram showed worsening tricuspid valve stenosis with associated right-to-left shunting across a patent foramen ovale (PFO; a hole between the left and right atria).

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She was transferred to the Cardiac Intensive Care Unit at Massachusetts General Hospital for percutaneous valve repair. As part of her staging procedure for her valve repair, the patient received a cardiac CT which showed extensive veno-venous collaterals between anterior, systemic, and chest wall veins connecting directly to the patient's right superior pulmonary veins and left atrium. Her tricuspid valve was repaired successfully a few days later, with a reversal of shunt physiology across her PFO, and near-immediate resolution of her profound oxygen requirement. The remainder of her hospital course was notable for some moderate pulmonary edema which responded to diuretics, and the patient was discharged without oxygen support with a plan for outpatient right heart catheterization and venogram.

The Pathways Service in the Department of Medicine at Mass General was consulted and focused on the patient's remarkable veno-venous collaterals connecting her anterior, systemic, chest wall veins directly to her right superior pulmonary veins and left atrium, driven by two questions:

1. How is pressure within blood vessels sensed?
2. How does intravascular pressure drive vascular remodeling?

Background and Diagnosis

The mechanisms by which the cardiovascular system senses intravascular flow and pressure and responds to these forces remain to be fully elucidated. In brief, the primary ways by which pressure is sensed in a vessel include laminar or parallel flow, turbulent flow causing shear stress, and hydrostatic pressure causing wall distention (Exp Mol Med). A variety of different mechanisms detect these forces. The extracellular matrix and cytoskeletal components of endothelial cells lining vessels are key sensors of mechanical forces on vessel walls. For example, laminar blood flow acts on endothelial cytoskeletal components to induce nitric oxide synthesis, which induces vessel dilation, lowers vascular resistance, and facilitates tissue perfusion (Exp Mol Med, Arterioscler Thromb Vasc Biol). We were especially curious to explore the membrane receptors that facilitate mechano-sensing in blood vessels.

One of the best examples of mechano-sensitive receptors is Piezo ion channels, the discovery of which earned Ardem Patapoutian the Nobel Prize in 2021. Piezo1 channels are cation channels expressed on the luminal side of endothelial cells and are activated by blood flow, membrane tension and pressure, and localized membrane stretch (Trends Pharmacol Sci). Piezo1 channels are an excellent example of the close relationship between structure and function, displaying a unique structure with trimeric propeller blades that are highly sensitive to mechanical stimuli (Arterioscler Thromb Vasc Biol). When mechanical forces induce conformational changes in the propeller structures, the channel opens and cations, notably calcium, enter the endothelial cell, inducing cell depolarization as well as activating numerous calcium-dependent intracellular signaling pathways (Trends Pharmacol Sci).

Interestingly, Piezo1 channels mediate diverse downstream signaling pathways depending on the type of force present and the context in which it occurs. For example, increased flow in venous endothelial cells activates Piezo1, leading to calcium influx and activation of matrix metalloproteinases, which help promote the generation of new blood vessels (Trends Pharmacol Sci). Increased hydrostatic pressure in lung vasculature also activates Piezo1 channels but induces a different downstream signaling pathway involving activation of proteolytic enzymes that degrade junctions between endothelial cells, leading to leakage of plasma into lung parenchyma and pulmonary edema (Trends Pharmacol Sci).

While we hypothesize that increased pressure was one of the key factors leading to increased angiogenesis and the development of veno-venous collaterals in our patient, mechanical forces are not the only factor leading to angiogenesis. Notably, venous endothelial cells are thought to be primarily responsible for angiogenic expansion in adulthood since these cells migrate against blood flow, have a high degree of mitotic activity, and can assume the molecular and functional identities of other endothelial subtypes (Exp Mol Med). This may explain why the patient's collaterals largely stemmed from the venous circulation. However, the location of her obstruction in the tricuspid valve and superior vena cava was a key predisposing factor for developing systemic thoracic venous collaterals (Insights Imaging).

A balance between pro- and anti-angiogenic factors regulates angiogenesis. Pro-angiogenic factors include mechanical forces, hypoxia, inflammation secondary to tissue or vessel injury, growth factors, and multiple tumor-specific factors including oncogene activation (Nature, Angiogenesis). We hypothesize that a combination of pro-angiogenic factors, including mechanical forces, drove the development of collaterals in this patient.

Our hypothesis is that localized pressure from our patient's severe tricuspid regurgitation and superior vena cava thrombi caused the formation of systemic veno-venous collaterals, bypassing her pulmonary circulation and feeding directly into her pulmonary veins and left atrium. We believe that our patient's localized pressure only partially explains the extent of her collaterals. Given the current literature and our patient's history, we believe that other factors may also be contributing. Thus, we proposed a 'multi-hit' theory that made our patient the perfect environment for these collaterals to develop. We grouped the contributing factors into subgroups including pulmonary, liver, dermatology, vascular, and iatrogenesis (unintentional causation of an unfavorable health condition resulting from medical care).

The most important subgroup is pulmonary. Our patient likely had poor pulmonary substrate or underlying disease such that her pulmonary circulation was circumvented by a right to left intracardiac shunt. Factors affecting her lungs include a history of septic emboli secondary to infective endocarditis and potentially, pro-inflammatory injected substances. From the liver perspective, she has radiologic evidence of cirrhosis and a history of untreated hepatitis C. It is possible that she has portal hypertension and vasoactive substances bypass the liver and cause vascular remodeling in the lungs. Her dermatologic contributor manifests through the development of keloids (thick, raised scars), causing abnormal hypertrophic scarring and wound healing. Her keloid history coupled with her vascular history of IgA nephropathy and pre-eclampsia, likely have implications for abnormal vascular remodeling. Finally, it is possible that her surgical history played a role due to her repeated tricuspid valve replacements. For example, from her most recent admission cardiac CT scan, we see most of her veno-venous collaterals stem from her anterior chest wall. After the first valve replacement, several sternotomy wires had to be removed, causing extensive anterior chest wall scarring. The fact that the location of the collaterals is in the same area of the scarring could point to this surgical history as a contributing factor.

Overall, the multi-hit theory encapsulates the complexity of our patient's vascular substrate and points us to a more comprehensive hypothesis as to why we see such extensive veno-venous collaterals and right-to-left intracardiac shunting.

Summary and Future Steps

Piezo1 is a mechanosensitive protein channel that converts mechanical forces sensed by vessels into electrochemical signals. Hemodynamics and mechanical forces shape angiogenesis and vascular remodeling, among other complex factors. In the case of our patient, we hypothesize that her tricuspid valve stenosis and superior vena cava thrombus were the likely drivers of her collateralization.

Important considerations for future research could focus on two primary questions:

1. What would a biopsy of the patient's collateral vessels show?
2. What happens to the veno-venous collaterals after valve replacement and subsequent decrease in intravascular pressure?

For the first question, we speculate that a biopsy may reveal upregulation of mechanosensory channels. To understand the implications of these channels, we could create a knockout Piezo1 mouse model, surgically create elevated pressures within the right-side of the mouse's heart and observe whether the absence of the Piezo1 protein affects venous collateralization. For our second question, we hypothesize that the same channels activated by the high-pressure gradients at the time of severe tricuspid stenosis will be deactivated. One could imagine that this will lead to atrophy of the venous collaterals over time. These experiments would provide better understanding to the pathophysiology that occurred in our patient and identify new research avenues.

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