Human Immunodeficiency Viruses and its effect on the Pulmonary Vascular bed

December. 1st 2021 is "World AIDS Day" reminding us that HIV infection is still widespread and that many of its long-term effects can be deadly. One of these complications is its effect on the pulmonary vascular beds, leading to an increase in the pulmonary pressure, causing the clinical manifestation of "pulmonary hypertension". Unfortunately, we are still far from fully understanding the prevalence, mechanics, and pathobiology of "HIV pulmonary hypertension", especially in Africa and other developing countries where HIV is still common. In addition, the impact of other factors like co-infection and illicit drugs can add and modify the effect on the pulmonary vascular bed, complicating the pathological and clinical effects of HIV. Thus, "World AIDS Day" can be an impetus to pursue further research in this area.

The pulmonary vascular bed in patients with functionally univentricular physiology and a Fontan circulation

Fontan palliation represents one of the most remarkable surgical advances in the management of individuals born with functionally univentricular physiology. The operation secures adult survival for all but a few with unfavourable anatomy and/or physiology. Inherent to the physiology is passive transpulmonary blood flow, which produces a vulnerability to adequate filling of the systemic ventricle at rest and during exertion. Similarly, the upstream effects of passive flow in the lungs are venous congestion and venous hypertension, especially marked during physical activity. The pulmonary vascular bed has emerged as a defining character on the stage of Fontan circulatory behaviour and clinical outcomes. Its pharmacologic regulation and anatomic rehabilitation therefore seem important strategic therapeutic targets. This review seeks to delineate the important aspects of pulmonary artery development and maturation in functionally univentricular physiology patients, pulmonary artery biology, pulmonary vascular reserve with exercise, and pulmonary artery morphologic and pharmacologic rehabilitation.

Abstract 17119: Sufficient Pulmonary Vascular Bed Before Fontan Surgery Secures Favorable Fontan Hemodynamics

Introduction: While improvement of perioperative care markedly expanded candidacy of Fontan surgery, increasing number of Fontan patients is currently subjected to advanced heart failure therapies. Low pulmonary flow before Fontan procedure has been considered to be acceptable as it keeps pulmonary resistance low, however, compromised growth of pulmonary vascular bed after Fontan completion may deteriorate potential to preserve better Fontan circulation later. We tested our hypothesis that sufficient growth of pulmonary vascular bed before Fontan surgery chronically preserves favorable Fontan hemodynamics and prevents patients from cardiovascular remodeling. Methods and Results: Consecutive 33 patients who had undergone Fontan operation (median year after the surgery: 5.3years) were enrolled in this study. During cardiac catheterization, pulmonary arterial index (PAI) as the representative of vascular bed both before and after Fontan procedure was measured and hemodynamics as well as blood samples as a marker for end-organ dysfunction were analyzed. Before Fontan procedure, PAI ranged 74-426 and resistance of pulmonary artery (PAR) ranged 0.4-3.1. After median of 5.3 years of Fontan procedure, CVP exhibited modest decline with preserving cardiac index (CI). Interestingly, central venous pressure (CVP) with chronic Fontan circulation was negatively correlated with PAI of pre-Fontan procedure (P=0.02) whereas it was independent of PAR. Consistent with this, higher PAI before Fontan procedure was also significantly associated with higher CI (P<0.01) and lower levels of plasma brain natriuretic peptides (P=0.03). Importantly, patients with low PAI showed markedly elevated activation of renin-angiotensin-aldosterone (RAAS) activation and elevation of serum gamma-gltamyl transferase (P<0.01), a surrogate marker of liver congestion. Multivariate analysis revealed that high PAI was determinant of low CVP in the chronic Fontan patients, independent of body size, postoperative interval and pulmonary arterial resistance. Conclusion: Sufficient pulmonary vascular bed before Fontan procedure independently lowers CVP, may prevent cardiovascular remodeling by RAAS suppression as well as end organ dysfunction in chronic Fontan patients. Our result suggested importance of strategies to accelerate pulmonary vascular growth before Fontan procedure.

Lower limb exercise generates pulsatile flow into the pulmonary vascular bed in the setting of the Fontan circulation

The absence of a subpulmonary ventricle in the Fontan circulation results in non-pulsatile pulmonary blood flow. Lower limb exercise in this setting can generate pulsatile pulmonary blood flow.

Platelet Release from Infused CD34+-Derived Human Megakaryocytes: Lessons from a Natural-Occurring Platelet Bioreactor

The release of biologically intact platelets from in vitro-grown megakaryocytes remains one of the challenges in an attempt to replace donor-derived platelets with platelets prepared from in vitro-grown megakaryocytes. Thrombopoiesis, the process by which megakaryocytes release platelets, is thought to occur as megakaryocytes exit from the medullar space and transit into the blood stream. Two-photon fluorescence microscopy studies by several groups have documented megakaryocytes transitioning into the blood stream and extending mostly a single protrusion that appears to release large cytoplasmic fragments downstream. These studies have been widely interpreted to support platelet release in the bone marrow environment. A counter proposal made by Dr. William Howell over 75 years ago is that either whole megakaryocytes or large cytoplasmic fragments circulate to the lungs and release platelets in the lungs. Studies by our group infusing in vitro-grown megakaryocytes (both human and mouse) have shown that infused megakaryocytes do indeed become entrapped in the lungs and release platelets. These in vivo-released platelets have a much longer half-life than in vitro-prepared platelets from static cultures and have the same size distribution and nearly the same functionality as infused donor-derived platelets. Using confocal intravital microscopy, we now directly visualized the lungs of recipient NOD-SCID interferon 2 receptor γ-deficient mice during the infusion of calcein-loaded CD34+-derived megakaryocytes. Infused human megakaryocytes were immediately arrested in the pulmonary bed in vessels ~50 µm in diameter. Each cell then extended several distinct protrusions winding down presumed pulmonary capillaries that are presumably wrapped around alveoli. Some of these protrusions reached 200-300 µm in length and assumed the appearance of beads on a string. Consistent with our recently published data, this thrombopoiesis process appears to take 30 minutes to be near-complete, similar to the timeframe we showed for detecting newly released human platelet-like particles after megakaryocyte infusion. At 30 minutes, remaining bodies of the megakaryocytes are still present and we presume these are mostly the remaining nuclei. To better define whether the pulmonary bed is unique for releasing platelets, we also infused megakaryocytes intra-arteriole rather than intravenously to have the megakaryocytes encounter other organ capillary beds before the lung. These studies showed poor platelet release compared to parallel studies in mice receiving the megakaryocytes intravenously. Many of the intra-arterial infused megakaryocytes were entrapped in the spleen and very few were notable in other organs, including the lungs, liver and kidney. Our studies showed that megakaryocytes can shed platelets in the lungs where they may take advantage of the unique three-dimensional organization of the pulmonary vascular bed, flow conditions, vascular surface receptors and glycocalyx as well as a sudden shift from hypoxic to normoxic conditions. Whether these features of the pulmonary vascular bed can be simulated ex vivo and whether this will enhance true platelet release from megakaryocytes in vitro needs to be examined. Disclosures No relevant conflicts of interest to declare.