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[Role of Ca2+ in hypoxic pulmonary vasoconstriction].
Wei, G, Cheng, Y, Huang, Y, He, Q
Zhonghua wei zhong bing ji jiu yi xue. 2019;(5):647-649
Abstract
In acute hypoxia, pulmonary vascular will contract and divert blood to better ventilated area to optimize ventilation/perfusion matching, which is known as hypoxic pulmonary vasoconstriction (HPV). In chronic hypoxia, irreversible pulmonary vascular remodeling can be induced, characterized by pulmonary artery middle smooth muscle cells and the outer fiber cell hyperplasia in luminal stenosis and pulmonary artery hypertension (PAH) eventually. Furthermore, PAH can cause increased ventricular afterload, and right heart failure in severe cases. Pulmonary artery smooth muscle cell (PASMC) elevated Ca2+ concentration is one of the most important factors of its contractions, proliferation and migration. Recent studies on Ca2+ promoting in HPV were summarized in order to provide evidence for clinical prevention of hypoxia and therapeutic PAH.
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Pulmonary artery perfusion versus no pulmonary per-fusion during cardiopulmonary bypass.
Buggeskov, KB
Danish medical journal. 2018;(3)
Abstract
During conventional cardiopulmonary bypass (CPB) there is no active perfusion of the pulmonary circulation and the mechanical ventilation is ceased leaving the lungs exposed to warm ischemia.
Pulmonary dysfunction is seen in varying degrees after major surgery, but more severe in cardiac surgery patients probably due to the effects of CPB. The evidence for effect and safety are limited, but active pulmonary artery perfusion during CPB could be beneficial for the patients' postoperative oxygenation.
Our aim was in a randomised clinical trial to assess primarily the effect of pulmonary artery perfusion during CPB on postoperative oxygenation in patients diagnosed with chronic obstructive pulmonary disease (COPD), secondarily to assess other possible benefits and harms. Furthermore, we wanted in a systematic review with meta-analyses of all randomised clinical trials to investigate the pooled effects of pulmonary artery perfusion during CPB.
We planned and conducted a randomised, partly blinded, clinical trial assigning cardiac surgery patients diagnosed with COPD to receive pulmonary artery perfusion with oxygenated blood or histidine-tryptophan-ketoglutarate (HTK) solution compared to no pulmonary perfusion during CPB. The primary outcome was the oxygenation index measured during and after surgery. Secondary outcomes were intubation time, serious adverse events, days alive outside the intensive care unit and outside the hospital, 30- and 90-days mortality.
Secondly, we conducted a systematic review of randomised clinical trials comparing benefits and harms of using pulmonary artery perfusion versus no pulmonary perfusion during CPB pooling results in meta-analyses and trial sequential analyses (TSA).
Of the 90 randomised patients 89 were included in analysis of the primary outcome, the inverse oxygenation index, measured at a single time point 21 hours after CPB start and longitudinally 1, 3, 5, 7, and 21 hours after CPB start. At 21 hours, patients randomised to pulmonary artery perfusion with oxygenated blood had a higher inverse oxygenation index compared to patients randomised to no pulmonary perfusion during CPB (mean difference (MD) 0.94; 95% confidence interval (CI), 0.05 to 1.83; P=0.04). The inverse oxygenation index was also significantly higher at 21 hours after CPB start (MD 0.99; CI, 0.29 to 1.69; P=0.007), and longitudinally (P=0.009), for patients receiving pulmonary artery perfusion with oxygenated blood compared to pulmonary artery perfusion with HTK solution. This corresponds to a PaO2 difference of 23 mmHg with a median FiO2 of 0.32. We found no additional significant differences for the remaining comparisons of the inverse oxygenation index neither for any of the secondary outcomes.
The systematic review identified 4 trials with a total of 210 patients. In meta-analyses pulmonary artery perfusion with blood versus no pulmonary perfusion during CPB was not associated with relative risk of death (1.7; 95% CI, 0.4 to 6.9; 210 patients in three trials with high and one trial with low risk of bias), serious adverse events (1.2; 95% CI, 0.8 to 1.8; 180 patients in two trials with high and one trial with low risk of bias) or intubation time (-0.4 hours; 95% CI, -1.1 to 0.4; 176 patients in three trials with high and one trial with low risk of bias). TSA on mortality, serious adverse events, and PaO2/FiO2 ratio showed that required information sizes have not been reached, but pulmonary artery perfusion with blood was associated with a higher PaO2/FiO2 ratio (27.8 mmHg; 95% CI, 5.7 to 50.0 mmHg; 119 patients in two trials with high and one trial with low risk of bias). TSA on intubation time showed that the boundary for lack of superiority (futility) was crossed refuting a shorten intubation time of 1.5 hours or more.
Our trial provided additional knowledge about the use of pulmonary artery perfusion during CPB in cardiac surgery patients with COPD, and improved oxygenation for patients receiving pulmonary artery perfusion with oxygenated blood. Pulmonary artery perfusion with HTK solution did not result in an improved oxygenation. In line with this, the systematic review including data from additional trials showed a possible association between pulmonary artery perfusion with blood and improved oxygenation, but no significant associations with mortality, serious adverse events or intubation time. However, all data are too sparse to be conclusive.
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3.
Review of the Ongoing Story of Appetite Suppressants, Serotonin Pathway, and Pulmonary Vascular Disease.
Bazan, IS, Fares, WH
The American journal of cardiology. 2016;(10):1691-1696
Abstract
Obesity is pandemic in the Western Hemisphere, especially in the United States (US) and is associated with morbidity and mortality. Recent data show that a large proportion of the US population is at least overweight and almost 2 in 5 Americans are obese. This ongoing trend of increasing obesity rates has led to a thriving market for anorexigens. Despite the health benefits of weight loss, several anorexigens had devastating side effects including pulmonary vascular disease which manifests as the clinical syndrome of pulmonary arterial hypertension (PAH). PAH is an incurable and fatal disease and is characterized by vascular constriction, hypertrophy, and proliferation that over time lead to right-sided cardiac failure. Over the past few decades, several weight loss medications have been associated with the development of PAH, possibly caused by an increase in systemic serotonin levels, resulting in vasoconstriction of the pulmonary arteries and initiating a cascade of pathologic vascular remodeling leading to vascular fibrosis. Once sufficient evidence for the association of these drugs with PAH or other related pathologies was found, many were removed from the market. However, there are other appetite suppressants still currently on the market (whether Food and Drug Administration-approved or "dietary supplements") that have to some extent similar mechanisms of action to those associated with PAH but lack robust enough data to prove or disprove an association. The serotonin pathway seems to be repeatedly implicated. In conclusion, given that PAH is a progressive and debilitating disease, it is important to highlight possible risk factors that could be avoided.
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Oral treprostinil diethanolamine for pulmonary arterial hypertension.
Feldman, J, Im, Y, Gill, K
Expert review of clinical pharmacology. 2015;(1):55-60
Abstract
The approval of oral treprostinil is a landmark event in the treatment of pulmonary arterial hypertension. Nineteen years after epoprostenol was approved we now have an oral prostanoid available in the USA. Although the current data in prostanoid naïve patients are unimpressive, emerging data suggest that in carefully selected patients oral treprostinil may be able to replace continuously infused treprostinil; however, many hurdles exist for this new medication including overcoming a complex side effect profile, astronomical cost and perhaps other entrants into the oral prostanoid space.
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Pulmonary arteriovenous malformations.
Shovlin, CL
American journal of respiratory and critical care medicine. 2014;(11):1217-28
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Abstract
Within the past decade, pulmonary arteriovenous malformations (PAVMs) have evolved from rare curiosities to not uncommon clinical states, with the latest estimates suggesting a prevalence of ~1 in 2,600. PAVMs provide anatomic right-to-left shunts, allowing systemic venous blood to bypass gas exchange and pulmonary capillary bed processing. Hypoxemia and enhanced ventilatory demands result, although both are usually asymptomatic. Paradoxical emboli lead to strokes and cerebral abscesses, and these commonly occur in individuals with previously undiagnosed PAVMs. PAVM hemorrhage is rare but is the main cause of maternal death in pregnancy. PAVM occlusion by embolization is the standard of care to reduce these risks. However, recent data demonstrate that currently recommended management protocols can result in levels of radiation exposure that would be classified as harmful. Recent publications also provide a better appreciation of the hematologic and cardiovascular demands required to maintain arterial oxygen content and oxygen consumption in hypoxemic patients, identify patient subgroups at higher risk of complications, and emphasize the proportion of radiologically visible PAVMs too small to treat by embolization. This review, therefore, outlines medical states that exacerbate the consequences of PAVMs. Chief among these is iron deficiency, which is commonly present due to concurrent hereditary hemorrhagic telangiectasia: iron deficiency impairs hypoxemia compensations by restricting erythropoiesis and increases the risk of ischemic strokes. Management of periodontal disease, dental interventions, pulmonary hypertension, and pregnancy also requires specific consideration in the setting of PAVMs. The review concludes by discussing to what extent previously recommended protocols may benefit from modification or revision.
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Assessment of pulmonary vasculature and right heart by invasive haemodynamics and echocardiography.
Hemnes, AR, Forfia, PR, Champion, HC
International journal of clinical practice. Supplement. 2009;(162):4-19
Abstract
Understanding the haemodynamical profile of the right ventricle and pulmonary circulation is critical to not only the initial evaluation of, but also the continued management of pulmonary hypertension. Despite advances in non-invasive imaging techniques, right heart catheterisation (RHC) remains the gold standard for diagnosis of pulmonary hypertension and its various causes. Even so, integration of invasive haemodynamical data with the echo-Doppler exam provides the most comprehensive assessment of the pathophysiology of pulmonary hypertension in the individual patient. Here, we review technical aspects of basic RHC as well as specialised procedures including exercise and fluid challenge in the evaluation of pulmonary hypertension. Interpretation of data in the context of pulmonary vascular disease is discussed. Echocardiographical assessment of the right ventricular structure and function in pulmonary vascular disease are discussed along with the integration of haemodynamical and echocardiographical data in the clinical context.
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Pulmonary arterial hypertension in adults with congenital heart disease: distinct differences from other causes of pulmonary arterial hypertension and management implications.
Dimopoulos, K, Giannakoulas, G, Wort, SJ, Gatzoulis, MA
Current opinion in cardiology. 2008;(6):545-54
Abstract
PURPOSE OF REVIEW To present the available data on pathophysiology, clinical presentation, prognosis, and especially management strategies for adult patients with congenital heart disease (CHD) and pulmonary arterial hypertension (PAH). Particular emphasis is placed on differences between other types of PAH and CHD-related PAH, in which clinical presentation and management relate to a constellation of factors, both pulmonary and cardiac. RECENT FINDINGS Pulmonary vascular disease in adults with CHD and especially its extreme expression, the Eisenmenger syndrome, is a chronic disease with slow progression, leading to multiorgan failure and death, decades after its first clinical presentation. In the last few years, oral advanced therapies for PAH have emerged and are considered for mono or combination therapy for CHD, though the evidence is limited. Supportive care and prevention of complications seem to be at least as important in the overall care of these patients. SUMMARY Although new advanced therapies hold promise in PAH secondary to CHD, long-term data are clearly needed. Advanced therapies should be considered when other causes of functional limitation, such as iron deficiency, have been first addressed. Expertise in CHD as well as PAH is essential for providing adequate care for this patient group with a unique pathophysiology.
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High altitude pulmonary hypertension: role of K+ and Ca2+ channels.
Remillard, CV, Yuan, JX
High altitude medicine & biology. 2005;(2):133-46
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Abstract
Global alveolar hypoxia, as experienced at high-altitude living, has a serious impact on vascular physiology, particularly on the pulmonary vasculature. The effects of sustained hypoxia on pulmonary arteries include sustained vasoconstriction and enhanced medial hypertrophy. As the major component of the vascular media, pulmonary artery smooth muscle cells (PASMC) are the main effectors of the physiological response(s) induced during or following hypoxic exposure. Endothelial cells, on the other hand, can sense humoral and hemodynamic changes incurred by hypoxia, triggering their production of vasoactive and mitogenic factors that then alter PASMC function and growth. Transmembrane ion flux through channels in the plasma membrane not only modulates excitation- contraction coupling in PASMC, but also regulates cell volume, apoptosis, and proliferation. In this review, we examine the roles of K+ and Ca2+ channels in the pulmonary vasoconstriction and vascular remodeling observed during chronic hypoxia-induced pulmonary hypertension.
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Comparative analysis of clinical trials and evidence-based treatment algorithm in pulmonary arterial hypertension.
Galiè, N, Seeger, W, Naeije, R, Simonneau, G, Rubin, LJ
Journal of the American College of Cardiology. 2004;(12 Suppl S):81S-88S
Abstract
The numerous controlled clinical trials performed recently in pulmonary arterial hypertension (PAH) can allow us to abandon a clinical-based treatment strategy and adopt an evidence-based therapy. Both uncontrolled and controlled clinical trials with different compounds and procedures are reviewed and compared in order to define the efficacy-to-side-effect ratio of each treatment. A grading system for the level of evidence of treatments based on the number of favorable controlled clinical trials performed with a given compound is adopted; a treatment algorithm based on the evidence derived by clinical trials is proposed. It includes drugs approved by regulatory agencies for the treatment of patients with PAH and/or drugs available on the market for other indications. The algorithm is restricted to patients in New York Heart Association (NYHA) functional class III or IV because they represent the largest population included in controlled clinical trials. In addition, the different treatments have been evaluated mainly in sporadic, idiopathic PAH and in PAH associated with scleroderma or to anorexigen use. Extrapolation of these recommendations to the other PAH subgroups should be done with caution. Oral anticoagulation is proposed for all patients, whereas diuretic treatment and supplemental oxygen are indicated in cases of fluid retention and hypoxemia, respectively. High doses of calcium channel blockers are indicated only in the minority of patients who are responders to acute vasoreactivity testing. Nonresponders to acute vasoreactivity testing, or responders who remain in NYHA functional class III, should be considered candidates for treatment with either an endothelin receptor antagonist or a prostanoid. Continuous intravenous administration of epoprostenol is proposed as rescue treatment in NYHA functional class IV patients. Phosphodiesterase-V inhibitors should be considered in patients who have failed or are not candidates to other therapies. Combination therapy can be attempted in selected cases. Both balloon atrial septostomy and lung transplantation are indicated for refractory patients or where medical treatment is unavailable.