Acute Vasodilator Research Articles

Lasting Effects of Surgically Used Topical Vasodilators on DIEP Artery Vascular Function.

Surgeons routinely apply papaverine, lidocaine, or verapamil to produce acute vasodilation and prevent vasospasms during microvascular surgeries. There is evidence that topical vasodilators may induce postoperative endothelial and smooth muscle dysfunction, which would present after the acute vasodilatory effects of the topical drugs wear off. Therefore, the purpose of the current study was to evaluate the lasting effects of papaverine, lidocaine, and verapamil on human deep inferior epigastric perforator artery vasodilatory function after the acute effects of the topical drugs had worn off. Deep inferior epigastric arterial samples were obtained from 12 patients during surgery. Each artery was dissected into four rings which where incubated for 1 minute in either physiological saline solution (control), papaverine (30 mg/mL), lidocaine (20 mg/mL), or verapamil (2.5 mg/mL), followed by a 2-hour washout. Endothelial-dependent and -independent vasorelaxation were then assessed by the isometric tension responses to acetylcholine or sodium nitroprusside, respectively. Peak acetylcholine-evoked vasorelaxation (mean ± standard deviation) was not different between control (62 ± 23%) and lidocaine (57 ± 18%, p = 0.881), but was reduced (all p < 0.002) in papaverine (22 ± 27%) and verapamil (22 ± 20%). Peak sodium nitroprusside-evoked vasorelaxation was not different (all p > 0.692) among control (132 ± 35%), lidocaine (121 ± 22%), and verapamil (127 ± 22%), but was less in papaverine (104 ± 41%; p = 0.045) than control. Surgically used doses of papaverine and verapamil, but not lidocaine, have lasting negative effects on arterial vasodilatory function despite the acute effects of the drugs having worn off. These findings, in conjunction with the spasmolytic properties of each drug, may help guide the selection of an optimal topical vasodilator for use during microvascular surgeries.

Efficacy of inhaled iloprost in children with pulmonary hypertension after pediatric cardiac surgery: a case series

BackgroundThe postoperative phase of cardiac surgery in pediatric patients with congenital heart disease often involves the management of pulmonary hypertension, which can significantly affect recovery and long-term prognosis. Inhaled iloprost is a potent acute pulmonary vasodilator with a rapid onset of action and has been shown to be effective and safe in patients with pulmonary arterial hypertension, improving clinical parameters by lowering pulmonary artery pressure. In our study, we will share the results of patients with pulmonary hypertension after pediatric cardiac surgery in whom we used inhaled iloprost.ResultsA total of 9 patients who received inhaled iloprost between 2020 and 2023 were included in the retrospective study. The age of the patients ranged between 10 days and 11 months, with a mean of 207.77 days (6.92 months) ± 105.78 days (3.52 months). Five patients were male (55.55%), and four were female (44.45%). Three of the patients had trisomy 21 (33.3%) genetic mutations.ConclusionsThe limited number of case series in the literature support the potential of inhaliloprost as an effective and safe therapeutic option for the treatment of pulmonary hypertension in the pediatric population after congenital heart surgery. The findings of this study support the literature and suggest that inhaliloprost is effective. Due to the limited number of patients, further research is needed to determine the safety and efficacy of these drugs, especially to determine the dose, route, and duration of administration in intubated patients.

The effects of oxygenation on acute vasodilator challenge in pulmonary arterial hypertension.

Identification of long-term calcium channel blocker (CCB) responders with acute vasodilator challenge is critical in the evaluation of patients with pulmonary arterial hypertension. Currently there is no standardized approach for use of supplemental oxygen during acute vasodilator challenge. In this retrospective analysis of patients identified as acute vasoresponders, treated with CCBs, all patients had hemodynamic measurements in three steps: (1) at baseline; (2) with 100% fractional inspired oxygen; and (3) with 100% fractional inspired oxygen plus inhaled nitric oxide (iNO). Those meeting the definition of acute vasoresponsiveness only after first normalizing for the effects of oxygen in step 2 were labeled "iNO Responders." Those who met the definition of acute vasoresponsiveness from a combination of the effects of 100% FiO2 and iNO were labeled "oxygen responders." Survival, hospitalization for decompensated right heart failure, duration of CCB monotherapy, and functional data were collected. iNO responders, when compared to oxygen responders, had superior survival (100% vs. 50.1% 5-year survival, respectively), fewer hospitalizations for acute decompensated right heart failure (0% vs. 30.4% at 1 year, respectively), longer duration of CCB monotherapy (80% vs. 52% at 1 year, respectively), and superior 6-min walk distance. Current guidelines for acute vasodilator testing do not standardize oxygen coadministration with iNO. This study demonstrates that adjusting for the effects of supplemental oxygen before assessing for acute vasoresponsiveness identifies a cohort with superior functional status, tolerance of CCB monotherapy, and survival while on long-term CCB therapy.

Effect of Acute Vasodilator Testing Using Oxygen in Pulmonary Hypertension Due to Left Heart Disease.

Pulmonary vasodilators, including oxygen, have not shown consistent beneficial effects on pulmonary hypertension due to valvular heart disease (PH-VHD). Therefore, the study aimed to assess the effect of 100% fractional inspiration of oxygen (FiO2) on pulmonary and systemic hemodynamics in patients with combined pre- and post-capillary pulmonary hypertension (CpcPH) and isolated post-capillary pulmonary hypertension (IpcPH) due to PH-VHD. This prospective study was conducted among patients with PH-VHD undergoing mitral or aortic valve replacement or repair. The study was conducted after induction of anesthesia and pulmonary artery catheterization. Cardiac output was obtained using thermodilution and all direct, and derived hemodynamic variables were obtained at 30% and 100% FiO2. The patients were stratified a priori into responders {(≥10mmHg fall in mean pulmonary artery pressure (MPAP)} and non-responders. Fifty-seven patients completed the acute vasodilator test. The mean age and body mass index of the study population was 41.8 ± 14.1years and 21.4 ± 4.6kg/m2, respectively. There was a significant decrease in MPAP (40.77 ± 12.07mmHg vs 36.74 ± 13.3mmHg; P < .001) and pulmonary vascular resistance (PVR) {(median; Interquartile range (IQR); 388; 371 vs 323; 362dynes sec.cm-5; P < .001) at 100% FiO2. Transpulmonary gradient (TPG) and diastolic pulmonary gradient (DPG) also decreased significantly (P < .001 and P < .001). Cardiac output did not change significantly. The magnitude of decrease in MPAP, PVR, TPG, DPG, and pulmonary artery compliance (PAC) between CpcPH and IpcPH was comparable. Responders did not show a significantly greater fall in MPAP, PVR, TPG, DPG, and PAC after surgery. Hyperoxia may lead to reduction in MPAP and PVR in both hemodynamic phenotypes of PH-VHD. A larger sample size is required to support or refute the findings of this study.

A Review of the Diagnostic and Therapeutic Gaps in Rosacea Management: Consensus Opinion.

Rosacea is a common, chronic inflammatory disease characterized by both fluctuating and fixed heterogeneous signs such as facial erythema, papules/pustules, telangiectasia, acute vasodilation (flushing), and phymatous changes, and symptoms such as cutaneous stinging and burning. The shift to a phenotype-based approach to rosacea management has improved the consistency of recommendations across recent published guidelines. Consistent and thorough guidance for the classification, diagnosis, and management of the disease is difficult, as the mechanisms underlying the development of rosacea are still not completely understood nor universally accepted. Here, we provide a critical review of current published guidance, and gaps in the knowledge and management of rosacea. We present the recently approved microencapsulated benzoyl peroxide as an effective topical treatment option for papulopustular rosacea. Benzoyl peroxide (BPO) has been used in acne management for many years; however, many clinicians perceive treatment of rosacea with any BPO formulation to be counterintuitive because of concerns of potential skin irritation, while the lack of an accepted mechanism of action on rosacea pathophysiology means that others may be hesitant to use BPO as a treatment. Minocycline foam 1.5% is also an option for the treatment of inflammatory lesions in rosacea, with a decreased risk of systemic adverse events compared with oral minocycline.

Role of CB1 Cannabinoid Receptors in Vascular Responses and Vascular Remodeling of the Aorta in Female Mice.

Both the endocannabinoid system (ECS) and estrogens have significant roles in cardiovascular control processes. Cannabinoid type 1 receptors (CB1Rs) mediate acute vasodilator and hypotensive effects, although their role in cardiovascular pathological conditions is still controversial. Estrogens exert cardiovascular protection in females. We aimed to study the impact of ECS on vascular functions. Experiments were performed on CB1R knockout (CB1R KO) and wild-type (WT) female mice. Plasma estrogen metabolite levels were determined. Abdominal aortas were isolated for myography and histology. Vascular effects of phenylephrine (Phe), angiotensin II, acetylcholine (Ach) and estradiol (E2) were obtained and repeated with inhibitors of nitric oxide synthase (NOS, Nω-nitro-L-arginine) and of cyclooxygenase (COX, indomethacin). Histological stainings (hematoxylin-eosin, resorcin-fuchsin) and immunostainings for endothelial NOS (eNOS), COX-2, estrogen receptors (ER-α, ER-β) were performed. Conjugated E2 levels were higher in CB1R KO compared to WT mice. Vasorelaxation responses to Ach and E2 were increased in CB1R KO mice, attenuated by NOS-inhibition. COX-inhibition decreased Phe-contractions, while it increased Ach-relaxation in the WT group but not in the CB1R KO. Effects of indomethacin on E2-relaxation in CB1R KO became opposite to that observed in WT. Histology revealed lower intima/media thickness and COX-2 density, higher eNOS and lower ER-β density in CB1R KO than in WT mice. CB1R KO female mice are characterized by increased vasorelaxation associated with increased utilization of endothelial NO and a decreased impact of constrictor prostanoids. Our results indicate that the absence or inhibition of CB1Rs may have beneficial vascular effects.

In vivo noninvasive systemic myography of acute systemic vasoactivity in female pregnant mice

Altered vasoactivity is a major characteristic of cardiovascular and oncological diseases, and many therapies are therefore targeted to the vasculature. Therapeutics which are selective for the diseased vasculature are ideal, but whole-body selectivity of a therapeutic is challenging to assess in practice. Vessel myography is used to determine the functional mechanisms and evaluate pharmacological responses of vascularly-targeted therapeutics. However, myography can only be performed on ex vivo sections of individual arteries. We have developed methods for implementation of spherical-view photoacoustic tomography for non-invasive and in vivo myography. Using photoacoustic tomography, we demonstrate the measurement of acute vascular reactivity in the systemic vasculature and the placenta of female pregnant mice in response to two vasodilators. Photoacoustic tomography simultaneously captures the significant acute vasodilation of major arteries and detects selective vasoactivity of the maternal-fetal vasculature. Photoacoustic tomography has the potential to provide invaluable preclinical information on vascular response that cannot be obtained by other established methods.

Hesperetin-7-O-glucoside/β-cyclodextrin Inclusion Complex Induces Acute Vasodilator Effect to Inhibit the Cold Sensation Response during Localized Cold-Stimulate Stress in Healthy Human Subjects: A Randomized, Double-Blind, Crossover, and Placebo-Controlled Study.

Hesperetin, a citrus flavonoid, exerts vasodilation and is expected to improve endothelial function and alleviate cold sensation by activating nervous system thermal transduction pathways. In this randomized, double-blind, crossover, and placebo-controlled study, the purpose was to assess the effect of an orally administered highly bioavailable soluble inclusion complex of hesperetine-7-O-glucoside with β-cyclodextrin (HEPT7G/βCD; SunActive® HES/HCD) on cold sensation response during localized cold-stimulated stress in healthy humans. A significant (p ≤ 0.05) dose-dependent increase in skin cutaneous blood flow following relatively small doses of HEPT7G/βCD inclusion complex ingestion was confirmed, which led to a relatively effective recovery of peripheral skin temperature. The time delay of an increase in blood flow during rewarming varied significantly between low- and high-dose HEPT7G/βCD inclusion complex consumption (e.g., 150 mg and 300 mg contain 19.5 mg and 39 mg of HEPT7G, respectively). In conclusion, the substantial alteration in peripheral skin blood flow observed during local cooling stress compared to placebo suggested that deconjugated hesperetin metabolites may have a distinct capacity for thermoregulatory control of human skin blood flow to maintain a constant body temperature during cold stress exposure via cutaneous vasodilation and vasoconstriction systems.

Frequency of acute vasodilator response (AVR) in incident and prevalent patients with pulmonary arterial hypertension: Results from the pulmonary vascular disease phenomics study.

The prevalence of acute vasodilator response (AVR) to inhaled nitric oxide (iNO) during right heart catheterization (RHC) is 12% in idiopathic pulmonary arterial hypertension (IPAH). AVR, however, is reportedly lower in other disease-associated pulmonary arterial hypertension (PAH), such as connective tissue disease (CTD). The prevalence of AVR in patients on PAH therapy (prevalent cases) is unknown. We sought to determine AVR prevalence in Group 1 PH in the PVDOMICS cohort of incident and prevalent patients undergoing RHC. AVR was measured in response to 100% O2 and O2 plus iNO, with positivity defined as (1) decrease in mean pulmonary artery pressure (mPAP) by ≥10 mmHg to a value ≤40 mmHg, with no change or an increase in cardiac output (definition 1); or (2) decrease in mPAP by ≥12% and pulmonary vascular resistance by ≥30% (definition 2). AVR rates and cumulative survival were compared between incident and prevalent patients. In 338 mainly prevalent (86%) patients, positive AVR to O2-only was <2%, and 5.1% to 16.9%, based on definition 1 and 2 criteria, respectively; following O2 + iNO. IPAH AVR prevalence (4.1%-18.7%) was similar to prior reports. AVR positivity was 7.7% to 15.4% in mostly CTD-PAH prevalent cases, and 2.6% to 11.8% in other PAH groups. Survival was 89% in AVRresponders versus 77% in nonresponders from PAH diagnosis, and 91% versus 86% from PVDOMICS enrollment (log-rank test p = 0.04 and p = 0.05, respectively). In conclusion, AVR in IPAH patients is similar to prior studies. AVR in non-IPAH patients was higher than previously reported. The relationship between PAH therapy, AVR response, and survival warrants further investigation.

Impact of a TAK-1 inhibitor as a single or as an add-on therapy to riociguat on the metabolic reprograming and pulmonary hypertension in the SUGEN5416/hypoxia rat model.

Background: Despite increasing evidence suggesting that pulmonary arterial hypertension (PAH) is a complex disease involving vasoconstriction, thrombosis, inflammation, metabolic dysregulation and vascular proliferation, all the drugs approved for PAH mainly act as vasodilating agents. Since excessive TGF-β signaling is believed to be a critical factor in pulmonary vascular remodeling, we hypothesized that blocking TGFβ-activated kinase 1 (TAK-1), alone or in combination with a vasodilator therapy (i.e., riociguat) could achieve a greater therapeutic benefit. Methods: PAH was induced in male Wistar rats by a single injection of the VEGF receptor antagonist SU5416 (20mg/kg) followed by exposure to hypoxia (10%O2) for 21 days. Two weeks after SU5416 administration, vehicle, riociguat (3mg/kg/day), the TAK-1 inhibitor 5Z-7-oxozeaenol (OXO, 3mg/kg/day), or both drugs combined were administered for 7days. Metabolic profiling of right ventricle (RV), lung tissues and PA smooth muscle cells (PASMCs) extracts were performed by magnetic resonance spectroscopy, and the differences between groups analyzed by multivariate statistical methods. Results: In vitro, riociguat induced potent vasodilator effects in isolated pulmonary arteries (PA) with negligible antiproliferative effects and metabolic changes in PASMCs. In contrast, 5Z-7-oxozeaenol effectively inhibited the proliferation of PASMCs characterized by a broad metabolic reprogramming but had no acute vasodilator effects. In vivo, treatment with riociguat partially reduced the increase in pulmonary arterial pressure (PAP), RV hypertrophy (RVH), and pulmonary vascular remodeling, attenuated the dysregulation of inosine, glucose, creatine and phosphocholine (PC) in RV and fully abolished the increase in lung IL-1β expression. By contrast, 5Z-7-oxozeaenol significantly reduced pulmonary vascular remodeling and attenuated the metabolic shifts of glucose and PC in RV but had no effects on PAP or RVH. Importantly, combined therapy had an additive effect on pulmonary vascular remodeling and induced a significant metabolic effect over taurine, amino acids, glycolysis, and TCA cycle metabolism via glycine-serine-threonine metabolism. However, it did not improve the effects induced by riociguat alone on pulmonary pressure or RV remodeling. None of the treatments attenuated pulmonary endothelial dysfunction and hyperresponsiveness to serotonin in isolated PA. Conclusion: Our results suggest that inhibition of TAK-1 induces antiproliferative effects and its addition to short-term vasodilator therapy enhances the beneficial effects on pulmonary vascular remodeling and RV metabolic reprogramming in experimental PAH.

Loss of response to calcium channel blockers after long-term follow-up treatment in patients with idiopathic pulmonary arterial hypertension.

Idiopathic pulmonary arterial hypertension (PAH) patients with a positive response to acute vasodilator challenge and a clinical response to calcium channel blockers (CCBs) for at least one year are traditionally designated true responders. Nevertheless, little is known about a sustained response to CCBs over longer periods of time. We evaluated the loss of response to CCBs after long-term treatment in a cohort of idiopathic PAH patients previously classified as being true responders. Our data suggest that idiopathic PAH patients can lose clinical response to CCBs even after one year of clinical stability, reinforcing the need for constant multidimensional reevaluation to assess the need for targeted PAH therapies and to classify these patients correctly.

Acute vasoreactivity testing during right heart catheterization in chronic thromboembolic pulmonary hypertension: Results from the pulmonary vascular disease phenomics study.

Chronic thromboembolic pulmonary hypertension (CTEPH) is believed to involve both vascular obstruction and vasoconstriction; hence, pulmonary vasodilators such as riociguat may be beneficial. Acute vasoreactivity testing (AVT) is seldom performed routinely in CTEPH patients, so there is limited understanding of the frequency and significance of an acute vasodilator response. Systematic vasodilator testing with oxygen (O2) and oxygen plus inhaled nitric oxide (O2 + iNO) was performed as part of the Pulmonary Vascular Disease Omics (PVDOMICS) NHLBI project, providing an opportunity to examine AVT responses in CTEPH. Patients with CTEPH enrolled in PVDOMICS (n = 49, 40 with prevalent CTEPH[82%])underwent right heart catheterization including AVT with O2 and O2 + iNO. Hemodynamics were obtained at baseline and with each challenge. Fourteen of 49 patients (29%) had >20% drop in pulmonary vascular resistance (PVR) with O2. With O2 + iNO, 30/49 (61%) had >20% drop in PVR, 20% had >20% drop in mean pulmonary artery pressure(mPAP) and PVR, and 8% had >10 mmHg decline in mPAP to mPAP < 40 with normal cardiac output. Patients on riociguat had less response to O2 + iNO than patients on phosphodiesterase-5inhibitors. Our findings shed light on the significant variability in vascular tone that is present in CTEPH, confirming that CTEPH represents a combination of mechanical obstruction and vasoconstriction that appears similar to that observed with Group 1 PAH. Additional study regarding whether results of acute vasodilator testing predict response to therapy and relate to prognosis is warranted.

Battling Hypotension in Cesarean Section

Perhaps the greatest day in a mother's life is the birth of her child. As a father of two, I will never forget those two drastically different, yet equally beautiful moments. In each circumstance, the obstetricians, nurses, anesthesia providers, and technicians all worked seamlessly to provide a safe and enjoyable childbirth experience for our new and growing family. One key element of the childbirth experience is maternal pain control. Depending on several factors, the parturient may receive an epidural, a spinal, a combined spinal/epidural, IV analgesics or perhaps nothing at all. One key commonality after any anesthetic administration is its propensity to cause hypotension, which is usually most profound after spinal anesthesia (SA). SA is the preferred method during elective cesarean sections due to the rapid and predictable onset and duration of action of local anesthetics injected directly into the cerebrospinal fluid. Immediately after SA is administered, the patient is helped to lay supine which assists the hyperbaric local anesthetic to move with gravity and rise cephalad from the lower lumber injection site (L3-L5) towards the desired T4 vertebra. While marching up those 12 dermatome levels, the local anesthetic quickly begins to attenuate sympathetic tone at every level along the way. Depending on the health of the patient's cardiovascular system, intravascular volume status and other factors, the sympathectomy and subsequent vasodilation can result in significant and symptomatic hypotension, causing a vast array of symptoms such as maternal nausea, vomiting, dizziness, and cardiovascular collapse as well as fetal acidosis and decreased Apgar scores. Preanesthesia fluid boluses are commonly administered in hopes to increase intravascular volume and lessen the severity of hypotension, but its effectiveness is unreliable. Acute arterial vasodilation is the primary cause of hypotension after SA. Intravenous vasoactive medications such as phenylephrine and ephedrine offer the fastest and most effective means of arterial vasoconstriction and subsequent correction of blood pressure; yet healthcare providers will always continue to search for alternative and less invasive methods of preventing and/or treating hypotension after SA.

Long-term prognostic value of cardiac catheterization and acute vasodilator testing with inhaled iloprost in pediatric idiopathic pulmonary arterial hypertension.

To assess the long-term prognostic value of cardiac catheterization and acute vasodilator testing (AVT) with inhaled iloprost in children with idiopathic pulmonary arterial hypertension (IPAH).Data on 81 consecutive children with IPAH referred to our center who underwent cardiac catheterization and AVT between June 2008 and August 2019 were collected. The correlation between the invasive hemodynamic data and transplant-free survival was analyzed. Twenty-four patients died and 1 underwent lung transplantation during a median follow-up of 3.8 years, with a 5-year transplant-free survival rate of 64.9%. Univariate analysis showed that predictors associated with improved survival included a lower pulmonary vascular resistance index (PVRI), PVRI/systemic vascular resistance index (SVRI), mean pulmonary arterial pressure (mPAP)/mean systemic arterial pressure, mean right atrial pressure, and a higher cardiac index (CI), mixed systemic venous oxygen saturations (SvO2), and acute vasodilator response (AVR) according to the Barst criteria (decrease in mPAP and PVRI/SVRI ratio of >20% without a decrease in CI). In multivariate Cox regression analysis, Barst AVR and SvO2 were independently related to transplant-free survival. Multiple hemodynamic variables from cardiac catheterization and AVT with inhaled iloprost have important prognostic value for long-term survival in children with IPAH, of which pulmonary vasoreactivity defined by the Barst criteria and SvO2 are independent prognostic factors.

Comparison of intravenous sildenafil with inhaled nitric oxide for acute vasodilator testing in pulmonary arterial hypertension.

Acute vasodilator testing (AVT) identifies acute responders for initiation of calcium channel blockers in pulmonary arterial hypertension (PAH) and operability in congenital heart disease (CHD). We sought to determine the feasibility of intravenous sildenafil (ivS) as an alternative to inhaled nitric oxide (iNO) in AVT. All patients with PAH undergoing cardiac catheterization for AVT (November 2015 to December 2020) were prospectively enrolled. Hemodynamic data were obtained at baseline, with iNO 20 ppm and ivS (0.25 mg/kg for children and 10 mg for adults). We studied 44 patients with a mean age of 20.5 ± 14.4 years (27 [61%] females and 20 [45%]children). There were 17 (38.6%) patients in theCHD group for operability assessment and 27 patients in non-CHD group (idiopathic pulmonary arterial hypertension-16 [36.3%], residual PAH after shunt closure-7 [15.9%], and 2 cases [4.5%] each of familial PAH and portopulmonary hypertension). There was an excellent intraclass correlation for mean pulmonary artery pressures (0.903, 95% confidence interval,CI: 0.809-0.949, p < 0.001), mean aortic pressures (0.745, 95% CI: 0.552-0.858, p < 0.001), pulmonary vascular resistance index (0.920, 95% CI: 0.858-0.956, p < 0.001), systemic vascular resistance (SVR) index (0.828, 95% CI: 0.706-0.902, p < 0.001), and the ratio of pulmonary and SVR indices (0.857, 95% CI: 0.752-0.919, p < 0.001) between the two agents. There were two responders, both in non-CHD group, and were identified by iNO and ivS. The hemodynamic effects of ivS show excellent correlation with iNO and could be a potential alternative agent for identifying acute responders during AVT.

Safety of chronic high-dose calcium channel blockers exposure in children with pulmonary arterial hypertension.

BackgroundChronic calcium channel blockers (CCBs) are indicated in children with idiopathic/heritable pulmonary arterial hypertension (IPAH/HPAH) and positive response to acute vasodilator challenge. However, minimal safety data are available on the long-term high-dose exposure to CCBs in this population.MethodsPatients aged 3 months to 18 years who were diagnosed with IPAH/HPAH and treated with CCB in the past 15 years were retrospectively reviewed. The maximum tolerated dose and the long-term safety of high-dose CCBs on the cardiovascular and noncardiovascular systems were assessed.ResultsThirty-two eligible children were enrolled in the study, with a median age of 9 (6–11) years old. Thirty-one patients were treated with diltiazem after diagnosis. The median maximum tolerated dose was 12.9 (9.8–16.8) mg/kg/day. Children younger than 7 years used higher doses than children in the older age group, 16.4 (10.5–28.5) mg/kg/day vs. 12.7 (6.6–14.4) mg/kg/day, P < 0.05. Patients were followed up for a median period of 6.2 (2.6–10.8) years. One patient died from a traffic accident, and others showed a stable or improved WHO functional class status. Thirteen (40.6%) and 10 (31.3%) patients developed arrhythmias and hypotension. Nine (28.1%) patients had sinus bradycardia, five (21.9%) had first-degree or second-degree type II atrial-ventricular blocks, and two (6.3%) had second-degree type II atrial-ventricular blocks. Most of these arrhythmias were transient and relieved after CCB dose adjustment. The most reported noncardiovascular adverse effect was gingival hyperplasia (13, 40.6%), accompanied by different degrees of dental dysplasia. No liver or kidney dysfunction was reported.ConclusionDiltiazem was used in a very high dose for eligible children with IPAH/HPAH. The toxicity of long-term CCB use on the cardiovascular system is mild and controllable. Clinicians should also monitor the noncardiovascular adverse effects associated with drug therapy.

Acute vasodilator response testing in the adult Fontan circulation using non-invasive 4D Flow MRI: a proof-of-principle study.

Pulmonary vasodilator therapy in Fontan patients can improve exercise tolerance. We aimed to assess the potential for non-invasive testing of acute vasodilator response using four-dimensional (D) flow MRI during oxygen inhalation. Six patients with well-functioning Fontan circulations were prospectively recruited and underwent cardiac MRI. Ventricular anatomical imaging and 4D Flow MRI were acquired at baseline and during inhalation of oxygen. Data were compared with six age-matched healthy volunteers with 4D Flow MRI scans acquired at baseline. All six patients tolerated the MRI scan well. The dominant ventricle had a left ventricular morphology in all cases. On 4D Flow MRI assessment, two patients (Patients 2 and 6) showed improved cardiac filling with improved preload during oxygen administration, increased mitral inflow, increased maximum E-wave kinetic energy, and decreased systolic peak kinetic energy. Patient 1 showed improved preload only. Patient 5 showed no change, and patient 3 had equivocal results. Patient 4, however, showed a decrease in preload and cardiac filling/function with oxygen. Using oxygen as a pulmonary vasodilator to assess increased pulmonary venous return as a marker for positive acute vasodilator response would provide pre-treatment assessment in a more physiological state - the awake patient. This proof-of-concept study showed that it is well tolerated and has shown changes in some stable patients with a Fontan circulation.

Response to acute vasodilator challenge and haemodynamic modifications after MitraClip in patients with functional mitral regurgitation and pulmonary hypertension.

The effectiveness of transcatheter edge-to-edge repair (TEER) in patients with functional mitral regurgitation (FMR) and pulmonary hypertension (PH) is still debated and pre-procedural predictors of haemodynamic improvement after TEER in this setting are currently unknown. We investigated whether normalization of pulmonary artery wedge pressure (PAWP) in response to sodium nitroprusside (SNP) during baseline right heart catheterization might be predictive of a favourable haemodynamic response to MitraClip in patients with FMR and PH. Among 22 patients enrolled, 13 had a positive response to SNP (responders), nine were non-responders. At 6-months follow-up, responders showed a 33% reduction in PAWP and a 25% reduction in mean pulmonary artery pressure (PAP) (P = 0.002 and 0.004, respectively); no significant change occurred in non-responders. In patients with FMR and PH, pre-procedural vasodilator challenge with SNP may help define patients who may have haemodynamic improvement after TEER.

TGF-β receptor mutations and clinical prognosis in Chinese pediatric patients with idiopathic/hereditary pulmonary arterial hypertension.

The relationship between clinical prognosis and transforming growth factor‐β (TGF‐β) receptor mutations in Chinese pediatric patients with idiopathic/hereditary pulmonary arterial hypertension (IPAH/HPAH) remains unclear. We retrospectively studied the clinical characteristics and outcomes of pediatric patients with IPAH/HPAH who visited our Hospital from September 2008 to December 2020. One hundred and five pediatric patients with IPAH/HPAH were included, 46 of whom carried TGF‐β receptor mutations with a mean age at diagnosis of 82.8 ± 52.7 months, and 67 of them underwent right cardiac catheterization examinations and acute vasodilator testing. The result showed that mutation carriers demonstrated higher pulmonary vascular resistance (p = 0.012), higher right atrial pressure (p = 0.026), and lower cardiac index (p = 0.003). The 1‐, 2‐, and 3‐year survival rates of mutation carriers were 79.4%, 61.5% and 55.6%, respectively, compared with 96.6%, 91.1%, and 85.4% for nonmutation carriers (p = 0.0001). The prognosis of mutation carriers was significantly worse than that of nonmutation carriers. TGF‐β receptor gene mutation is an independent risk factor for death (p = 0.049, odd raito = 3.809, 95% confidence interval 1.006−14.429). In conclusion, TGF‐β receptor mutation is an important genetic factor for the onset of IPAH/PAH in Chinese pediatric patients. Those who carrying TGF‐β receptor mutations have a poor clinical prognosis. Therefore, TGF‐β receptor gene screening for pediatric patients with PAH and more aggressive treatment for mutation carriers are recommended.

Inhaled iloprost induces long-term beneficial hemodynamic changes in patients with pulmonary arterial hypertension receiving combination therapy.

Inhaled iloprost is an established treatment for pulmonary arterial hypertension (PAH). However, the long‐term hemodynamic changes that inhaled iloprost induces are unclear. Here, we retrospectively enrolled 18 patients with PAH who received inhaled iloprost as add‐on to oral combination therapy from December 2016 to January 2021 at our institute in Japan. We then examined the changes in hemodynamic parameters induced by iloprost in these patients during right heart catheterization (RHC). To examine the long‐term effects of iloprost, we repeated the RHC examination at follow‐up (median time to follow‐up, 8.5 months). During both catheterization procedures, iloprost was administered by using an I‐neb AAD system (Philips NV). In a comparison of pre‐inhalation values at the first and follow‐up RHCs, inhaled iloprost significantly improved mean pulmonary artery pressure (mPAP; 39.9 ± 7.8 to 32.5 ± 7.2 mmHg, p = 0.016) and pulmonary vascular resistance (PVR; 588.5 ± 191.7 to 464.4 ± 188.5 dyn s cm−5, p = 0.047). During the follow‐up RHC, in a comparison of the pre‐inhalation and best recorded values out to 30 min after the end of iloprost inhalation, iloprost significantly decreased mPAP (32.5 ± 7.2 to 30.0 ± 6.6 mmHg, p = 0.007) and PVR (457.8 ± 181.4 to 386.2 ± 142.8 dyn s cm−5, p = 0.025) and significantly increased cardiac output (4.19 ± 0.91 to 4.64 ± 1.01 L/min, p = 0.035). Iloprost may have not only acute vasodilation effects but also long‐term hemodynamic benefits in PAH patients receiving combination therapy.