Increase In Vascular Resistance Research Articles

MYOCARDITIS, CORONARY ARTERY DISSECTION OR BOTH: A JUVENILE ENIGMA

Abstract A 26–year–old man was admitted to the Coronary Care Unit for severe, non–irradiated, oppressive anterothoracic pain. He had no relevant pathological history, but reported an episode of gastroenteritis the week before. EKG showed sinus rhythm and accelerated idioventricular rhythm phases. Blood pressure and 2D echo were normal. Inflammation indeces were negative, hsTnT reached a peak of 2026 ng/L. Despite the absence of inflammation signs, our first guess was myocarditis. Cardiac magnetic resonance (CMR) was performed: T2w–STIR images showed edema of the middle inferior wall and of the mid–basal anterior and anterolateral wall, while T1–weighted post gadolinium images showed transmural enhancement of the mid–basal anterior, antero lateral and inferior walls with a dubious origin from the sub endocardium in the anterior and anterolateral segments; LVEF was 55%. Invasive coronary angiography (ICA) was performed to rule out ischemic etiology: LAD showed a very thin lumen in its periphery and two obtuse marginal branches had an amputated appearance: it made us think of healing dissections. Then it turned out that the patient have been working out with heavy weights the day before: we therefore considered spontaneous coronary artery dissection. Such hypothesis was consistent with the absence of inflammations indices, but didn’t explain the basal and middle inferior involvement that CMR had shown. On the other hand, the angiographic finding may be consistent with peripheral vascular suffering linked to myocarditis induced inflammation. To date, we haven’t found univocal interpretation. Anti–remodeling therapy with IACE and beta blockers was administered, in addition to acetylsalicylic acid. CMR will be performed in two months and may provide further results once the edema will be reabsorbed. ICA will be repeated to make sure that distal coronary blood flow is improved. Take Home Messages Myocarditis can also occur with no signs of inflammation. In myocarditis it has been demonstrated that slower distal coronary blood flow may occur, due to the increase in peripheral vascular resistance linked to the presence of edema. In the acute phase, especially if CMR is performed very early, the large amount of edema can make the enhancement transmural, masking the site of origin of the damage.

Consensus on the procedure of balloon pulmonary angioplasty for chronic thromboembolic pulmonary hypertension

Chronic thromboembolic pulmonary hypertension (CTEPH) is classified as group IV pulmonary hypertension, characterized by thrombotic occlusion of the pulmonary arteries leading to vascular stenosis or obstruction, progressive increase in pulmonary vascular resistance and pulmonary arterial pressure, and eventual right heart failure. Unlike other types of pulmonary hypertension, the prognosis of CTEPH can be significantly improved by surgery, vascular intervention, and/or targeted drug therapy. Pulmonary endarterectomy (PEA) is the preferred treatment of choice for CTEPH. However, PEA is an invasive procedure with high operative risks, and is currently only performed in a few centers in China. Balloon pulmonary angioplasty (BPA) is an emerging interventional technique for CTEPH, serving as an alternative for patients who are ineligible for PEA or with residual pulmonary hypertension after PEA. BPA is gaining traction in China, but its widespread adoption is limited due to its complexity, operator skills, and equipment requirements, a lack of standard operating procedures and technical guidance, which limit the further improvement and development of BPA in China. To address this, a multidisciplinary panel of experts was convened to develop the Consensus on the Procedure of Balloon Pulmonary Angioplasty for the Chronic Thromboembolic Pulmonary Hypertension, which fomulates guidelines on BPA procedural qualification, perioperative management, procedural planning, technical approach, and complication prevention, with the aim of providing recommendations and clinical guidance for BPA treatment in CTEPH and standardizing its clinical application in this setting. Summary of recommendations: Recommendation 1: It is recommended that physicians who specialize in pulmonary vascular diseases take the lead in formulating the diagnostic and treatment plans for CTEPH, using a multidisciplinary approach.Recommendation 2: Training in BPA technique is critical; novice operators should undergo standardized operative training with at least 50 procedures under the guidance of experienced physicians before embarking on independent BPA procedures.Recommendation 3: BPA requires catheterization labs, angiography systems, standard vascular interventional devices and consumables, drugs, and emergency equipment.Recommendation 4: Patient selection for BPA should consider cardiac and pulmonary function, coagulation status, and comorbid conditions to determine indications and contraindications, thereby optimizing the timing of the procedure and improving safety.Recommendation 5: In experienced centers, patients deemed likely to benefit from early BPA, based on clinical and imaging features of CTEPH and without elevated D-dimer levels, could bypass standard 3-month anticoagulation therapy.Recommendation 6: BPA is a complex interventional treatment that requires thorough pre-operative assessment and preparation.Recommendation 7: The use of perioperative anticoagulants in BPA requires a comprehensive risk assessment of intraoperative bleeding by the operator for individualized decision making.Recommendation 8: A variety of venous access routes are available for BPA; unless contraindicated, the right femoral vein is usually preferred because of its procedural convenience and reduced radiation exposure.Recommendation 9: For the different types of vascular lesion in CTEPH, treatment of ring-like stenoses, web-like lesions, and subtotal occlusions should be prioritized before addressing complete occlusions and tortuous lesions, in order to reduce complications and improve procedural safety.Recommendation 10: A targeted, incremental balloon dilatation strategy based on vascular lesions is recommended for BPA.Recommendation 11: Intravascular pulmonary artery imaging technologies, such as OCT and IVUS can assist in accurate vessel sizing and confirmation of wire placement in the true vascular lumen. Pressure wires can be used to objectively assess the efficacy of dilatation during BPA.Recommendation 12: Endpoints for BPA treatment should be individually assessed, taking into account improvements in clinical symptoms, hemodynamics, exercise tolerance, and quality of life.Recommendation 13: Post-BPA routine monitoring of vital signs is essential; anticoagulation therapy should be initiated promptly post-procedure in the absence of complications. In cases of intraoperative hemoptysis, postoperative anticoagulation regimen adjustments should be adjusted according to the bleeding severity.Recommendation 14: If reperfusion pulmonary edema occurs during or after BPA, ensure adequate oxygenation, diuresis, and consider non-invasive positive-pressure ventilation if necessary, while severe cases may require early mechanical ventilation assistance or ECMO.Recommendation 15: In cases of intraoperative hemoptysis, temporary balloon occlusion to stop bleeding is recommended, along with protamine to neutralize heparin. Persistent bleeding may warrant the use of gelatin sponges, coil embolization, or covered stent implantation.Recommendation 16: For contrast imaging during BPA, non-ionic, low or iso-osmolar contrast agents are recommended, with hydration status determined by the patient's clinical condition, cardiac and renal function, and intraoperative contrast volume used.

Management of Pregnant Women with Atrial Septal Defect and Pulmonary Hypertension: A Case Report

Background: Pulmonary Hypertension (PH) is a condition where there is an increase in Pulmonary Vascular Resistance (PVR) and an increase in the mean Pulmonary Arterial Pressure (mPAP) to more than 20 mmHg. PH can occur in someone with Congenital Heart Disease (CHD). PH conditions can aggravate pregnancy in women with CHD. Women with PH are recommended not to undergo pregnancy. However, it is possible for women with CHD with PH conditions to undergo pregnancy. In these conditions, optimizing PH therapy is essential so that pregnant women with PH do not experience a worsening of the condition and can carry out their pregnancy well until delivery. Case presentation: A 38-year-old female patient with a history of Atrial Septal Defect-Pulmonary Hypertension came for common control to the cardiac clinic with the pregnancy condition of her 4th child, who was just discovered when she was six months pregnant. Since giving birth to her third child, the patient began complaining of being quickly tired when doing activities accompanied by swollen legs that disappeared with rest. The patient went to a cardiologist for an echocardiography examination and was diagnosed with Atrial Septal Defect (ASD)-Pulmonary Hypertension (PH). Since then, the patient has been routinely treated by a cardiologist with Pulmonary Hypertension drugs, including Phospodiesterase5 (PDE5) inhibitors (Sildenafil) and Prostacyclin Analogue (Dorner). The patient had done Transesophageal Echocardiography (TEE) with the results of ASD secundum suitable for closure by the device. Patients with Right Heart Catheterization (RHC) results, ASD secundum with PH High Flow High Resistance reactive to Vasoreactivity Test. Since the patient was found to be pregnant, the patient continued to use Sildenafil and discontinued the use of Dorner. The patient then continued treatment in a multidisciplinary team. Conclusion: Management of pregnant women with CHD and PH is essential because the condition of PH itself further aggravates the condition of pregnancy. Medical management for PH in pregnant women follows the guidelines for the safety of drugs in pregnancy so that the choice of therapy is crucially related to the goal of treatment to control the PH condition in the patient but still pay attention to safety in pregnancy conditions. Keyword: Congenital Heart Disease, Phosphodiesterase-5 (PDE-5)- Inhibitor, Prostacyclin Analogue, Pulmonary Hypertension.

Clinical Features and Multimodality Diagnostic Tools of Pulmonary Hypertension

Pulmonary hypertension (PH) is defined as an increase in mean pulmonary arterial pressure (mPAP) above normal (> 20 mmHg) and an increase in pulmonary vascular resistance (pulmonary vascular resistance / PVR) above normal in resting settings. The pathophysiology of PH involves remodeling of the pulmonary vessels, from the main pulmonary arteries, lobar arteries, segmental arteries, distal arteries, pulmonary arterioles, capillaries to the postcapillary pulmonary veins. In general, the epidemiological figures for PH are not known with certainty. The United Kingdom reported a PH prevalence of 97 cases per one million people, with a female-to-male ratio of 1.8. The diagnostic strategy for PH focuses primarily on two issues. The primary objective is to improve the early detection of PH and expedite the transfer of patients at high risk for PAH, CTEPH, or other forms of severe PH to a PH center. The second objective is to identify the underlying disease, including left heart disease (Group 2 PH) and lung disease (Group 3 PH), as well as comorbidities, in order to assure proper classification, risk assessment, and therapy. The gold standard for detecting and categorizing pulmonary hypertension is right heart catheterization (RHC). Clinical scoring in the form of shortness of breath without any obvious cause accompanied by physical examination, ECG and Thorax X-ray images which depict an enlarged right heart have good specificity and sensitivity for the diagnosis of pulmonary hypertension in patients with congenital heart disease. A high right ventricular pressure, mean PAP, and BNP values during observation, as well as heart size on chest X-ray can be predictors of a poorer prognosis in this population. Keyword: Clinical Risk Scoring, Pulmonary Hypertension, Right Heart Catheterization.

Indicators of intracardiac haemodynamics in patients with chronic coronary syndrome with concomitant coronavirus disease (COVID-19)

the nature of cardiovascular damage caused by SARS-CoV-2 coronavirus infection due to acute severe respiratory distress syndrome is associated with high mortality. However, the pathophysiological impact of COVID-19 (C19) on intracardiac haemodynamics remains unknown. The aim of our study was to evaluate intracardiac haemodynamics in patients with chronic coronary syndrome (CCS) in combination with coronavirus disease (COVID-19). The prospective study included: 30 patients with CAD with a negative PCR test for COVID-19 (1Agroup), 38 patients with CAD with a positive PCR test for COVID-19 (1Bgroup), of whom 12 were diagnosed with an increase in the level of troponin I (1B/T+), 26 patients had a normal level of troponin I (1B/T-). As a comparison, 30 patients with COVID-19 with PCR(+), without signs of CAD - group 2, as well as 30 healthy volunteers without signs of CAD and with negative PCR were studied. Clinical and laboratory data, treatment, and intracardiac haemodynamics were assessed by echocardiography in all groups. The left ventricular myocardial mass index, left ventricular end-diastolic volume, right ventricular size, and pulmonary artery systolic pressure were highest in the group of CAD with COVID-19 with a positive troponin test (1B/T+), compared with the (1B/T-) group, also in the (1B/T+) group, the ejection fraction and total longitudinal strain by speckle tracking were lower than in the (1B/T-) group. When compared with group 1A, LVEF was lower in the (1B/T+) group, and STla was higher in the (1B/T+) group. When comparing the indicators of group 1A and (1B/T-), a similar pattern of changes in intracardiac haemodynamics was noted: LV myocardial mass index, right ventricular diameter, systolic pressure in the pulmonary artery were higher, while longitudinal strain was slightly lower in (1B/T-) than in group 1A. When comparing the echocardiography parameters of patients in the (1B/T+) subgroup with group 2, larger left ventricular end-diastolic volume, left atrium, left ventricular myocardial mass index were found in (1B/T+), but the ejection fraction was lower in (1B/T+), while the right ventricular size and pulmonary artery systolic pressure were slightly higher than in group 2. In the subgroup (1B/T-), the nature of the changes was similar, but the size of the RV and PASP did not differ from those in group 2. The echocardiographic parameters of group 1A differed from those of group 2 by higher values of LVEF, LVEDV, LVMMS and lower EF, but the size of the RV and PASP were larger in patients with COVID-19. Cardiac damage associated with SARS-CoV-2 in patients with concomitant CAD has an effect on the myocardium, which is manifested in an increase in left ventricular EF due to increased preload, at the expense of a decrease in global strain and systolic function of the LV myocardium, due to the direct cytotoxic effect of SARS-CoV-2 on the one hand, and destabilisation of existing atherosclerotic plaques, as well as hypoxia and worsening of endothelial dysfunction on the other. An increase in the size of the right ventricle is associated with an increase in peripheral vascular resistance in the small circle as a consequence of increased systolic pressure in the pulmonary artery in covidassociated pneumonia. The impact of SARS-CoV-2 infection on the heart is associated with cardiovascular risk factors and the severity of the inflammatory process.

Basic aspects of pathophysiology, diagnosis and treatment of patients with pulmonary arterial hypertension associated with human immunodeficiency virus infection: what has been achieved and what remains to be achieved?

Human immunodeficiency virus (HIV) infection is characterized by high morbidity and is a significant threat to human health, increasing global mortality. The number of people living with HIV infection is estimated by the United Nations Joint Program on Human Immunodeficiency Virus/Acquired Immune Deficiency Syndrome (UNAIDS) to be 39 million (33.1-45.7 million) in 2022. With the introduction of highly effective antiretroviral therapy (cART) into clinical practice and the resulting increase in life expectancy in this cohort of patients, HIV-associated complications have come to the forefront, among which the most severe is pulmonary arterial hypertension (PAH), characterized by a progressive increase in pulmonary vascular resistance and pulmonary artery pressure, leading to the development of right ventricular failure. Subsequently, it became evident that this pathology can occur at all stages of HIV infection and, apparently, has no clear relationship with the degree of immunodeficiency, and is an independent predictor of mortality in patients with LAH-HIV, and therefore requires separate, close attention. This article provides an overview covering the basic pathophysiology, clinical manifestations, diagnosis and treatment of HIV-associated LAH (LAHHIV), emphasizing the challenges encountered at each stage. The review also considers current aspects aimed at studying LAH in patients with HIV, including new experimental drug therapies that take into account the interaction of different regimens with LAH-specific drugs.

The place of tadalafil in the treatment of PAH in the light of new clinical guidelines of the Eurasian Association of Cardiologists

Pulmonaryarterialhypertension(PAH)isalife-threateningcardiovascular disease that is characterized by a marked increase in pulmonary vascular resistance and pulmonary artery pressure due to obstructive remodeling of the pulmonary vascular bed with the development of right ventricular heart failure as a cause of premature mortality. Impaired synthesis and reduced bioavailability of nitric oxide is one of the key pathophysiological mechanisms of the development and progression of the disease. The review paper presents key data from the evidence base on the clinical use of tadalafil, a phosphodiesterase type 5 inhibitor (PDE5), which in August 2023 approved by the Pharmaceutical Committee of the Russian Ministry of Health for the indication – treatment of patients with PAH. Tadacardil from Canonpharma Production is the first and only drug in Russian practice today with the active substance tadalafil with the registered indication “PAH”, approved in the Eurasian Guidelines for the diagnosis and treatment of pulmonary hypertension 2023 and available on the territory of the Russian Federation and the EAEU. Tadacardil is indicated for use in adult patients with PAH functional class II and III according to the WHO classification to increase exercise tolerance. The efficacy of tadalafil has been shown in idiopathic PAH and PAH associated with connective tissue diseases. The recommended dose is 40 mg (2 tablets of 20 mg) once a day. The paper describes the mechanism of action and pharmacological effects of PDE5 inhibitors, features of the pharmacokinetics of tadalafil in comparison with other drugs of the class. The advantages of Tadacardil from Canonpharma Production are the proven effecacy of use in patients with PAH, ease of use due to a single dose of 2 tablets of 20 mg once a day in a standard dose; good tolerability and favorable safety profile; proven bioequivalence to the reference drug. In light of the new Eurasian recommendations for the diagnosis and treatment of PH, tadalafil has a wide field for clinical use, which will improve the treatment options for patients with PAH both in mono- and combination therapy.

ANMCO/SIC Consensus statement on pulmonary arterial hypertension

Pulmonary hypertension (PH) is a frequent pathological condition worldwide, mainly secondary to cardiovascular and respiratory diseases, with a poor prognosis. Pulmonary arterial hypertension (PAH) is a rare form that affects the arterial pulmonary vasculature. PH and PAH are characterized by non-specific symptoms and a progressive increase of pulmonary vascular resistance that results in progressive, sometimes irreversible, right ventricular dysfunction. In recent years, a growing medical and social commitment on this disease allowed more accurate diagnosis in shorter times. However, the gap between guidelines and clinical practice remains a challenge for all medical doctors involved in the disease management. Considering the needs to share and describe diagnostic and therapeutic pathways, to measure the results obtained and to address the economical and organizational problems of this disease, all involved figures should collaborate to improve its prognostic impact and health expenses. In this consensus document, the PH experts of the Italian Association of Hospital Cardiologists (ANMCO) together with those of the Italian Society of Cardiology (SIC), address 1) definition, classification and unmet needs of PH and PAH; 2) classification and characteristics of centers involved in the diagnosis and treatment of the disease; 3) proposal of organization of a diagnostic-therapeutic pathway, based on robust and recent scientific evidence.

Use of sildenafil for the treatment of neonatal persistent pulmonary hypertension

Introduction: Persistent pulmonary hypertension of the newborn is a neonatal respiratory and vascular pathology with a high mortality rate. Furthermore, its prevalence is 1 to 2 per 1000 live births, accounting for 8%-10% of neonatal deaths. The therapeutic approach involves supporting pulmonary recruitment and pharmacological vasodilation, most notably sildenafil. Methodology: The study is a narrative review of the literature that was carried out from the PUBMED database using the keywords “Persistent Pulmonary Hypertension of the Newborn” and “Sildenafil”, with the time filter in the last 30 years (1994- 2023). Discussion: Physiologically, during fetal life, the lungs remain filled with fluids, but immediately after birth, pulmonary vascular resistance decreases drastically, allowing alveolar oxygen tension and ventilation to be possible. However, in the pathogenesis of neonatal persistent pulmonary hypertension, there is an increase in pulmonary vascular resistance and remodeling of the vascular structure after birth, which potentiate this exaggerated vasoconstriction. Therefore, the standard exam for investigating the pathology is echocardiography. Sildenafil is a drug used to treat neonatal persistent pulmonary hypertension, as it enhances better blood flow and better delivery of oxygen to tissues, through its physiopharmacology aimed at vasodilation secondary to inhibition of phosphodiesterase-5. Conclusion: Neonatal persistent pulmonary hypertension is still one of the main neonatal pathologies with high morbidity and mortality in the neonatal population, due to the complexity of presentations and the variation in therapeutic responses to pharmacotherapy.

Inhaled Pulmonary Vasodilators for the Treatment of Right Ventricular Failure in Cardio-Thoracic Surgery: Is One Better than the Others?

Right ventricular failure (RFV) is a potential complication following cardio-thoracic surgery, with an incidence ranging from 0.1% to 30%. The increase in pulmonary vascular resistance (PVR) is one of the main triggers of perioperative RVF. Inhaled pulmonary vasodilators (IPVs) can reduce PVR and improve right ventricular function with minimal systemic effects. This narrative review aims to assess the efficacy of inhaled nitric oxide and inhaled prostacyclins for the treatment of perioperative RVF. The literature, although statistically limited, supports the clinical similarity between them. However, it failed to demonstrate a clear benefit from the pre-emptive use of inhaled nitric oxide in patients undergoing left ventricular assist device implantation or early administration during heart-lung transplants. Additional concerns are related to cost safety and IPV use in pathologies associated with pulmonary venous congestion. The largest ongoing randomized controlled trial on adults (INSPIRE-FLO) is addressing whether inhaled Epoprostenol and inhaled nitric oxide are similar in preventing RVF after heart transplants and left ventricular assist device placement, and whether they are similar in preventing primary graft dysfunction after lung transplants. The preliminary analysis supports their equivalence. Several key points may be achieved by the present narrative review. When RVF occurs in the setting of elevated PVR, IPV should be the preferred initial treatment and they should be preventively used in patients at high risk of postoperative RVF. If severe refractory postoperative RVF occurs, IPVs should be combined with complementary pharmacology (inotropes and inodilators). If unsuccessful, right ventricular mechanical support should be established.

Primary Role of the Kidney in Pathogenesis of Hypertension.

Previous transplantation studies and the concept of 'nephron underdosing' support the idea that the kidney plays a crucial role in the development of essential hypertension. This suggests that there are genetic factors in the kidney that can either elevate or decrease blood pressure. The kidney normally maintains arterial pressure within a narrow range by employing the mechanism of pressure-natriuresis. Hypertension is induced when the pressure-natriuresis mechanism fails due to both subtle and overt kidney abnormalities. The inheritance of hypertension is believed to be polygenic, and essential hypertension may result from a combination of genetic variants that code for renal tubular sodium transporters or proteins involved in regulatory pathways. The renin-angiotensin-aldosterone system (RAAS) and sympathetic nervous system (SNS) are the major regulators of renal sodium reabsorption. Hyperactivity of either the RAAS or SNS leads to a rightward shift in the pressure-natriuresis curve. In other words, hypertension is induced when the activity of RAAS and SNS is not suppressed despite increased salt intake. Sodium overload, caused by increased intake and/or reduced renal excretion, not only leads to an expansion of plasma volume but also to an increase in systemic vascular resistance. Endothelial dysfunction is caused by an increased intracellular Na+ concentration, which inhibits endothelial nitric oxide (NO) synthase and reduces NO production. The stiffness of vascular smooth muscle cells is increased by the accumulation of intracellular Na+ and subsequent elevation of cytoplasmic Ca++ concentration. In contrast to the hemodynamic effects of osmotically active Na+, osmotically inactive Na+ stimulates immune cells and produces proinflammatory cytokines, which contribute to hypertension. When this occurs in the gut, the microbiota may become imbalanced, leading to intestinal inflammation and systemic hypertension. In conclusion, the primary cause of hypertension is sodium overload resulting from kidney dysregulation.

Beta-adrenergic blockade increases pulmonary vascular resistance and causes exaggerated hypoxic pulmonary vasoconstriction at high altitude: a physiological study.

An increasing number of hypertensive persons travel to high altitude while using antihypertensive medications such as betablockers. Nevertheless, while hypoxic exposure initiates an increase in pulmonary artery pressure (Ppa) and pulmonary vascular resistance (PVR), the contribution of the autonomic nervous system is unclear. In animals, β-adrenergic blockade has induced pulmonary vasoconstriction in normoxia and exaggerated hypoxic pulmonary vasoconstriction (HPV) and both effects were abolished by muscarinic blockade. We thus hypothesized that in humans propranolol (PROP) increases Ppa and PVR in normoxia and exaggerates HPV, and that these effects of PROP are abolished by glycopyrrolate (GLYC). In seven healthy male lowlanders, pulmonary artery pressure was invasively measured without medication, with PROP and PROP+GLYC, both at sea level (SL, 488m) and after a three-week sojourn at 3454m altitude (HA). Bilateral thigh-cuff release maneuvers were performed to derive pulmonary pressure-flow relationships and pulmonary vessel distensibility. At SL, PROP increased Ppa and PVR from (mean±SEM) 14±1 to 17±1mmHg and from 69±8 to 108±11dyn*s*cm-5 (21 and 57% increase, p=0.01 and p<0.0001). The PVR response to PROP was amplified at HA to 76% (p<0.0001, p[interaction]=0.05). At both altitudes, PROP+GLYC abolished the effect of PROP on Ppa and PVR. Pulmonary vessel distensibility decreased from 2.9±0.5 to 1.7±0.2 at HA (p<0.0001) and to 1.2±0.2 with PROP, and further decreased to 0.9±0.2%*mmHg-1 with PROP+GLYC (p=0.01). Our data show that β-adrenergic blockade increases, and muscarinic blockade decreases PVR, whereas both increase pulmonary artery elastance. Future studies may confirm potential implications from the finding that β-adrenergic blockade exaggerates HPV for the management of mountaineers using β-blockers for prevention or treatment of cardiovascular conditions.

Calcineurin inhibition, cardiovascular consequences, vascular resistance, and potential responses.

To place the consequences of calcineurin inhibition in a cardiovascular context. Literature review coupled with personal encounters. Calcineurin is a calcium-binding and calmodulin-binding protein that is conserved across evolution from yeast to mammals. The enzyme functions as a calcium-dependent, calmodulin-stimulated protein phosphatase. Its role in regulating physiology has largely been elucidated by observing calcineurin inhibition. Calcineurin inhibition transformed organ transplantation from an experiment into a therapy and made much of general immunotherapy possible. The function of this phosphatase and how its inhibition leads to toxicity concern us to this date. Initial research from patients and animal models implicated a panoply of factors contributing to hypertension and vasculopathy. Subsequently, the role of calcineurin in regulating the effective fluid volume, sodium reabsorption, and potassium and hydrogen ion excretion was elucidated by investigating calcineurin inhibition. Understanding the regulatory effects of calcineurin on endothelial and vascular smooth muscle cell function has also made substantial progress. However, precisely how the increase in systemic vascular resistance arises requires further mechanistic research. Calcineurin inhibition continues to save lives; however, options to counteract the negative effects of calcineurin inhibition should be vigorously pursued.

Hypohydration attenuates increases in creatinine clearance to oral protein loading and the renal hemodynamic response to exercise pressor reflex.

Insufficient hydration is prevalent among free living adults. This study investigated whether hypohydration alters 1) renal functional reserve, 2) the renal hemodynamic response to the exercise pressor reflex, and 3) urine-concentrating ability during oral protein loading. In a block-randomized crossover design, 22 healthy young adults (11 females and 11 males) underwent 24-h fluid deprivation (Hypohydrated) or 24-h normal fluid consumption (Euhydrated). Renal functional reserve was assessed by oral protein loading. Renal hemodynamics during the exercise pressor reflex were assessed via Doppler ultrasound. Urine-concentrating ability was assessed via free water clearance. Creatinine clearance did not differ at 150 min postprotein consumption between conditions [Hypohydrated: 246 mL/min, 95% confidence interval (CI): 212-280; Euhydrated: 231 mL/min, 95% CI: 196-265, P = 0.2691] despite an elevated baseline in Hypohydrated (261 mL/min, 95% CI: 218-303 vs. 143 mL/min, 95% CI: 118-168, P < 0.0001). Renal artery vascular resistance was not different at baseline (P = 0.9290), but increases were attenuated in Hypohydrated versus Euhydrated at the end of handgrip (0.5 mmHg/cm/s, 95% CI: 0.4-0.7 vs. 0.8 mmHg/cm/s 95% CI: 0.6-1.1, P = 0.0203) and end occlusion (0.2 mmHg/cm/s, 95% CI: 0.1-0.3 vs. 0.4 mmHg/cm/s 95% CI: 0.3-0.6, P = 0.0127). There were no differences between conditions in free water clearance at 150 min postprotein (P = 0.3489). These data indicate that hypohydration 1) engages renal functional reserve and attenuates the ability to further increase creatinine clearance, 2) attenuates increases in renal artery vascular resistance to the exercise pressor reflex, and 3) does not further enhance nor impair urine-concentrating ability during oral protein loading.NEW & NOTEWORTHY Insufficient hydration is prevalent among free living adults. This study found that hypohydration induced by 24-h fluid deprivation engaged renal functional reserve and that oral protein loading did not further increase creatinine clearance. Hypohydration also attenuated the ability to increase renal vascular resistance during the exercise pressor reflex. In addition, hypohydration neither enhanced nor impaired urine-concentrating ability during oral protein loading. These data support the importance of mitigating hypohydration in free living adults.

Особливості гемодинаміки в системі «мати-плацента-плід» у жінок, які мали ускладнення з групи великих акушерських синдромів, що клінічно проявлялися плацентарною недостатністю

Purpose - to study the features of hemodynamics in the mother-placenta-fetus system during pregnancy in women who had complications from the group of major obstetric syndromes (MOS), clinically manifested by placental insufficiency. Materials and methods. A prospective analysis of ultrasound examination of blood circulation in the mother-placenta-fetus system during pregnancy in 99 pregnant women with complications from the group of MOS - placental insufficiency - was performed. These women constituted the Main group (MG). The Control group (CG) included 50 practically healthy pregnant women with a good reproductive history and an uncomplicated pregnancy. Statistical processing of research results was carried out using standard Microsoft Excel 5.0 and Statistica 6.0 programs. Results. The study revealed an increase in all vascular resistance indices. An increase in the vascular resistance index is associated with an increase in peripheral vascular resistance and a decrease in diastolic blood flow, which, in turn, is due to a decrease in vascularisation of the terminal villi as a morphological and functional manifestation of placental insufficiency after 35 weeks of pregnancy: the resistance index in the umbilical cord artery was 0.71±0.02 in the MG versus 0.48±0.07 in the CG (p&gt;0.05).In the study, the indices of vascular resistance in the fetal aorta increased: the resistance index was 0.74±0.05 in the MG vs. 0.44±0.55 in the CG (p&lt;0.05) and at 22-27 weeks of pregnancy 0.98±0.06 in the MG vs. 0.50±0.40 in the CG (p&lt;0.05). It was found that 69 (69.7%) pregnant women in the MG had hemodynamic disorders: 39 (39.4%) patients had uteroplacental circulation disorders with preserved fetal-placental circulation; 23 (23.2%) pregnant women had fetal-placental circulation disorders with preserved uteroplacental circulation; 7 (7.1%) pregnant women had simultaneous uteroplacental and fetal-placental circulation disorders. Conclusions. Dynamic ultrasound monitoring of the functional state of the fetoplacental complex in women with MOS revealed that from the early stages of gestation, there is a violation of placentogenesis, which is accompanied by functional failure of the fetoplacental complex and leads to early exhaustion of the compensatory capabilities of the fetoplacental system. The study was conducted in accordance with the principles of the Declaration of Helsinki. The study protocol was approved by the Local Ethics Committee of the institution mentioned in the paper. Women's informed consent was obtained for the study. No conflict of interests was declared by the author.

STUDY OF RISK FACTORS FOR CARDIOVASCULAR DISEASES AND CENTRAL HEMODYNAMICS IN SENIOR STUDENTS

HighlightsThe article examines the prevalence of risk factors for cardiovascular diseases (CVD) and the state of central hemodynamics (CHD) in senior students. Aim. To study the risk factors for CHD and CVD in senior students with the aim of early detection of arterial hypertension (AH) and the implementation of therapeutic and prophylactic measures.Methods. The study involved 223 senior students of medical universities in Moscow aged 20-27 years (the mean age was 22.8±0.17 years). The following cardiovascular risk factors were assessed for each student: age, gender, smoking, physical activity, genetic predispositions; body mass index. The indicators of CHD were studied by volumetric compression oscillometry using a portable automated software-hardware complex for non-invasive research of central hemodynamics (“SHCNIR CHD vco-“Globus” device).Results. The presence of CVD risk factors in senior students was revealed in 52.5% of cases; more than two risk factors were found in 19.3% of cases; 1st degree arterial hypertension (AH) in 11.2% of cases; “white coat hypertension” in 10.8% of cases; genetic predisposition to CVD in 30.0% of cases; overweight in 17.0% of cases; obesity in 5.4% of cases; low physical activity in 23.8% of cases; smoking in 16.1% of cases. An altered CHD profile was found in 62.1% of students. An increase in total peripheral vascular resistance at normal blood pressure levels was noted in 31.8% of cases. Indicators of total peripheral vascular resistance, mean blood pressure, systolic and diastolic blood pressure were significantly higher in the group of students with CHD risk factors.Conclusion. Outpatient follow-up groups should include students with established risk factors for cardiovascular diseases, diagnosed AH, and with altered indicators of CHD. Preventive examinations should include a simple method for studying hemodynamics – compression oscillometry.

Possible Hereditary Pulmonary Arterial Hypertension: from Clinical to Genetic Investigation in Precision Medicine Era

Background: Pulmonary Hypertension is a life-threatening disease characterized by a progressive increase of pulmonary vascular resistance that often leads to right ventricular (RV) failure and death. Major discoveries have been obtained within the last decade in the field of hereditary predisposition to pulmonary arterial hypertension (PAH). At least 6% of all PAH cases are familial in origin known as Familial Pulmonary Arterial Hypertension (FPAH) and display autosomal dominant inheritance with incomplete penetrance. While early diagnosis is associated with improved long-term survival, however at present, most patients are diagnosed at a very advanced stage of HPAH indicating that the early screening for HPAH is crucial. In this regard, genetic testing is an effective strategy for the early diagnosis and management of PAH, specifically Hereditary Pulmonary Arterial Hypertension (HPAH). We present two cases of Familial Pulmonary Arterial Hypertension and in-depth analysis of diagnostic cascade to allow an earlier and more reliable diagnosis of possible Hereditary Pulmonary Arterial Hypertension (HPAH). Case Illustration: Familial cases, a 44-years old man and his son a 17-years old boy, came with chief complaint of dyspnea. His daughter or his sister passed away when 4 years old due to PH. Both patients had been subsequently diagnosed with PAH with possible HPAH after the exclusion of primary and secondary heart anomalies using electrocardiography, echocardiography, and cardiac marker test. Both patients subsequently were performed right heart catheterization (RHC). Conclusions: We describe familial cases of pulmonary hypertension with clinically presenting right-sided heart failure. Diagnostic investigation was performed according to recent guideline to rule out and rule in all the possible cause of pulmonary hypertension. However, the final assessment showed unknown cause of pre-capillary pulmonary hypertension. Therefore, genetic investigation should be performed in precision medicine era due to high possibility of hereditary pulmonary arterial hypertension.

Differences in heart rate responses to upright posture are associated with variations in the high-frequency power of heart rate variability.

High resting heart rate is a cardiovascular risk factor, but limited data exist on the underlying hemodynamics and reproducibility of supine-to-upright increase in heart rate. We recorded noninvasive hemodynamics in 574 volunteers [age, 44.9 yr; body mass index (BMI), 26.4 kg/m2; 49% male] during passive head-up tilt (HUT) using whole body impedance cardiography and radial artery tonometry. Heart rate regulation was evaluated using heart rate variability (HRV) analyses. Comparisons were made between quartiles of supine-to-upright heart rate changes, in which heart rate at rest ranged 62.6-64.8 beats/min (P = 0.285). The average upright increases in heart rate in the quartiles 1-4 were 4.7, 9.9, 13.5, and 21.0 beats/min, respectively (P < 0.0001). No differences were observed in the low-frequency power of HRV, whether in the supine or upright position, or in the high-frequency power of HRV in the supine position. Upright high-frequency power of HRV was highest in quartile 1 with lowest upright heart rate and lowest in quartile 4 with highest upright heart rate. Mean systolic blood pressure before and during HUT (126 vs. 108 mmHg) and the increase in systemic vascular resistance during HUT (650 vs. 173 dyn·s/cm5/m2) were highest in quartile 1 and lowest in quartile 4. The increases in heart rate during HUT on three separate occasions several weeks apart were highly reproducible (r = 0.682) among 215 participants. To conclude, supine-to-upright increase in heart rate is a reproducible phenotype with underlying differences in the modulation of cardiac parasympathetic tone and systemic vascular resistance. As heart rate at rest influences prognosis, future research should elucidate the prognostic significance of these phenotypic differences.NEW & NOTEWORTHY Subjects with similar supine heart rates are characterized by variable increases in heart rate during upright posture. Individual heart rate increases in response to upright posture are highly reproducible as hemodynamic phenotypes and present underlying differences in the modulation of cardiac parasympathetic tone and systemic vascular resistance. These results indicate that resting heart rate obtained in the supine position alone is not an optimal means of classifying people into groups with differences in cardiovascular function.

Modulating NO-GC Pathway in Pulmonary Arterial Hypertension.

The pathogenesis of complex diseases such as pulmonary arterial hypertension (PAH) is entirely rooted in changes in the expression of some vasoactive factors. These play a significant role in the onset and progression of the disease. Indeed, PAH has been associated with pathophysiologic alterations in vascular function. These are often dictated by increased oxidative stress and impaired modulation of the nitric oxide (NO) pathway. NO reduces the uncontrolled proliferation of vascular smooth muscle cells that leads to occlusion of vessels and an increase in pulmonary vascular resistances, which is the mainstay of PAH development. To date, two classes of NO-pathway modulating drugs are approved for the treatment of PAH: the phosphodiesterase-5 inhibitors (PD5i), sildenafil and tadalafil, and the soluble guanylate cyclase activator (sGC), riociguat. Both drugs provide considerable improvement in exercise capacity and pulmonary hemodynamics. PD5i are the recommended drugs for first-line PAH treatment, whereas sGCs are also the only drug approved for the treatment of resistant or inoperable chronic thromboembolic pulmonary hypertension. In this review, we will focus on the current information regarding the nitric oxide pathway and its modulation in PAH.

Omics and Extreme Phenotyping Reveal Longitudinal Association Between Left Atrial Size and Pulmonary Vascular Resistance in Group 2 Pulmonary Hypertension.

Left heart disease is the most common cause of pulmonary hypertension (PH) and is frequently accompanied by increases in pulmonary vascular resistance. However, the distinction between phenotypes of PH due to left heart disease with a normal or elevated pulmonary vascular resistance-isolated postcapillary PH (IpcPH) and combined pre- and postcapillary PH (CpcPH), respectively-has been incompletely defined using unbiased methods. Patients with extremes of IpcPH versus CpcPH were identified from a single-center record of those who underwent right heart catheterization. Individuals with left ventricular ejection fraction <40% or with potential causes of PH beyond left heart disease were excluded. Medication usage in IpcPH and CpcPH was compared across Anatomical Therapeutic Chemical classes and identified vitamin K antagonists as the only medication with pharmacome-wide significance, being more commonly used in CpcPH and for an indication of atrial fibrillation in ≈90% of instances. Accordingly, atrial fibrillation prevalence was significantly higher in CpcPH in a phenome-wide analysis. Review of echocardiographic data most proximal to right heart catheterization revealed that left atrial diameter indexed to body surface area-known to be associated with atrial fibrillation-was increased in CpcPH regardless of the presence of atrial fibrillation. An independent cohort with serial right heart catheterizations and PH-left heart disease showed a significant positive correlation between change in left atrial diameter indexed to body surface area and change in pulmonary vascular resistance. Guided by pharmacomic and phenomic screens in a rigorously phenotyped cohort, we identify a longitudinal association between left atrial diameter indexed to body surface area and pulmonary vascular resistance with implications for the future development of diagnostic, prognostic, and therapeutic tools.