Pulmonary arterial hypertension (PAH) is an obstructive pulmonary vasculopathy, characterized by excess proliferation, apoptosis-resistance, inflammation, fibrosis and vasoconstriction. While PAH therapies target some of these vascular abnormalities (primarily vasoconstriction) most do not directly benefit the right ventricle (RV). This is suboptimal since a patient’s functional state and prognosis are largely determined by the success of the adaptation of the RV to the increased afterload. The RV initially hypertrophies but may ultimately decompensate, becoming dilated, hypokinetic and fibrotic. A number of pathophysiologic abnormalities have been identified in the PAH RV, including: ischemia and hibernation (partially reflecting RV capillary rarefaction), autonomic activation (due to GRK2-mediated down-regulation and desensitization of β-adrenergic receptors), mitochondrial-metabolic abnormalities (notably increased uncoupled glycolysis and glutaminolysis), and fibrosis. Many RV abnormalities are detectable by molecular imaging and may serve as biomarkers. Some molecular pathways, such as those regulating angiogenesis, metabolism and mitochondrial dynamics, are similarly deranged in the RV and pulmonary vasculature, offering the possibility of therapies that treat both the RV and pulmonary circulation. An important paradigm in PAH is that the RV and pulmonary circulation constitute a unified cardiopulmonary unit. Clinical trials of PAH pharmacotherapies should assess both components of the cardiopulmonary unit.

The mammalian homeostatic oxygen sensing system (HOSS) initiates changes in vascular tone, respiration, and neurosecretion that optimize oxygen uptake and tissue oxygen delivery within seconds of detecting altered environmental or arterial PO2. The HOSS includes carotid body type 1 cells, adrenomedullary cells, neuroepithelial bodies, and smooth muscle cells (SMC) in pulmonary arteries (PA), ductus arteriosus (DA) and fetoplacental arteries. Hypoxic pulmonary vasoconstriction (HPV) optimises ventilation-perfusion matching. In utero, HPV diverts placentally-oxygenated blood from the non-ventilated lung through the DA. At birth, increased alveolar and arterial oxygen tension dilate the pulmonary vasculature and, constrict the DA, respectively, thereby transitioning the newborn to an air-breathing organism. Though modulated by endothelial-derived relaxing and constricting factors, O2-sensing is intrinsic to PA- and DASMCs. Within the SMC’s dynamic mitochondrial network, changes in PO2 alter the reduction-oxidation state of redox couples (NAD+/NADH, NADP+/NADPH) and the production of reactive oxygen species, ROS (e.g. H2O2) by Complexes I and III of the electron transport chain (ETC). ROS and redox couples regulate ion channels, transporters, and enzymes, changing intracellular calcium [Ca2+]i and calcium sensitivity and eliciting homeostatic responses to hypoxia. In PASMC, hypoxia inhibits ROS production and reduces redox couples, thereby inhibiting O2-sensitive voltage-gated potassium (Kv) channels, depolarizing the plasma membrane, activating voltage-gated calcium channels (CaL), increasing [Ca2+]i and causing vasoconstriction. In DASMC, elevated PO2 causes mitochondrial fission, increasing ETC Complex I activity and ROS production. The DASMC’s downstream response to elevated PO2 (Kv channel inhibition, CaL activation, increased [Ca2+]i and rho kinase activation) is similar to the PASMC’s hypoxic response. Impaired O2-sensing contributes to human diseases, including pulmonary arterial hypertension and patent DA.

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ContextPhosphate has gained recognition as a risk factor for adverse cardiovascular outcomes, potentially due to accelerated vascular calcification. Fibroblast growth factor-23 (FGF-23) is a counter-regulatory hormone that increases renal phosphate excretion to maintain normal levels.ObjectiveThe purpose of the study was to determine the association of phosphate and FGF-23 to atherosclerosis.Design and SettingA prospective cohort study (n = 204) of outpatients referred for coronary angiography over of a 1-year recruitment period at the Kingston General Hospital.InterventionBlood was collected, and a focused carotid ultrasound was performed.Main Outcome MeasureDegree of angiographic coronary artery disease was scored. Carotid maximum plaque height, total area, grayscale median, and tissue pixel distribution were measured. Plasma phosphate was assessed by mineral assay and FGF-23 by ELISA.ResultsCarotid plaque burden [total plaque area (TPA)] was associated with higher levels of phosphate (TPA, r = 0.20, P < 0.01) and FGF-23 (r = 0.19, P < 0.01). FGF-23 was associated with increased plaque % calcium-like tissue. Participants with no coronary artery disease had significantly lower phosphate levels. Phosphate was associated with higher grayscale median (GSM) in male subjects but with lower GSM in female subjects. FGF-23 was associated with increased plaque % fat in male subjects but increased plaque % calcium in female subjects.ConclusionsPhosphate was independently associated with the severity of atherosclerosis in terms of plaque burden and composition. FGF-23 was associated with plaque calcification. These findings suggest that abnormal phosphate homeostasis may play an under-recognized but potentially modifiable role in cardiovascular disease.

Background L-carnitine (L-C), a ubiquitous nutritional supplement, has been investigated as a potential therapy for cardiovascular disease, but its effects on human atherosclerosis are unknown. Clinical studies suggest improvement of some cardiovascular risk factors, whereas others show increased plasma levels of pro-atherogenic trimethylamine N-oxide. The primary aim was to determine whether L-C therapy led to progression or regression of carotid total plaque volume (TPV) in participants with metabolic syndrome (MetS). Methods This was a phase 2, prospective, double blinded, randomized, placebo-controlled, two-center trial. MetS was defined as ≥ 3/5 cardiac risk factors: elevated waist circumference; elevated triglycerides; reduced HDL-cholesterol; elevated blood pressure; elevated glucose or HbA1c; or on treatment. Participants with a baseline TPV ≥ 50 mm3 were randomized to placebo or 2 g L-C daily for 6 months. Results The primary outcome was the percent change in TPV over 6 months. In 157 participants (L-C N = 76, placebo N = 81), no difference in TPV change between arms was found. The L-C group had a greater increase in carotid atherosclerotic stenosis of 9.3% (p = 0.02) than the placebo group. There was a greater increase in total cholesterol and LDL-C levels in the L-C arm. Conclusions Though total carotid plaque volume did not change in MetS participants taking L-C over 6-months, there was a concerning progression of carotid plaque stenosis. The potential harm of L-C in MetS and its association with pro-atherogenic metabolites raises concerns for its further use as a potential therapy and its widespread availability as a nutritional supplement. Trial registration: ClinicalTrials.gov, NCT02117661, Registered April 21, 2014, https://clinicaltrials.gov/ct2/show/NCT02117661.

The ability of point-of-care ultrasound (POCUS) to provide rapid and accurate bedside assessment of both the heart and lungs allows it to be a powerful tool in the management of patients presenting with dyspnea. However, while ultrasound equipment is readily available even in remote healthcare settings in Canada, physicians lack effective training opportunities to develop expertise in this potentially life-saving skill. To answer this critical call to action, we have developed the Accelerated Remote Consultation Tele-POCUS in Cardiopulmonary Assessment (ARCTICA) program to innovate POCUS training for today’s physician leaders. This article outlines the background, research methods, and progress-to-date of ARCTICA.

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