Echocardiographic probability of pulmonary hypertension: a validation study

BackgroundAccording to current guidelines, the diagnosis of pulmonary hypertension (PH) relies on echocardiographic probability followed by right heart catheterization. How echocardiography predicts PH recently re-defined by a mean pulmonary artery pressure (mPAP) >20 mmHg instead of ≥25 mmHg and pulmonary vascular disease defined by a pulmonary vascular resistance (PVR) >3 or >2 Wood units has not been established.MethodsA total of 278 patients referred for PH underwent a comprehensive echocardiography followed by a right heart catheterization. Fifteen patients (5.4%) were excluded because of insufficient quality echocardiography.ResultsWith PH defined by a mPAP >20 mmHg, 23 patients had no PH, 146 had pre-capillary and 94 post-capillary PH. At univariate analysis, maximum velocity of tricuspid regurgitation (TRV) ≥2.9 and ≤3.4 m s−1, left ventricle (LV) eccentricity index >1.1, right ventricle (RV) outflow tract (OT) notching or acceleration time <105 ms, RV-LV basal diameter >1 and PA diameter predicted PH, whereas inferior vena cava diameter and right atrial area did not. At multivariable analysis, only TRV ≥2.9 m s−1 independently predicted PH. Additional independent prediction of PVR >3 Wood units was offered by LV eccentricity index >1.1 and RVOT acceleration time <105 ms and/or notching, but with no improvement of optimal combination of specificity and sensibility or positive prediction.ConclusionsEchocardiography as recommended in current guidelines can be used to assess the probability of re-defined PH in a referral center. However, the added value of indirect signs is modest and sufficient quality echocardiographic signals may not be recovered in some patients.

MEK Inhibition in a Newborn with RAF1-Associated Noonan Syndrome Ameliorates Hypertrophic Cardiomyopathy but Is Insufficient to Revert Pulmonary Vascular Disease

The RAF1:p.Ser257Leu variant is associated with severe Noonan syndrome (NS), progressive hypertrophic cardiomyopathy (HCM), and pulmonary hypertension. Trametinib, a MEK-inhibitor approved for treatment of RAS/MAPK-mutated cancers, is an emerging treatment option for HCM in NS. We report a patient with NS and HCM, treated with Trametinib and documented by global RNA sequencing before and during treatment to define transcriptional effects of MEK-inhibition. A preterm infant with HCM carrying the RAF1:p.Ser257Leu variant, rapidly developed severe congestive heart failure (CHF) unresponsive to standard treatments. Trametinib was introduced (0.022 mg/kg/day) with prompt clinical improvement and subsequent amelioration of HCM at ultrasound. The appearance of pulmonary artery aneurysm and pulmonary hypertension contributed to a rapid worsening after ventriculoperitoneal shunt device placement for posthemorrhagic hydrocephalus: she deceased for untreatable CHF at 3 months of age. Autopsy showed severe obstructive HCM, pulmonary artery dilation, disarrayed pulmonary vascular anatomy consistent with pulmonary capillary hemangiomatosis. Transcriptome across treatment, highlighted robust transcriptional changes induced by MEK-inhibition. Our findings highlight a previously unappreciated connection between pulmonary vascular disease and the severe outcome already reported in patients with RAF1-associated NS. While MEK-inhibition appears a promising therapeutic option for HCM in RASopathies, it appears insufficient to revert pulmonary hypertension.

A Wrinkle in Time: Circadian biology in pulmonary vascular health and disease

An often over looked element of pulmonary vascular disease is time. Cellular responses to time, which are regulated directly by the core circadian clock, have only recently been elucidated. Despite an extensive collection of data regarding the role of rhythmic contribution to disease pathogenesis (such as systemic hypertension, coronary artery and renal disease), the roles of key circadian transcription factors in pulmonary hypertension remain under-studied. This is despite a large degree of overlap in the pulmonary hypertension and circadian rhythm fields, including not only shared signaling pathways, but also cell-specific effects of the core clock that are known to result in both protective and adverse lung vessel changes. Therefore, the goal of this review is to summarize the current dialogue regarding common pathways in circadian biology, with a specific emphasis on its implications in the progression of pulmonary hypertension. In this work, we emphasize specific proteins involved in the regulation of the core molecular clock while noting the circadian cell-specific changes relevant to vascular remodeling. Finally, we apply this knowledge to the optimization of medical therapy, with a focus on sleep hygiene and the role of chronopharmacology in patients with this disease. In dissecting the unique relationship between time and cellular biology, we aim to provide valuable insight into the practical implications of considering time as a therapeutic variable. Armed with this information, physicians will be positioned to more efficiently utilize the full four dimensions of patient care, resulting in improved morbidity and mortality of pulmonary hypertension patients.

Genotypes and Phenotypes: A Review of Pulmonary Hypertension in Genetic Syndromes

There has been significant advancement in the understanding of the genetics of pulmonary hypertension (PH), particularly in those with heritable or idiopathic pulmonary arterial hypertension. In addition to genetic variants with a primarily pulmonary vascular disease phenotype, the prevalence of PH in other genetic syndromes is increasingly recognized. We will review the current knowledge of PH associated with multisystem genetic syndromes. There is high prevalence of coexisting cardiac and pulmonary disease, making it challenging to discern whether PH is secondary to these processes or underlying genetic makeup. There is a paucity of data on response to PH-targeted therapy and implications on overall prognosis.

46 A clinical and echocardiographic score to differentiate pulmonary hypertension due to heart failure with preserved ejection fraction from idiopathic pulmonary hypertension: the PH-HFpEF score

Aims One of the most challenging differential diagnoses in pulmonary hypertension clinical practice, is the discrimination between idiopathic pulmonary arterial hypertension (IPAH) and pulmonary hypertension due to heart failure with preserved ejection fraction (PH-HFpEF). We elaborate a score (considering patient clinical history, demographics, and echocardiographic characteristics) that can predict, noninvasively, PH-HFpEF vs. IPAH diagnosis. Methods and results Data were prospectively collected on 466 consecutive patients with a final diagnosis of IPAH or PH-HFpEF referred to a single tertiary pulmonary vascular disease centre. Data included clinical history, demographics, and parameters of an electrocardiogram and a transthoracic echocardiogram. A multivariate regression model was developed to predict a PH-HFpEF diagnosis, and an integer risk score was generated using adjusted regression coefficients of the multivariate logistic regression analysis. At the multivariate logistic regression a high ratio between left and right ventricular dimensions, a history of atrial fibrillation (AF), a high body mass index (BMI), a reduced mitral deceleration time and a high E-wave at trans-mitral Doppler, an advanced age and a high right ventricular fractional area change (FAC) were predictors of PH-HFpEF. The derived PH-HFPEF score (Figure), with a cut-point ≥11, yielded a specificity/sensitivity, respectively, for the diagnosis of PH-HFpEF, of 100%/49% with an AUC of 0.987. ED, end-diastolic; LV, left ventricle; RV, right ventricle. Conclusions The PH-HFPEF score can predict PH-HFpEF vs. IPAH. The PH-HFPEF score may be used to potentially avoid an invasive diagnostic testing in almost half of PH-HFpEF patients.

EXPRESS: The association of six minute walk work and other clinical measures to cardiopulmonary exercise test parameters in pulmonary vascular disease

In pulmonary vascular disease (PVD) exercise abnormalities can include reduced exercise capacity, reduced oxygen pulse (O2 pulse) and elevated VE/VCO2. The association of clinical measures such as 6 minute walk work (6MWW), haemodynamics, lung function and echocardiogram to peak VO2, O2 pulse and VE/VCO2 has not been fully investigated in PVD Aims: To determine the relationship of 6MWW and other clinical measures to peak VO2, peak O2 pulse and VE/VCO2. Additionally, to investigate the ability to predict peak VO2 from 6MWW and other clinical parameters. Methods: Clinical data was retrospectively analysed from 63 chronic thromboembolic pulmonary hypertension (CTEPH) and 54 chronic thromboembolic disease (CTED) patients. 6 minute walk test measures, haemodynamics, lung function and echocardiographic measures were correlated with peak VO2, peak O2 pulse and VE/VCO2. Predictive equations were developed to predict peak V̇O2 in both CTEPH and CTED cohorts and subsequently validated. Results: A number of clinical parameters correlated to peak VO2, peak O2 pulse and VE/VCO2. 6MWW and TLCO demonstrated the strongest correlation to peak VO2 and peak O2 pulse. The validation of the predictive equations showed a variable level of agreement between measured peak VO2 and calculated peak VO2 from the predictive equations. Conclusion: 6MWW and additionally a number of clinical test parameters were associated to peak VO2, peak O2 pulse and VE/VCO2. 6MWW and TLCO were particularly highly correlated to peak VO2 and similarly to peak O2 pulse. The validation of the predictive equations showed a variable level of agreement and therefore may have limited clinical applicability.

Epigenetic Regulation of Endothelial Dysfunction and Inflammation in Pulmonary Arterial Hypertension

Once perceived as a disorder treated by vasodilation, pulmonary artery hypertension (PAH) has emerged as a pulmonary vascular disease with severe endothelial cell dysfunction. In the absence of a cure, many studies seek to understand the detailed mechanisms of EC regulation to potentially create more therapeutic options for PAH. Endothelial dysfunction is characterized by complex phenotypic changes including unchecked proliferation, apoptosis-resistance, enhanced inflammatory signaling and metabolic reprogramming. Recent studies have highlighted the role of epigenetic modifications leading to pro-inflammatory response pathways, endothelial dysfunction, and the progression of PAH. This review summarizes the existing literature on epigenetic mechanisms such as DNA methylation, histone modifications, and non-coding RNAs, which can lead to aberrant endothelial function. Our goal is to develop a conceptual framework for immune dysregulation and epigenetic changes in endothelial cells in the context of PAH. These studies as well as others may lead to advances in therapeutics to treat this devastating disease.

The physiologic basis of pulmonary arterial hypertension

Pulmonary arterial hypertension (PAH) is a rare dyspnea-fatigue syndrome caused by a progressive increase in pulmonary vascular resistance (PVR) and eventual right ventricular (RV) failure. In spite of extensive pulmonary vascular remodeling, lung function in PAH is generally well preserved, with hyperventilation and increased physiologic dead space, but minimal changes in lung mechanics and only mild to moderate hypoxemia and hypocapnia. Hypoxemia is mainly caused by a low mixed venous PO2 from a decreased cardiac output. Hypocapnia is mainly caused by an increased chemosensitivity. Exercise limitation in PAH is cardiovascular rather than ventilatory or muscular. The extent of pulmonary vascular disease in PAH is defined by multipoint pulmonary vascular pressure-flow relationships with a correction for hematocrit. Pulsatile pulmonary vascular pressure-flow relationships in PAH allow for the assessment of RV hydraulic load. This analysis is possible either in the frequency-domain or in the time-domain. The RV in PAH adapts to increased afterload by an increased contractility to preserve its coupling to the pulmonary circulation. When this homeometric mechanism is exhausted, the RV dilates to preserve flow output by an additional heterometric mechanism. Right heart failure is then diagnosed by imaging of increased right heart dimensions and clinical systemic congestion signs and symptoms. The coupling of the RV to the pulmonary circulation is assessed by the ratio of end-systolic to arterial elastances, but these measurements are difficult. Simplified estimates of RV-PA coupling can be obtained by magnetic resonance or echocardiographic imaging of ejection fraction.