A Review of the Role of Tests of Coronary Reactivity in Clinical Practice.

Vasoreactivity testing is used by cardiologists in the diagnosis of coronary spasm endotypes, such as epicardial and microvascular spasm. Intracoronary injection of acetylcholine and ergonovine is defined as a standard class I method according to the Coronary Vasomotion Disorder (COVADIS) Group. Because single vasoreactivity testing may have some clinical limitations in detecting the presence of coronary spasm, supplementary or sequential vasoreactivity testing should be reconsidered. The majority of cardiologists do not consider pseudonegative results when performing these vasoreactivity tests. Vasoreactivity testing may have some limitations when it comes to documenting clinical spasm. In the future, cardiologists around the world should use multiple vasoreactivity tests to verify the presence or absence of epicardial and microvascular spasms in the cardiac catheterisation laboratory.

Impact of Age and of the Patent Ductus Arteriosus on Pulmonary Hemodynamics in Children with Complete Atrioventricular Septal Defect.

Complete atrioventricular septal defect (CAVSD) can lead to the development of pulmonary obstructive vascular disease due to high pulmonary blood flow and pressures. This study aimed to evaluate the changes in pulmonary hemodynamics with aging and with patent ductus arteriosus (PDA) in children with CAVSD. We retrospectively evaluated 137 children (94% with trisomy 21, median age of 195 (25-2963) days, 58.4% female) with CASVD referred to cardiac catheterization from January 2000 to December 2020. Those with associated congenital heart disease, except PDA, had been excluded. They were divided into three age terciles (T1, T2, and T3). Aging was directly associated with higher mean (T1: 34.2 ± 9.1; T2: 37.1 ± 5.8; T3: 42 ± 10.6 mmHg, p < 0.001) and diastolic (T1: 19.4 ± 5.3; T2 21.6 ± 5.0; T3: 26.0 ± 9.5 mmHg, P < 0.001) pulmonary arterial pressures, and with higher pulmonary vascular resistance (T1: 3.24 ± 1.69, T2: 3.47 ± 1.19; T3: 4.49 ± 3.91 Wu.m2, p = 0.023). This resulted in a loss of eligibility for anatomical correction, which became evident only after 300 days of age. PDA was associated with a higher mean (37.2 [35.9; 38.5] vs. 41.3 [37.5; 45.0] mmHg, p = 0.049) and diastolic (21.7 [20.7; 22.6] vs. 26.4 [24.1; 29.0] mmHg, p = 0.001) pulmonary pressure, and resistor-compliance time (0.28 [0.26; 0.29] vs. 0.36 [0.31; 0.40], p = 0.001) after adjusting for age and sex. In children with CAVSD, aging was associated with worsening of pulmonary vascular hemodynamics, particularly when PDA was associated, resulting in loss of eligibility for anatomical correction after 10 months of age as the first surgical option.

Lack of Class I Vasoreactivity Testing for Diagnosing Patients With Coronary Artery Spasm.

BACKGROUND: Vasoreactivity testing, such as intracoronary acetylcholine (ACh) or ergometrine (EM), is defined as Class I for the diagnosis of patients with vasospastic angina (VSA) according to recommendations from the Coronary Vasomotion Disorders International Study (COVADIS) group and guidelines from the Japanese Circulation Society (JCS). HYPOTHESIS: Although vasoreactivity testing is a clinically useful tool, it carries some risks and limitations in diagnosing coronary artery spasm. METHODS: Previous reports on vasoreactivity testing for diagnosing the presence of coronary spasm are summarized from the perspective of Class I. RESULTS: There are several problems such as reproducibility, underestimation, overestimation, and inconclusive/nonspecific results associated with daily spasm. Because provoked spasm caused by intracoronary ACh is not always similar to that caused by intracoronary EM, possibly due to different mediators, supplementary use of these vasoreactivity tests is necessary for cardiologists to diagnose VSA when a provoked spasm is not revealed by each vasoactive agent. CONCLUSIONS: Cardiologists should understand the imperfection of these vasoreactivity tests when diagnosing patients with VSA.

A review regarding the article `Right heart catheterization in idiopathic pulmonary hypertension: An all-inclusive necessity'.

Right heart catheterization (RHC) stands as a unique tool for both diagnosing and managing a broad spectrum of cardiovascular diseases. Though its origins trace back to the 18th century, the most substantial progress was achieved in the 20th century. The focus of this review is on pulmonary hypertension (PH), where RHC is recognized as the diagnostic gold standard. Parameters derived from this procedure are crucial for classifying PH into various subgroups, assessing the risk of adverse events or mortality, and informing treatment strategies. The European Society of Cardiology guidelines define PH as an increase in mean pulmonary artery pressure (PAPm) greater than 25 mmHg. The differentiation between pre- and post-capillary PH is based on the levels of pulmonary artery wedge pressure (PAWP). Furthermore, right atrial pressure (RAP), cardiac index (CI), and mixed venous oxygen saturation (SvO2) are the sole parameters recommended for prognostic assessment, specifically in patients with pulmonary arterial hypertension (PAH). Patients presenting with RAP exceeding 14 mmHg, CI less than 2.0 L/min/m2, and SvO2 below 60% are considered to be at a high risk (greater than 10%) of death within the subsequent year. A primary goal in the management of PAH is the early diagnosis to facilitate the swift initiation of treatment. This aims to minimize symptom burden, optimize the patient's biochemical, hemodynamic, and functional profile, and curtail adverse events. To achieve these objectives, clinicians must remain informed about emerging risk factors and be familiar with the revised hemodynamic definition for PAH.

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.

Data-based modeling of cerebral hemodynamics quantifies impairment of cerebral blood flow regulation in type-2 diabetes.

We studied the regulation dynamics of cerebral blood velocity (CBv) at middle cerebral arteries (MCA) in response to spontaneous changes of arterial blood pressure (ABP), termed dynamic cerebral autoregulation (dCA), and end-tidal CO2 as proxy for blood CO2 tension, termed dynamic vasomotor reactivity (DVR), by analyzing time-series data collected at supine rest from 36 patients with Type-2 Diabetes Mellitus (T2DM) and 22 age/sex-matched non-diabetic controls without arterial hypertension. Our analysis employed a robust dynamic modeling methodology that utilizes Principal Dynamic Modes (PDM) to estimate subject-specific dynamic transformations of spontaneous changes in ABP and end-tidal CO2 (viewed as two "inputs") into changes of CBv at MCA measured via Transcranial Doppler ultrasound (viewed as the "output"). The quantitative results of PDM analysis indicate significant alterations in T2DM of both DVR and dCA in terms of two specific PDM contributions that rise to significance (p < 0.05). Our results further suggest that the observed DVR and dCA alterations may be due to reduction of cholinergic activity (based on previously published results from cholinergic blockade data) that may disturb the sympatho-vagal balance in T2DM. Combination of these two model-based "physio-markers" differentiated T2DM patients from controls (p = 0.0007), indicating diabetes-related alteration of cerebrovascular regulation, with possible diagnostic implications.

Clinical Limitations of Vasoreactivity Testing as a Diagnostic Tool in Patients with Vasospastic Angina.

The Japanese Circulation Society guidelines recommend a class I vasoreactivity test to diagnose patients with vasospastic angina (VSA). However, the acetylcholine or ergonovine test has been established as the gold standard for variant angina (VA). The sensitivity and specificity of intracoronary vasoreactivity testing in patients with VA were acceptable. Cardiologists have employed these vasoreactivity tests to conveniently diagnose the presence of coronary spasms in patients with all VSA. The majority of VSAs may have lower disease activity than VA cases. We have summarized the usefulness of spasm provocation tests in patients with VA and VSA. A positive-provoked spasm diagnosed by standard vasoreactivity testing may indicate a disease state similar to that of VA, whereas a negative-provoked spasm after standard vasoreactivity testing may indicate a lower disease state than that of VA. Cardiologists should reconsider the limited usefulness of vasoreactivity testing when diagnosing the presence of coronary spasms in all VSAs, but not VA.

Cerebral autoregulation, spreading depolarization, and implications for targeted therapy in brain injury and ischemia.

Cerebral autoregulation is an intrinsic myogenic response of cerebral vasculature that allows for preservation of stable cerebral blood flow levels in response to changing systemic blood pressure. It is effective across a broad range of blood pressure levels through precapillary vasoconstriction and dilation. Autoregulation is difficult to directly measure and methods to indirectly ascertain cerebral autoregulation status inherently require certain assumptions. Patients with impaired cerebral autoregulation may be at risk of brain ischemia. One of the central mechanisms of ischemia in patients with metabolically compromised states is likely the triggering of spreading depolarization (SD) events and ultimately, terminal (or anoxic) depolarization. Cerebral autoregulation and SD are therefore linked when considering the risk of ischemia. In this scoping review, we will discuss the range of methods to measure cerebral autoregulation, their theoretical strengths and weaknesses, and the available clinical evidence to support their utility. We will then discuss the emerging link between impaired cerebral autoregulation and the occurrence of SD events. Such an approach offers the opportunity to better understand an individual patient's physiology and provide targeted treatments.

Calcium channel blockers in patients with pulmonary arterial hypertension receiving PAH-specific treatment.

BACKGROUND: Calcium channel blockers (CCB) are the first effective therapy for vasoreactive patients with idiopathic pulmonary arterial hypertension (IPAH). However, the advent of modern PAH-specific drugs may undermine the role of vasoreactivity tests and CCB treatment. We aimed to clarify the effect of acute vasoreactivity testing and CCB on patients with IPAH receiving PAH-specific treatment. METHODS: We retrospectively investigated consecutive patients with IPAH (n = 136) diagnosed between 2000 and 2020 and collected data from patients who underwent acute vasoreactivity testing using inhaled nitric oxide (NO). The effects of vasoreactivity testing and CCB therapy were reviewed. Long-term survival was analysed using the Kaplan-Meier method. RESULTS: Acute vasoreactivity testing was performed in 49% of patients with IPAH (n = 67), including 23 patients (34%) receiving PAH-specific therapy without vasoreactivity testing. Eight patients (12%), including three patients (4.4%) receiving PAH-specific therapy, presented acute responses at vasoreactivity testing. They received high-dose CCB therapy (CCB monotherapy for five patients [7.5%] and CCB therapy and PAH-specific therapy for three patients [4.4%]). They presented a significant improvement in clinical parameters and near-normalisation of haemodynamics (mean pulmonary arterial pressure decreased from 46 [interquartile range: 40-49] to 19.5 [interquartile range: 18-23] mmHg [P < .001] at 1-year follow-up). All eight vasoreactive responders receiving CCB therapy showed better long-term survival than non-responders treated with PAH-specific therapy (P < .001). CONCLUSIONS: CCB therapy benefited patients with IPAH who showed acute response to vasoreactivity testing using inhaled NO, even when receiving modern PAH-specific therapy. Acute vasoreactive responders may benefit more from CCB than from PAH-specific therapy.

Positive Vasoreactivity Testing in Pulmonary Arterial Hypertension: Therapeutic Consequences, Treatment Patterns, and Outcomes in the Modern Management Era.

BACKGROUND: Among patients with pulmonary arterial hypertension (PAH), acute vasoreactivity testing during right heart catheterization may identify acute vasoresponders, for whom treatment with high-dose calcium channel blockers (CCBs) is recommended. However, long-term outcomes in the current era remain largely unknown. We sought to evaluate the implications of acute vasoreactivity response for long-term response to CCBs and other outcomes. METHODS: Patients diagnosed with PAH between January 1999 and December 2018 at 15 pulmonary hypertension centers were included and analyzed retrospectively. In accordance with current guidelines, acute vasoreactivity response was defined by a decrease of mean pulmonary artery pressure by ≥10 mm Hg to reach <40 mm Hg, without a decrease in cardiac output. Long-term response to CCBs was defined as alive with unchanged initial CCB therapy with or without other initial PAH therapy and World Health Organization functional class I/II and/or low European Society of Cardiology/European Respiratory Society risk status at 12 months after initiation of CCBs. Patients were followed for up to 5 years; clinical measures, outcome, and subsequent treatment patterns were captured. RESULTS: Of 3702 patients undergoing right heart catheterization for PAH diagnosis, 2051 had idiopathic, heritable, or drug-induced PAH, of whom 1904 (92.8%) underwent acute vasoreactivity testing. A total of 162 patients fulfilled acute vasoreactivity response criteria and received an initial CCB alone (n=123) or in combination with another PAH therapy (n=39). The median follow-up time was 60.0 months (interquartile range, 30.8-60.0), during which overall survival was 86.7%. At 12 months, 53.2% remained on CCB monotherapy, 14.7% on initial CCB plus another initial PAH therapy, and the remaining patients had the CCB withdrawn and/or PAH therapy added. CCB long-term response was found in 54.3% of patients. Five-year survival was 98.5% in long-term responders versus 73.0% in nonresponders. In addition to established vasodilator responder criteria, pulmonary artery compliance at acute vasoreactivity testing, low risk status and NT-proBNP (N-terminal pro-B-type natriuretic peptide) levels at early follow-up correlated with long-term response and predicted survival. CONCLUSIONS: Our data display heterogeneity within the group of vasoresponders, with a large subset failing to show a sustained satisfactory clinical response to CCBs. This highlights the necessity for comprehensive reassessment during early follow-up. The use of pulmonary artery compliance in addition to current measures may better identify those likely to have a good long-term response.

Assessment of Neurovascular Coupling by Spectral Analysis of Cerebral Blood Flow Velocity With Transcranial Doppler.

OBJECTIVE: Neurovascular coupling (NVC) represents the increase in regional blood flow associated with neural activity. The aim here was to describe a new approach to non-invasive measurement of NVC by spectral analysis of the cerebral blood flow velocity (CBFV) with transcranial Doppler. METHODS: In a sample of 20 healthy participants, we monitored systolic CBFV in the left posterior cerebral artery (PCA) during off (eyes closed) and on (flickering checkerboard) periods. The contralateral middle cerebral artery was simultaneously monitored as a control. Each participant was submitted to three experiments, each having five cycles, with increasing duration of the cycles, from 10 s (0.1 Hz) to 20 s (0.05 Hz) and lastly 40 s (0.025 Hz), half the time for on and for off periods, constituting a total of 6 min. The successive cycles were expected to cause oscillation in CBFV in a sinusoidal pattern that could be characterized by spectral analysis. We also measured the classic CBFV overshoot as the relative increase in percentage of systolic CBFV from baseline. The relationship and agreement between the two methods were analyzed by linear regression and Bland-Altman plots. In every participant, a clear peak of amplitude in the PCA CBFV spectrum was discernible at 0.1, 0.05 and 0.025 Hz of visual stimulation. RESULTS: On average, this amplitude was 7.1 ± 2.3%, 10.9 ± 3.5% and 17.3 ± 6.5%, respectively. This response contrasted significantly with an absent peak in middle cerebral artery monitoring (p < 0.0001). The spectral amplitude and classic overshoot were highly correlated and linearly related (p < 0.0001). CONCLUSION: NVC can be quantified by the spectral amplitude of PCA CBFV at slower and higher frequencies of visual stimulation. This method represents an alternative to classic overshoot without the need for stimulus marking or synchronization.

What is the meaning of provoked spasm phenotypes by vasoreactivity testing?

Coronary artery epicardial spasm is involved in the pathogenesis of many cardiac disorders. Vasoreactivity testing, such as intracoronary injection of acetylcholine (ACH) or ergonovine (ER), is the gold standard method for the diagnosis of vasospastic angina. Provoked epicardial spasm phenotypes are classified as focal spasm and diffuse spasm. Multiple factors, including sex, ethnicity, and use of coronary vasoactive stimulators, are related to the provoked phenotypes of epicardial spasm. Diffuse-provoked spasm is often observed in females, where focal-provoked spasm is markedly more common in males. ACH provokes more diffuse and distal spasms, whereas ER induces more focal and proximal spasms. Yellow plaque and coronary thrombi are often observed in lesions with focal spasms, and intimal thickness with a sonolucent zone is significantly more common in lesions with focal spasm. Furthermore, clinical outcomes in patients with focal spasm are unsatisfactory compared with those in patients with diffuse spasm. However, the reproducibility and eternality of provoked spasm phenotypes by vasoreactivity testing is uncertain. Coronary atherosclerosis or endothelial damage may affect coronary vasomotor tone. Although coronary artery spasm may persist in the same coronary artery, provoked coronary spasm phenotypes may exhibit a momentary coronary reaction by intracoronary ACH or ER testing.

Characterization of Vasoreactivity in a Semi-Arboreal Snake, the Tokara Habu (Protobothrops tokarensis).

Vasoreactivity is relatively well documented in terrestrial snakes but has previously been investigated in only one semi-arboreal snake species. Consequently, the extent to which vasoreactivity is common across snake taxa or varies by habitat is unclear. The Tokara habu (Protobothrops tokarensis) is a semi-arboreal snake endemic to only two small adjacent Japanese islands, and hence a useful species for further investigation of vasoreactivity. We evaluated responses to known vasoactive substances in thoracic aortas isolated from Tokara habu. Under resting tension, noradrenaline and angiotensin II induced concentration-dependent contraction, but acetylcholine, serotonin (5-hydroxytriptamine; 5-HT), and isoproterenol induced relaxation followed by contraction. Histamine and rattlesnake bradykinin had no effect. Experiments with receptor-specific antagonists suggest that M1 and M3 receptors are involved in the acetylcholine-induced response; 5-HT1, 5-HT2, and 5-HT7 receptors in the serotonin-induced response; and ß1 and ß2 adrenoceptors in isoproterenol-induced relaxation. This is the first report on such response patterns in snakes (including serotonin- and isoproterenol-induced relaxation). Nitric oxide may be involved in acetylcholine-induced relaxation but not in the responses to serotonin or isoproterenol. In contrast to the uniform vasoreactivity observed in terrestrial snakes, the vasoreactivity of semi-arboreal snakes may be governed by diverse regulatory mechanisms.

Impaired cerebrovascular CO2 reactivity at high altitude in prematurely born adults.

Premature birth impairs cardiac and ventilatory responses to both hypoxia and hypercapnia, but little is known about cerebrovascular responses. Both at sea level and after 2 days at high altitude (3375 m), 16 young preterm-born (gestational age, 29 ± 1 weeks) and 15 age-matched term-born (40 ± 0 weeks) adults were exposed to two consecutive 4 min bouts of hyperoxic hypercapnic conditions (3% CO2 -97% O2 ; 6% CO2 -94% O2 ), followed by two periods of voluntary hyperventilation-induced hypocapnia. We measured middle cerebral artery blood velocity, end-tidal CO2 , pulmonary ventilation, beat-by-beat mean arterial pressure and arterialized capillary blood gases. Baseline middle cerebral artery blood velocity increased at high altitude compared with sea level in term-born (+24 ± 39%, P = 0.036), but not in preterm-born (-4 ± 27%, P = 0.278) adults. The end-tidal CO2 , pulmonary ventilation and mean arterial pressure were similar between groups at sea level and high altitude. Hypocapnic cerebrovascular reactivity was higher at high altitude compared with sea level in term-born adults (+173 ± 326%, P = 0.026) but not in preterm-born adults (-21 ± 107%, P = 0.572). Hypercapnic reactivity was altered at altitude only in preterm-born adults (+125 ± 144%, P < 0.001). Collectively, at high altitude, term-born participants showed higher hypocapnic (P = 0.012) and lower hypercapnic (P = 0.020) CO2 reactivity compared with their preterm-born peers. In conclusion, exposure to high altitude revealed different cerebrovascular responses in preterm- compared with term-born adults, despite similar ventilatory responses. These findings suggest a blunted cerebrovascular response at high altitude in preterm-born adults, which might predispose these individuals to an increased risk of high-altitude illnesses. KEY POINTS: Cerebral haemodynamics and cerebrovascular reactivity in normoxia are known to be similar between term-born and prematurely born adults. In contrast, acute exposure to high altitude unveiled different cerebrovascular responses to hypoxia, hypercapnia and hypocapnia. In particular, cerebral vasodilatation was impaired in prematurely born adults, leading to an exaggerated cerebral vasoconstriction. Cardiovascular and ventilatory responses to both hypo- and hypercapnia at sea level and at high altitude were similar between control subjects and prematurely born adults. Other mechanisms might therefore underlie the observed blunted cerebral vasodilatory responses in preterm-born adults at high altitude.

Can Inhaled Nitric Oxide Response Predict Tolerance to Therapies and Survival in Patients With Combined Precapillary and Postcapillary Pulmonary Hypertension?

Inhaled nitric oxide (iNO) relaxes the pulmonary circulation and variably increases the left ventricular preload and pulmonary artery wedge pressure (PAWP)-hemodynamic information that may help guide treatment decisions and assess prognosis in patients with combined precapillary and postcapillary pulmonary hypertension (PH). We included consecutive patients with combined precapillary and postcapillary PH (mean pulmonary artery pressure >20 mm Hg, PAWP >15 mm Hg, and pulmonary vascular resistance [PVR] >2 Woods unit [WU]) who underwent right-sided cardiac catheterization with iNO at the Cleveland Clinic Pulmonary Vascular Disease program between 2017 and 2022. We included 104 patients with baseline PAWP and PVR of 22.2 ± 4.2 mm Hg and 6.1 ± 3.2 WU, respectively. Pulmonary arterial hypertension (PAH) with postcapillary component and PH left heart disease with precapillary component were identified in 27 (26%) and 77 patients (74%), respectively. No side effects were noted during the administration of iNO. During iNO, the PVR decreased 1.1 ± 1.4 WU and the PAWP increased 1.3 ± 3.7 mm Hg. A more pronounced increase in PAWP with iNO was associated with a decrease in PVR (R -0.35, p <0.001) and increase in stroke volume (R 0.20, p = 0.046). Tolerance to PAH-specific medications, overall survival, and heart failure hospitalizations were not significantly associated with the change in PAWP or PVR with iNO. In conclusion, in patients with combined precapillary and postcapillary PH, iNO challenge is safe and caused a significant decrease in PVR, with an increase in PAWP. The changes in PAWP and PVR during iNO administration were not associated with tolerance to PAH-specific medications, heart failure-related hospitalization, or survival.

Inhaled nitric oxide testing in predicting prognosis in pulmonary hypertension due to left-sided heart diseases.

AIMS: The pathophysiology of pulmonary hypertension (PH) due to left-sided heart disease (Group 2 PH) is distinct from that of other groups of PH, yet there are still no approved therapies that selectively target pulmonary circulation. The increase in pulmonary capillary pressure due to left-sided heart disease is a trigger event for physical and biological alterations of the pulmonary circulation, including the nitric oxide (NO)-soluble guanylate cyclase-cyclic guanosine monophosphate axis. This study investigated inhaled NO vasoreactivity tests for patients with Group 2 PH and hypothesized that these changes may have a prognostic impact. METHODS AND RESULTS: This was a single-centre, retrospective study with a median follow-up of 365 days. From January 2011 to December 2015, we studied 69 patients with Group 2 PH [age, 61.5 ± 13.0 (standard deviation) years; male:female, 49:20; left ventricular ejection fraction, 50.1 ± 20.4%; mean pulmonary arterial pressure, ≥25 mmHg; and pulmonary arterial wedge pressure (PAWP), >15 mmHg]. No adverse events were observed after NO inhalation. Thirty-four patients with Group 2 PH showed increased PAWP (ΔPAWP: 3.26 ± 2.22 mmHg), while the remaining 35 patients did not (ΔPAWP: -2.11 ± 2.29 mmHg). Multivariate analysis revealed that increased PAWP was the only significant predictor of all-cause death or hospitalization for heart failure (HF) after 1 year (hazard ratio 4.35; 95% confidence interval, 1.27-14.83; P = 0.019). The acute response of PAWP to NO differed between HF with preserved and reduced ejection fractions. CONCLUSIONS: Patients with Group 2 PH were tolerant of the inhaled NO test. NO-induced PAWP is a novel prognostic indicator.

Comparison of Near-Infrared Spectroscopy-Based Cerebral Autoregulatory Indices in Extremely Low Birth Weight Infants.

BACKGROUND: Premature infants are born with immature cerebral autoregulation function and are vulnerable to pressure passive cerebral circulation and subsequent brain injury. Measurements derived from near-infrared spectroscopy (NIRS) have enabled continuous assessment of cerebral vasoreactivity. Although NIRS has enabled a growing field of research, the lack of clear standardization in the field remains problematic. A major limitation of current literature is the absence of a comparative analysis of the different methodologies. OBJECTIVES: To determine the relationship between NIRS-derived continuous indices of cerebral autoregulation in a cohort of extremely low birth weight (ELBW) infants. METHODS: Premature infants of birth weight 401-1000 g were studied during the first 72 h of life. The cerebral oximetry index (COx), hemoglobin volume index (HVx), and tissue oxygenation heart rate reactivity index (TOHRx) were simultaneously calculated. The relationship between each of the indices was assessed with Pearson correlation. RESULTS: Fifty-eight infants with a median gestational age of 25.8 weeks and a median birth weight of 738 g were included. Intraventricular hemorrhage (IVH) was detected in 33% of individuals. COx and HVx demonstrated the highest degree of correlation, although the relationship was moderate at best (r = 0.543, p < 0.001). No correlation was found either between COx and TOHRx (r = 0.318, p < 0.015) or between HVx and TOHRx (r = 0.287, p < 0.029). No significant differences in these relationships were found with respect to IVH and no IVH in subgroup analysis. CONCLUSIONS: COx, HVx, and TOHRx are not numerically equivalent. Caution must be applied when interpreting or comparing results based on different methodologies for measuring cerebral autoregulation. Uniformity regarding data acquisition and analytical methodology are needed to firmly establish a gold standard for neonatal cerebral autoregulation monitoring.

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 AVR responders 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.

Vasoreactivity of the optic nerve head, nailfold, and facial skin in response to cold provocation in normal-tension glaucoma patients.

BACKGROUND: The dysfunction of optic nerve head (ONH) hemodynamics has been suggested to be involved in the pathogenesis of normal-tension glaucoma (NTG). The aim of this study was to compare vasoreactivity in the ONH, nailfold, and facial skin in response to cold-water provocation in NTG patients and healthy controls. METHODS: We performed cold-water provocation in 14 eyes of 14 NTG patients and 15 eyes of 15 age-matched control subjects. Laser speckle flowgraphy-derived tissue-area mean blur rate (MT), skin blood flowmetry-derived pulse wave amplitude (PA), nailfold capillaroscopy-derived nailfold capillary diameter, and other clinical parameters were recorded at baseline and 4 and 6 min after the cold stimulus. We compared changes (as percentages) in these variables in the NTG and control subjects with a linear mixed-effects model and evaluated correlations between these changes with Spearman's rank correlation coefficient. RESULTS: The interaction term between the NTG group (reference, control group) and the 4-min protocol step (reference, baseline) significantly affected the changes in MT, nailfold capillary diameter and PA (ß = -9.51%, P = 0.017, ß = -20.32%, P = 0.002; ß = + 18.06%, P = 0.017, respectively). The change in MT was positively correlated with the change in nailfold capillary diameter, and negatively correlated with the change in PA (r = 0.39, P = 0.036; r = -0.40, P = 0.031, respectively). CONCLUSION: NTG patients showed abnormal vasoconstriction in the ONH and nailfold and vasodilation in the facial skin in response to cold-water provocation.