Pulmonary hypertension secondary to valvular heart disease: a state-of-the-art review.

Pulmonary hypertension (PH) is a common disease affecting up to 1% of the population and at least 50% of patients diagnosed with heart failure (HF) (Hoeper et al. in Lancet Respir Med 4(4):306-322, 2016). It is estimated that PH is present in 15% to 60% of patients with valvular heart disease (VHD) which can result from an increase in pulmonary blood flow and subsequently in pulmonary venous congestion and pulmonary vascular resistance (PVR). It is important to identify the severity of PH in patients with VHD to appropriately risk stratify and manage these patients (Magne et al. in JACC Cardiovasc Imaging 8(1):83-99, 2015). In this review, we examine the diagnostic criteria for PH and its pathophysiology. We also focus on the growing evidence supporting the presence of PH secondary to VHD and describe the contemporary surgical and medical therapeutic interventions in this patient population (Fig. 1).

Novel inhaled pulmonary vasodilators in adult cardiac surgery: a scoping review.

PURPOSE: Pulmonary hypertension (PH) is a common cause of postoperative mortality in cardiac surgery that is commonly treated with conventional inhaled therapies, specifically nitric oxide and prostacyclin. Alternative therapies include inhaled milrinone and levosimendan, which are receiving more research interest and are increasing in clinical use as they may cut costs while allowing for easier administration. We sought to conduct a scoping review to appraise the evidence base for the use of these two novel inhaled vasodilators as an intervention for PH in cardiac surgery. SOURCE: We searched Embase and MEDLINE for relevant articles from 1947 to 2022. PRINCIPAL FINDINGS: We identified 17 studies including 969 patients. The included studies show that inhaled milrinone and levosimendan are selective pulmonary vasodilators with potential benefits ranging from ease of weaning from cardiopulmonary bypass to reduction in ventricular dysfunction. Nevertheless, high-quality data are limited, and study design and comparators are extremely heterogeneous, limiting the potential validity and generalizability of findings. CONCLUSION: The findings of this scoping review suggest that milrinone and levosimendan may be effective alternatives to current inhaled therapies for cardiac dysfunction in the setting of PH. Nevertheless, randomized trials have focused on specific agents and consistent outcome measures are needed to better validate the early-stage promise of these agents. STUDY REGISTRATION: Open Science Framework ( https://osf.io/z3k6f/ ); first posted 21 July 2022.

RéSUMé: OBJECTIF: L'hypertension pulmonaire (HTP) est une cause fréquente de mortalité postopératoire en chirurgie cardiaque généralement traitée par des thérapies inhalées conventionnelles, en particulier le monoxyde d'azote et la prostacycline. Les thérapies alternatives comprennent la milrinone et le lévosimendan inhalés, qui suscitent de plus en plus d'intérêt dans la recherche et sont de plus en plus utilisés en clinique car ils peuvent réduire les coûts tout en permettant une administration plus facile. Nous avons cherché à réaliser une étude de portée afin d'évaluer la base de données probantes concernant l'utilisation de ces deux nouveaux vasodilatateurs inhalés comme intervention pour l'HTP en chirurgie cardiaque. SOURCES: Nous avons cherché des articles pertinents dans Embase et MEDLINE de 1947 à 2022. CONSTATATIONS PRINCIPALES: Nous avons identifié 17 études incluant 969 patient·es. Les études incluses montrent que la milrinone et le lévosimendan inhalés sont des vasodilatateurs pulmonaires sélectifs possédant des avantages potentiels allant de la facilité de sevrage de la circulation extracorporelle à la réduction de la dysfonction ventriculaire. Néanmoins, les données de haute qualité sont limitées, et la conception des études et les comparateurs sont extrêmement hétérogènes, ce qui limite la validité potentielle et la généralisabilité des résultats. CONCLUSION: Les résultats de cette étude de portée suggèrent que la milrinone et le lévosimendan pourraient être des solutions de rechange efficaces aux traitements inhalés actuels pour le dysfonctionnement cardiaque dans un contexte d'HTP. Néanmoins, les études randomisées se sont concentrées sur des agents spécifiques et des mesures cohérentes des résultats sont nécessaires pour mieux valider les promesses de ces agents à un stade précoce. ENREGISTREMENT DE L'éTUDE: Open Science Framework ( https://osf.io/z3k6f/ ); première publication le 21 juillet 2022.

Inhaled Nitric Oxide and Higher Necrotizing Enterocolitis Rates in Congenital Heart Disease Patients.

INTRODUCTION: Certain congenital cardiac lesions are at increased risk for the development of necrotizing enterocolitis (NEC). These patients are often reliant on pulmonary and systemic vasomodulators to maintain adequate perfusion and oxygenation. This study sought to determine whether pulmonary or systemic vasodilator treatment is protective against the development of NEC in this population. METHODS: We utilized International Classification of Diseases (ICD) codes to identify high risk congenital cardiac disease patients ≤6 mo of age, cared for at a tertiary children's hospital between January 2011 and January 2021. Cardiac anomalies were stratified into ductal dependent (pulmonary DD-P or systemic DD-S) or independent lesions. The rate of NEC development in those who received vasodilators (inhaled nitric oxide [iNO], pulmonary vasodilators, systemic vasodilators) was compared to controls in a multivariate analysis. RESULTS: Of the 352 patients, who met inclusion criteria, 77.6% had ductal dependent lesions (DD-S 41.9%, DD-P 35.7%), 19.5% received iNO, and 37.5% received other vasodilatory drugs. The overall NEC rate was 15.1%. On univariate analysis, DD-S, iNO use, and systemic vasodilators was associated with a significantly higher risk of NEC, while DD-P was associated with lower NEC risk. On multivariate analysis, only iNO (odds ratio 2.725, confidence interval [1.36-5.44]) and DD-S (odds ratio 2.279, confidence interval [1.02-5.11]) were independent risk factors for NEC. CONCLUSIONS: In patients with at-risk congenital cardiac disease lesions, a ductus dependent systemic circulation or iNO treatment is associated with an increased risk of developing NEC. The presence of iNO or DD-S should be utilized as markers of increased risk both in the prevention and workup of suspected NEC.

The safety of carotid stenosis during vasodilator pharmacologic stress testing.

BACKGROUND: While thousands of patients undergo stress testing annually, the risk of exercise and pharmacologic stress in patients with carotid artery disease has not been fully defined but is of concern as patients are at risk for cerebrovascular accidents and transient ischemic attacks. METHODS: All patients with either ultrasound or CTA evaluation of their carotid arteries from over a 10 year period who underwent stress testing within 180 days without intervening carotid intervention were reviewed for any adverse events within 24 hours of their stress test. The primary end point was any cerebrovascular event or syncope while the secondary endpoints included death, myocardial infarction, urgent angiography, urgent revascularization, or exaggerated hemodynamic response (systolic BP drop > 20 mmHg or systolic BP > 180 mmHg at peak stress). Patients were stratified into categories based on their level of carotid disease. Patients with severe carotid stenosis were propensity matched to those with mild or no stenosis. RESULTS: A total of 4457 patients underwent carotid ultrasound, 10,644 CTA, and 16,011 had stress testing during this time period with 514 having both a carotid evaluation and a stress test within 6 months. After propensity matching, 62 patients with severe carotid stenosis were matched to 170 patients with mild or no carotid stenosis. Incidentally, all patients with severe carotid stenosis underwent pharmacologic stress. There were no primary endpoints and only three secondary endpoints in two patients in the mild or no carotid stenosis group. The proportion of exaggerated hemodynamic response to stress was similar in both groups-21.0% in the carotid stenosis group vs 31.2% without (P = .17) having a significant drop in systolic BP, and 3.2% vs 4.7% (P = 1.0) having a significantly elevated systolic BP. CONCLUSION: In this study cohort there were few primary and secondary outcome events with no events occurring in patients with significant carotid stenosis. Additionally, there was no difference in exaggerated hemodynamic responses. While these results suggest that stress testing entails no demonstrable increased risk in patients with significant carotid stenosis, continued care should be taken given the limitations of the small size of this study.

Hemodynamic Response to Oral Vasodilator Therapy in Systemic Sclerosis-Related Pulmonary Hypertension.

PURPOSE: Although classified as group 1 pulmonary arterial hypertension (PAH), patients with systemic sclerosis-related pulmonary hypertension (SSc-PH) experience poorer clinical response to PAH therapy and increased mortality compared to those with idiopathic PAH. Due to heterogeneity in phenotypes, identifying patients likely to respond to therapy is challenging. The goal of this study was to determine clinical factors associated with hemodynamic response, defined by a > 20% reduction in pulmonary vascular resistance on repeat right heart catheterization. METHODS: We applied a time-to-event model using a retrospective cohort of 39 patients with precapillary SSc-PH, defined by a mean pulmonary artery pressure of ≥ 25 mmHg and pulmonary arterial wedge pressure (PAWP) ≤ 15 mmHg on right heart catheterization. RESULTS: Patients with PAWP ≤ 8 mmHg were nearly fourfold more likely to achieve a hemodynamic response compared to those with PAWP > 8 mmHg (HR 3.88; 95% CI: 1.20, 12.57); each 1 mmHg increase in PAWP was associated with a decreased hazard for hemodynamic response (HR 0.84; 95% CI: 0.70, 1.00). CONCLUSION: In patients with precapillary SSc-PH, PAWP was associated with time to hemodynamic response, suggesting the importance of subclinical cardiac disease in determining hemodynamic response to oral vasodilator therapy.

Gastro-protective effect of l-arginine against nitric oxide deficiency-related mucosal injury induced by indomethacin: Does age matter?

Gastric ulcer is a common disease with increased prevalence in the aged population. Aged gastric mucosa has increased susceptibility to injury along with nonsteroidal anti-inflammatory drugs use due to impaired mucosal defense and decreased vasodilator release. We investigated whether l-arginine could protect against age-related gastric ulceration induced by indomethacin. Aged and adult male Wistar rats were administered sole and combined treatment of  l-arginine and Nω -nitro-l-arginine methyl ester ( l-NAME) before induction of gastric ulceration by indomethacin. The gastroprotective effect of  l-arginine was displayed only in adult rats with indomethacin-induced gastric ulceration, as evidenced by a significant decrease in ulcer index, oxidative stress parameters, and mucosal myeloperoxidase activity along with increased mucosal PGE2 levels. Interestingly, the mucosal gene expressions of NF-кB, iNOS, and COX-2 were significantly suppressed by  l-arginine pretreatment and aggregated upon pretreatment with  l-NAME in both adult and aged rats treated with indomethacin. In conclusion,  l-arginine protected the rats' gastric mucosa against indomethacin-induced gastric ulceration, possibly, at least in part, by enhancement of mucosal nitric oxide/PGE2 content along with suppressing gastric inflammation and oxidative stress. This study supposed that the gastroprotective effect of  l-arginine depends on aging, and even so, the adoption of a new approach to gastric ulcer treatment for the aged population is warranted.

Management of neonatal pulmonary hypertension-a survey of neonatal intensive care units in India.

BACKGROUND: Persistent pulmonary hypertension of the newborn (PPHN) is a common neonatal condition associated with significant morbidity and mortality. First-line diagnostic and treatment options such as echocardiography and inhaled nitric oxide (iNO) are not routinely available in resource limited settings and alternative treatment modalities need to be utilized. This study was conducted to assess current diagnostic and management strategies used for PPHN in Indian neonatal intensive care units (NICUs). METHODS: A questionnaire in multiple choice question format was sent to practising neonatologists in India via an online survey tool between July to August 2021. Information pertaining to demographic data, diagnostic criteria and management strategies of PPHN was requested. The responses were collated and information processed. RESULTS: There were 118 respondent NICUs (response rate 74%). The majority of neonatal units (65%) admitted an average of 1-3 patients of PPHN per month. Targeted neonatal echocardiography (TnECHO) was practised in 80% of the units. Most common management strategies being followed were pulmonary vasodilators (88.1%), inotropes (85.6%), conventional ventilation (68.6%) and high frequency ventilation (59.3%). The most preferred pulmonary vasodilator was sildenafil (79%) and inotropic agent was milrinone (32%). Only 25% of respondents reported use of iNO. None of the participating units used extracorporeal membrane oxygenation. CONCLUSION: We found wide variability in management practices of PPHN across Indian NICUs. Non-selective pulmonary vasodilators are more widely used than iNO. There is an urgent need for structured TnECHO training programs and evidence based national guidelines for standardized management of PPHN as per availability of resources in India. Additional research on low cost alternative therapies to iNO in Indian settings might be helpful.

Therapies for Delayed Cerebral Ischemia in Aneurysmal Subarachnoid Hemorrhage.

Delayed cerebral ischemia (DCI) is one of the most important complications of subarachnoid hemorrhage. Despite lack of prospective evidence, medical rescue interventions for DCI include hemodynamic augmentation using vasopressors or inotropes, with limited guidance on specific blood pressure and hemodynamic parameters. For DCI refractory to medical interventions, endovascular rescue therapies (ERTs), including intraarterial (IA) vasodilators and percutaneous transluminal balloon angioplasty, are the cornerstone of management. Although there are no randomized controlled trials assessing the efficacy of ERTs for DCI and their impact on subarachnoid hemorrhage outcomes, survey studies suggest that they are widely used in clinical practice with significant variability worldwide. IA vasodilators are first line ERTs, with better safety profiles and access to distal vasculature. The most commonly used IA vasodilators include calcium channel blockers, with milrinone gaining popularity in more recent publications. Balloon angioplasty achieves better vasodilation compared with IA vasodilators but is associated with higher risk of life-threatening vascular complications and is reserved for proximal severe refractory vasospasm. The existing literature on DCI rescue therapies is limited by small sample sizes, significant variability in patient populations, lack of standardized methodology, variable definitions of DCI, poorly reported outcomes, lack of long-term functional, cognitive, and patient-centered outcomes, and lack of control groups. Therefore, our current ability to interpret clinical results and make reliable recommendations regarding the use of rescue therapies is limited. This review summarizes existing literature on rescue therapies for DCI, provides practical guidance, and identifies future research needs.

Mildly Elevated Pulmonary Hypertension: Gray Zone or Already a Disease?

During the sixth World Symposium on Pulmonary Hypertension, the threshold of mean pulmonary arterial pressure (mPAP) for the definition of pulmonary hypertension (PH) has been lowered to a value of greater than 20 mmHg, measured by means of right heart catheterization at rest. In this review, we aim at describing the impact of the new definition of PH, analyzing the available data from the latest scientific literature concerning subjects with mPAP between 21 and 24 mmHg (defined as "mildly elevated PH"), discussing the impact of the new threshold for mPAP in the clinical practice, and highlighting the new perspectives in this field.

Smooth Muscle Cell Relaxation Worsens Aortic Dilatation and Clinical Presentation in a BAPN/Angiotensin II-Induced Aortic Dissection Model in Rats.

INTRODUCTION: Beta-aminopropionitrile (BAPN) administration is a chemically induced model for preclinical aortic pathologies research. Angiotensin II (AngII) has been widely used to promotes aortic dissections in mice. Here, we provide insight on a modified aortic dissection model in rats. The effect of smooth muscle cell (SMC) relaxation with vasodilators is studied in this model. METHODS: Forty Sprague-Dawley rats were divided in 4 groups: control, isosorbide dinitrate (ISDN, 30 mg/kg/day) in the drinking water, BAPN (0.02%) in the food, BAPN + ISDN (same doses). Thoracic and abdominal aortic diameters were evaluated through transthoracic ultrasound echography. After 6 weeks, all rats were infused with AngII (1 mg/kg/day) subcutaneously. Survival and type of aortic events were numbered. Histological and histochemical analyses of aorta were performed. RESULTS: Initial telesystolic ascending aorta diameters were equal in all groups and became significantly larger in the BAPN + ISDN group compared to the BAPN group (control: 3.37 ± 0.17 mm, ISDN: 3.49 ± 0.16 mm, BAPN: 3.53 ± 0.13 mm, BAPN + ISDN: 3.61 ± 0.16 mm, analysis of variance p < 0.0001). BAPN followed by AngII infusion showed a significant lower survival rate (p = 0.029) and produced a large panel of aortic events. Association of ISDN and BAPN significantly reduces survival (p = 0.001) and provides more aortic events compared to BAPN alone (p = 0.031). In both BAPN-treated groups, orcein staining revealed split and dissected elastic fibers in the media, alcian blue staining showed mucoid degeneration of the aortic wall, and Perls-diaminobenzidine staining revealed an accumulation of Fe2+. CONCLUSION: SMC relaxation with ISDN increases aortic dilatation, worsens aortic prognosis, and reproduces human histological findings in a low-dose BAPN/AngII-induced aortic dissection model in rats.

Management of Pulmonary Hypertension in Patients on Left Ventricular Assist Device Support.

Left ventricular assist devices (LVADs) are increasingly utilized for patients with end-stage heart failure (HF). Pulmonary hypertension (PH) is highly prevalent in this patient population mainly due to prolonged left ventricular (LV) failure and chronically elevated filling pressures. The effect of LVADs on pulmonary circulation and right ventricular (RV) function has recently become an area of great attention in literature. PH can lead to post-LVAD right ventricular failure (RVF) that confers a high risk of morbidity and mortality. Multiple pulmonary vasodilators, that are primarily used for the treatment of pulmonary arterial hypertension (PAH), have been studied for the treatment of PH after LVAD implantation, and some of them have shown promising results. This review aims to investigate the treatment options for PH in patients on LVADs, as well as to give an overview about the pathophysiology of PH and RVF in these patients.

Abnormal vasodilator stress electrocardiogram with normal myocardial perfusion: Clinical decision-making and review of literature.

Ischemic electrocardiographic (ECG) changes during vasodilator stress testing in the presence of abnormal myocardial perfusion imaging (MPI) are associated with more severe coronary artery disease (CAD). However, significance of ECG changes during vasodilator stress test with normal MPI has been controversial. Here, we discuss two cases of significant ischemic ECG changes with vasodilator stress and normal MPI, whose subsequent workup revealed severe obstructive CAD. We also review the available literature on the occurrence and mechanism of these discrepant findings and propose recommendations for management.

Hemiplegic migraine episode triggered by regadenoson.

SPECT and PET myocardial perfusion imaging (MPI) are widely used to evaluate patients for coronary artery disease. Regadenoson (a selective A2A adenosine receptor agonist) is a commonly used vasodilator agent for stress MPI because of its safety profile and ease of use. Common adverse reactions such as headache, shortness of breath, flushing, and chest and abdominal discomfort are typically mild and can be effectively reversed using methylxanthines such as aminophylline and caffeine. Neurological adverse reactions such as seizure and stroke have rarely been reported with the use of regadenoson. The hemodynamic changes associated with regadenoson administration, such as an exaggerated hypotensive or hypertensive response, may be the cause for the reported cerebrovascular accidents. Activation of central nervous system A2A adenosine receptors is thought to be responsible for seizure episodes in patients with or without known histories of seizure. A2A adenosine receptors activation is also believed to play a role in headaches and migraine. This patient reported who has a history of hemiplegic migraine developed left side weakness and headache following the administration of regadenoson during a PET MPI study. Imaging work-up to rule out cerebrovascular accident was normal. After 1 hour from the onset of his symptoms, his weakness and headache significantly improved with complete resolution within 24 hours. We concluded that regadenoson triggered a hemiplegic migraine episode in this patient, which has not been previously reported in the literature. It may be prudent to avoid regadenoson and adenosine use in patients with a history of hemiplegic migraine.

Quantitative myocardial perfusion response to adenosine and regadenoson in patients with suspected coronary artery disease.

BACKGROUND: The aim of the present study was to compare the quantitative flow responses of regadenoson against adenosine using cardiac 15O-water PET imaging in patients with suspected or known coronary artery disease (CAD). METHODS: Hyperemic myocardial blood flow (MBF) after adenosine and regadenoson was compared using correlation and Bland-Altman analysis in 21 patients who underwent rest and adenosine 15O-water PET scans followed by rest and regadenoson 15O-water PET scans. RESULTS: Global mean (± SD) MBF values at rest and stress were 0.92 ± 0.27 and 2.68 ± 0.80 mL·g·min for the adenosine study and 0.95 ± 0.29 and 2.76 ± 0.79 mL·g·min for the regadenoson study (P = 0.55 and P = 0.49). The correlations between global and regional adenosine- and regadenoson-based stress MBF were strong (r = 0.80 and r = 0.77). The biases were small for both global and regional MBF comparisons (0.08 and 0.09 mL·min·g), but the limits of agreement were wide for stress MBF. CONCLUSION: The correlation between regadenoson- and adenosine-induced hyperemic MBF was strong but the agreement was only moderate indicating that established cut-off values for 150-water PET should be used cautiously if using regadenoson as vasodilator.

Evolution of symptoms in patients with stable angina after normal regadenoson myocardial perfusion imaging: The Radionuclide Imaging and Symptomatic Evolution study (RISE).

BACKGROUND: Assessment of quality of life in patients with stable angina and normal gated single-photon emission computed tomography myocardial perfusion imaging (MPI) remains undefined. Symptom evolution in response to imaging findings has important implications on further diagnostic testing and therapeutic interventions. METHODS: Prospective cohort study was conducted at the University of Alabama at Birmingham enrolling 87 adult participants with stable chest pain from the emergency room, hospital setting, and outpatient clinics. Patients underwent MPI with technetium-99m Sestamibi and had a normal study. Participants filled out Seattle Angina Questionnaires initially and at 3-month follow-up. RESULTS: Among the 87 participants (60 ± 12 years; 40% African American, 70% women, 29% diabetes), the mean score increased by an absolute value of 14.2 [95% CI 10.4-18.7, P < .001] in physical limitation, 23.2 [95% CI 17.1-29.4, P < .001] in angina stability, 10.9 [95% CI 7.6-14.1, P < .001] in angina frequency, and 20.6 [95% CI 16.5-24.7, P < .001] in disease perception. There was no significant change in the mean score of treatment satisfaction [- 1.4, 95% CI - 4.7 to 1.8, P = .38]. At 3-month follow-up, 28 of 87 participants (32%) were angina free. CONCLUSIONS: Patients with stable chest pain and normal MPI experience significant improvement in functional status, quality of life, and disease perception in the short term.

Papillary muscle ischemia on high-resolution cine imaging of nitrogen-13 ammonia positron emission tomography: Association with myocardial flow reserve and prognosis in coronary artery disease.

BACKGROUND: The evaluation of papillary muscle (PM) perfusion through existing perfusion imaging, including single-photon emission computed tomography and magnetic resonance imaging, is not possible. Therefore, this study sought to investigate the detection of PM ischemia in coronary artery disease (CAD) using nitrogen-13 (N-13) ammonia positron emission tomography (NH3 PET) and its association with global myocardial flow reserve (MFR) and major adverse cardiac events (MACE). METHODS: Data of adenosine-stress NH3 PET for 263 consecutive patients with known or suspected CAD were retrospectively analyzed. PM ischemia was defined as the absence of PM accumulation under stress conditions and PM presence at rest on high-resolution cine imaging derived from PET-computed tomography scanner with time-of-flight technology. The primary outcome was MACE. RESULTS: Of 263 patients, 30 experienced mean follow-up period of 910 days (MACE), while 31 (11.8%) presented PM ischemia. Compared to patients without PM ischemia, those with PM ischemia reported a significantly lower global MFR and a significantly higher rate of MACE (P < .0001). CONCLUSION: NH3 PET enables the detection of PM ischemia in approximately 10% of patients with known or suspected CAD. PM ischemia is associated with reduced global MFR and is an important sign in predicting prognosis.

Splenic switch-off as a novel marker for adenosine response in nitrogen-13 ammonia PET myocardial perfusion imaging: Cross-validation against CMR using a hybrid PET/MR device.

BACKGROUND: No methodology is available to distinguish truly reduced myocardial flow reserve (MFR) in positron emission tomography myocardial perfusion imaging (PET MPI) from seemingly impaired MFR due to inadequate adenosine response. The adenosine-induced splenic switch-off (SSO) sign has been proposed as a potential marker for adequate adenosine response in cardiac magnetic resonance (CMR). We assessed the feasibility of detecting SSO in nitrogen-13 ammonia PET MPI using SSO in CMR as the standard of reference. METHODS AND RESULTS: Fifty patients underwent simultaneous CMR and PET MPI on a hybrid PET/MR device with co-injection of a gadolinium-based contrast agent and nitrogen-13 ammonia during rest and adenosine-induced stress. In CMR, SSO was assessed visually (positive vs negative SSO) and quantitatively by calculating the ratio of the peak signal intensity of the spleen during stress over rest (SIR). In PET MPI, the splenic signal activity ratio (SAR) was calculated as the maximal standard uptake value of the spleen during stress over rest. The median SIR was significantly lower in patients with positive versus negative SSO in CMR (0.57 [IQR 0.49 to 0.62] vs 0.89 [IQR 0.76 to 0.98]; P < .001). Similarly, median SAR in PET MPI was significantly lower in patients with positive versus negative SSO (0.40 [IQR 0.32 to 0.45] vs 0.80 [IQR 0.47 to 0.98]; P < .001). CONCLUSION: Similarly to CMR, SSO can be detected in nitrogen-13 ammonia PET MPI. This might help distinguish adenosine non-responders from patients with truly impaired MFR due to microvascular dysfunction or multivessel coronary artery disease.

Phenotype-based management of coronary microvascular dysfunction.

40-70% of patients undergoing invasive coronary angiography with signs and symptoms of ischemia are found to have no obstructive coronary artery disease (INOCA). When this heterogeneous group undergo coronary function testing, approximately two-thirds have demonstrable coronary microvascular dysfunction (CMD), which is independently associated with adverse prognosis. There are four distinct phenotypes, or subgroups, each with unique pathophysiological mechanisms and responses to therapies. The clinical phenotypes are microvascular angina, vasospastic angina, mixed (microvascular and vasospastic), and non-cardiac symptoms (reclassification as non-INOCA). The Coronary Vasomotor Disorders International Study Group (COVADIS) have proposed standardized criteria for diagnosis. There is growing awareness of these conditions among clinicians and within guidelines. Testing for CMD can be done using invasive or non-invasive modalities. The CorMicA study advocates the concept of 'functional angiography' to guide stratified medical therapy. Therapies broadly fall into two categories: those that modulate cardiovascular risk and those to alleviate angina. Management should be tailored to the individual, with periodic reassessment for efficacy. Phenotype-based management is a worthy endeavor for both patients and clinicians, aligning with the concept of 'precision medicine' to improve prognosis, symptom burden, and quality of life. Here, we present a contemporary approach to the phenotype-based management of patients with INOCA.

Compassionate use of Pulmonary Vasodilators in Acute Severe Hypoxic Respiratory Failure due to COVID-19.

BACKGROUND: There have been over 200 million cases and 4.4 million deaths from COVID-19 worldwide. Despite the lack of robust evidence one potential treatment for COVID-19 associated severe hypoxaemia is inhaled pulmonary vasodilator (IPVD) therapy, using either nitric oxide (iNO) or prostaglandins. We describe the implementation of, and outcomes from, a protocol using IPVDs in a cohort of patients with severe COVID-19 associated respiratory failure receiving maximal conventional support. METHODS: Prospectively collected data from adult patients with SARS-CoV-2 admitted to the intensive care unit (ICU) at a large teaching hospital were analysed for the period 14th March 2020 - 11th February 2021. An IPVD was considered if the PaO2/FiO2 (PF) ratio was less than 13.3kPa despite maximal conventional therapy. Nitric oxide was commenced at 20ppm and titrated to response. If oxygenation improved Iloprost nebulisers were commenced and iNO weaned. The primary outcome was percentage changes in PF ratio and Alveolar-arterial (A-a) gradient. RESULTS: Fifty-nine patients received IPVD therapy during the study period. The median PF ratio before IPVD therapy was commenced was 11.33kPa (9.93-12.91). Patients receiving an IPVD had a lower PF ratio (14.37 vs. 16.37kPa, p = 0.002) and higher APACHE-II score (17 vs. 13, p = 0.028) at ICU admission. At 72 hours after initiating an IPVD the median improvement in PF ratio was 33.9% (-4.3-84.1). At 72 hours changes in PF ratio (70.8 vs. -4.1%, p < 0.001) and reduction in A-a gradient (44.7 vs. 14.8%, p < 0.001) differed significantly between survivors (n = 33) and non-survivors (n = 26). CONCLUSIONS: The response to IPVDs in patients with COVID-19 associated acute hypoxic respiratory failure differed significantly between survivors and non-survivors. Both iNO and prostaglandins may offer therapeutic options for patients with severe refractory hypoxaemia due to COVID-19. The use of inhaled prostaglandins, and iNO where feasible, should be studied in adequately powered prospective randomised trials.

Inhaled Pulmonary Vasodilators in COVID-19 Infection: A Systematic Review and Meta-Analysis.

Introduction: Inhaled pulmonary vasodilators (IPVD) have been previously studied in patients with non-coronavirus disease-19 (COVID-19) related acute respiratory distress syndrome (ARDS). The use of IPVD has been shown to improve the partial pressure of oxygen in arterial blood (PaO2), reduce fraction of inspired oxygen (FiO2) requirements, and ultimately increase PaO2/FiO2 (P/F) ratios in ARDS patients. However, the role of IPVD in COVID-19 ARDS is still unclear. Therefore, we performed this meta-analysis to evaluate the role of IPVD in COVID-19 patients. Methods: Comprehensive literature search of PubMed, Embase, Web of Science and Cochrane Library databases from inception through April 22, 2022 was performed for all published studies that utilized IPVD in COVID-19 ARDS patients. The single arm studies and case series were combined for a 1-arm meta-analysis, and the 2-arm studies were combined for a 2-arm meta-analysis. Primary outcomes for the 1-arm and 2-arm meta-analyzes were change in pre- and post-IPVD P/F ratios and mortality, respectively. Secondary outcomes for the 1-arm meta-analysis were change in pre- and post-IPVD positive end-expiratory pressure (PEEP) and lung compliance, and for the 2-arm meta-analysis the secondary outcomes were need for endotracheal intubation and hospital length of stay (LOS). Results: 13 single arm retrospective studies and 5 case series involving 613 patients were included in the 1-arm meta-analysis. 3 studies involving 640 patients were included in the 2-arm meta-analysis. The pre-IPVD P/F ratios were significantly lower compared to post-IPVD, but there was no significant difference between pre- and post-IPVD PEEP and lung compliance. The mortality rates, need for endotracheal intubation, and hospital LOS were similar between the IPVD and standard therapy groups. Conclusion: Although IPVD may improve oxygenation, our investigation showed no benefits in terms of mortality compared to standard therapy alone. However, randomized controlled trials are warranted to validate our findings.