Recurrent episodes of Takotsubo cardiomyopathy in systemic sclerosis.

Systemic sclerosis is an autoimmune disease characterized by fibrosis and small vessel vasculopathy, which affects various organ systems, such as the heart. Takotsubo cardiomyopathy is a transient cardiomyopathy in reaction to an emotional or physical trigger. There may be clinical and pathogenetic overlap between Takotsubo cardiomyopathy and primary systemic sclerosis heart disease, and some patients with systemic sclerosis have been diagnosed with recurrent Takotsubo cardiomyopathy. Our large systemic sclerosis clinical cohort was reviewed to identify cases diagnosed with Takotsubo cardiomyopathy. The clinical features, laboratory and imaging results were reviewed and evaluated to perform a comparison between cases. We identified five patients with systemic sclerosis, all female (age 68.6 ± 5.7 years), who were diagnosed with Takotsubo cardiomyopathy. Two of these patients had recurrent episodes: one case with a history of multiple episodes and the other with one recurrence. Typical features included repolarization abnormalities on the electrocardiogram and transient left ventricular dysfunction observed using echocardiography or cardiac magnetic resonance imaging. Our findings build upon previous reports and observations that systemic sclerosis may cause Takotsubo cardiomyopathy. To our knowledge, this is the largest case series of Takotsubo syndrome in patients with systemic sclerosis. This association may provide novel insights into the aetiopathogenesis of Takotsubo cardiomyopathy as part of primary systemic sclerosis heart involvement.

Deep phenotyping of p.(V142I)-associated variant transthyretin amyloid cardiomyopathy: Distinct from wild-type transthyretin amyloidosis?

AIMS: Transthyretin amyloid cardiomyopathy (ATTR-CM) is an increasingly recognized cause of heart failure. A total of 3-4% of individuals of African descent carry a TTR gene mutation encoding the p.(V142I) variant, a powerful risk factor for development of variant ATTR-CM (ATTRv-CM); this equates to 1.6 million carriers in the United States. We undertook deep phenotyping of p.(V142I)-ATTRv-CM and comparison with wild-type ATTR-CM (ATTRwt-CM). METHODS AND RESULTS: A retrospective study of 413 patients with p.(V142I) ATTRv-CM who attended the UK National Amyloidosis Centre (NAC) was conducted. Patients underwent evaluation at time of diagnosis, including clinical, echocardiography, and biomarker analysis; a subgroup had cardiac magnetic resonance (CMR) imaging. A total of 413 patients with ATTRwt-CM, matched for independent predictors of prognosis (age, NAC Stage, decade of first presentation), were used as a comparator group. At time of diagnosis, patients with ATTRv-CM had significant functional impairment by New York Heart Association classification (NHYA class ≥ III; 38%) and 6-min walk test distance (median 276 m). Median 5-year survival in ATTRv-CM patients was 31 versus 59 months in matched patients with ATTRwt-CM (p < 0.001). Patients with ATTRv-CM had significant impairment of functional parameters by echocardiography including biventricular impairment, high burden of regurgitant valvular disease and low cardiac output. Multivariable analysis revealed the prognostic importance of right ventricular dysfunction. CMR and histological analysis revealed myocyte atrophy and widespread myocardial infiltration in ATTRv-CM. CONCLUSION: p.(V142I)-ATTRv-CM has an aggressive phenotype characterized by myocyte loss and widespread myocardial infiltration which may account for frequent biventricular failure and poor prognosis in this ATTR-CM genotypic subgroup.

Balloon pulmonary angioplasty outcomes in patients previously treated by pulmonary endarterectomy surgery are inferior to those of inoperable patients.

Pulmonary endarterectomy (PEA) may not achieve full clearance of vascular obstructions in patients with more distal chronic thromboembolic pulmonary hypertension (CTEPH). Balloon pulmonary angioplasty (BPA) may be indicated to treat these residual vascular lesions. We compared whether patients post-PEA (PP) treated by BPA derived similar benefit to those who had inoperable CTEPH (IC), and assessed predictors of BPA response after surgery. We treated 109 patients with BPA-89 with IC and 20 PP. Serial right heart catheterization performed at baseline (immediately before BPA) and 3 months after completing BPA, compared pulmonary vascular resistance (PVR), mean pulmonary artery pressure (mPAP) as well as change in WHO functional class and 6-minute walk distance. We also assessed the impact of total thrombus tail length (TTTL) from photographed PEA surgical specimens and PP computed tomography pulmonary angiography (CTPA)-quantified residual disease burden on BPA response. PP and IC groups did not differ significantly in terms of demographics, baseline hemodynamics or procedural characteristics. However, IC derived greater hemodynamic benefit from BPA: ΔPVR (-27.9 ± 20.2% vs. -13.9 ± 23.9%, p < 0.05) and ΔmPAP (-17.1 ± 14.4% vs. -8.5 ± 18.0%, p < 0.05). There was a negative correlation between pre-BPA PVR and TTTL (r = -0.47, p < 0.05) which persisted post-BPA. PVR, mPAP, WHO FC and 6MWD were not improved significantly post-BPA in PP patients. BPA response was not related to TTTL terciles or CTPA-quantified residual disease burden. Patients PP experienced inferior response to BPA, despite similar baseline and procedural characteristics to IC. BPA does not abolish the relationship between TTTL and postsurgical PVR in PP patients, suggesting that BPA is less effective in treating residual PH after surgery in an experienced surgical center.

Right ventricular-pulmonary artery coupling in chronic thromboembolic pulmonary hypertension.

Chronic thromboembolic pulmonary hypertension occurs in a proportion of patients with prior acute pulmonary embolism and is characterised by breathlessness, persistently raised pulmonary pressures and right heart failure. Surgical pulmonary endarterectomy (PEA) offers significant prognostic and symptomatic benefits for patients with proximal disease distribution. For those with inoperable disease, management options include balloon pulmonary angioplasty (BPA) and medical therapy. Current clinical practice relies on the evaluation of pulmonary haemodynamics to assess disease severity, timing of and response to treatment. However, pulmonary haemodynamics correlate poorly with patient symptoms, which are influenced by right ventricular tolerance of the increased afterload. How best to manage symptomatic patients with chronic thromboembolic pulmonary disease (CTEPD) in the absence of pulmonary hypertension is not resolved.Right ventricular-pulmonary artery coupling (RV-PAC) describes the energy transfer within the whole cardiopulmonary unit. Thus, it can identify the earliest signs of decompensation even before pulmonary hypertension is overt. Invasive measurement of coupling using pressure volume loop technology is well established in research settings. The development of efficient and less invasive measurement methods has revived interest in coupling as a viable clinical tool. Significant improvement in RV-PAC has been demonstrated after both PEA and BPA. Further studies are required to understand its clinical utility and prognostic value, in particular, its potential to guide management in patients with CTEPD. Finally, given the reported differences in coupling between sexes in pulmonary arterial hypertension, further work is required to understand the applicability of proposed thresholds for decoupling in therapeutic decision making.

Risk stratification and response to therapy in patients with pulmonary arterial hypertension and comorbidities: A COMPERA analysis.

BACKGROUND: A diagnosis of idiopathic pulmonary arterial hypertension (IPAH) is frequently made in elderly patients who present with comorbidities, especially hypertension, coronary heart disease, diabetes mellitus, and obesity. It is unknown to what extent the presence of these comorbidities affects the response to PAH therapies and whether risk stratification predicts outcome in patients with comorbidities. METHODS: We assessed the database of COMPERA, a European pulmonary hypertension registry, to determine changes after initiation of PAH therapy in WHO functional class (FC), 6-minute walking distance (6MWD), brain natriuretic peptide (BNP) or N-terminal fragment of probrain natriuretic peptide (NT-pro-BNP), and mortality risk assessed by a 4-strata model in patients with IPAH and no comorbidities, 1-2 comorbidities and 3-4 comorbidities. RESULTS: The analysis was based on 1,120 IPAH patients (n = 208 [19%] without comorbidities, n = 641 [57%] with 1-2 comorbidities, and n = 271 [24%] with 3-4 comorbidities). Improvements in FC, 6MWD, BNP/NT-pro-BNP, and mortality risk from baseline to first follow-up were significantly larger in patients with no comorbidities than in patients with comorbidities, while they were not significantly different in patients with 1-2 and 3-4 comorbidities. The 4-strata risk tool predicted survival in patients without comorbidities as well as in patients with 1-2 or 3-4 comorbidities. CONCLUSIONS: Our data suggest that patients with IPAH and comorbidities benefit from PAH medication with improvements in FC, 6MWD, BNP/NT-pro-BNP, and mortality risk, albeit to a lesser extent than patients without comorbidities. The 4-strata risk tool predicted outcome in patients with IPAH irrespective of the presence of comorbidities.

Dynamic Prediction of Pulmonary Hypertension in Systemic Sclerosis Using Landmark Analysis.

OBJECTIVE: Pulmonary hypertension (PH) is a serious complication of systemic sclerosis (SSc). In this study, we explored the prediction of short-term risk for PH using serial pulmonary function tests (PFTs) and other disease features. METHODS: SSc patients in whom disease onset occurred ≥10 years prior to data retrieval and for whom autoantibody specificity and PFT data were available were included in this study. Mixed-effects modeling was used to describe changes in PFTs over time. Landmarking was utilized to include serial assessments and stratified Cox proportional hazards regression analysis with landmarks as strata was used to develop the PH prediction models. RESULTS: We analyzed data from 1,247 SSc patients, 16.3% of whom were male and 35.8% of whom had diffuse cutaneous SSc. Anticentromere, antitopoisomerase, and anti-RNA polymerase antibodies were observed in 29.8%, 22.0%, and 11.4% of patients, respectively, and PH developed in 13.6% of patients. Over time, diffusing capacity for carbon monoxide (DLco) and carbon monoxide transfer coefficient (Kco) declined in all SSc patients (up to 1.5% per year) but demonstrated much greater annual decline (up to 4.5% and 4.8%, respectively) in the 5-7 years preceding PH diagnosis. Comparisons between multivariable models including either DLco, Kco, or forced vital capacity (FVC)/DLco ratio, demonstrated that both absolute values and change over the preceding year in those measurements were strongly associated with the risk of PH (hazard ratio [HR] 0.93 and 0.76 for Kco and its change; HR 0.90 and 0.96 for DLco and its change; and HR 1.08 and 2.01 for FVC/DLco ratio and its change; P < 0.001 for all). The Kco-based model had the greatest discriminating ability (Harrell's C-statistic 0.903). CONCLUSION: Our findings strongly support the importance of PFT trends over time in identifying patients at risk of developing PH.

Acute lung injury after balloon pulmonary angioplasty results in a similar haemodynamic response and possible clinical advantage at follow-up.

Acute lung injury (ALI) is a common but poorly defined and understood complication of balloon pulmonary angioplasty (BPA) for chronic thromboembolic pulmonary hypertension (CTEPH). Little data are available on the medium term clinical outcomes of BPA complicated by ALI. We analyzed per-procedure data from 282 procedures in 109 patients and per-patient data from 85 patients. Serial right heart catheterization at baseline, after each BPA and at 3-month follow-up measured pulmonary vascular resistance (PVR), mean pulmonary artery pressure (mPAP), and cardiac output (CO). ALI (ALI+) was identified by chest radiography alone (ALIr+) or in association with hypoxia clinically (ALIcr+). Procedural predictors of ALI and patient outcomes at 3-months were compared no ALI (ALI-). ALI+ occurred in 17/282 (6.0%) procedures (ALIcr+: 2.5%, ALIr+: 3.5%). Prevailing haemodynamics (PVR: p < 0.01; mPAP: p < 0.05) at a procedural and patient level, as well as number of BPA sessions (p < 0.01), total number of vessels (p < 0.05), and occlusions (p < 0.05) treated at a patient level predicted ALI+. Those with ALI had greater percentage improvement in ΔCAMPHOR symptoms score (ALI+: -63.5 ± 35.7% (p < 0.05); ALIcr+: -84.4 ± 14.5% (p < 0.01); ALI-: -27.2 ± 74.2%) and ΔNT-proBNP (ALIcr+: -78.4 ± 11.9% (p < 0.01); ALI-: -42.9 ± 36.0%) at follow-up. There was no net significant difference in haemodynamic changes in ALI+ versus ALI- at follow-up. ALI is predicted by haemodynamic severity, number of vessels treated, number of BPA sessions, and treating occlusive disease. ALI in this cohort was associated with a clinical advantage at follow-up.

Mendelian randomisation and experimental medicine approaches to interleukin-6 as a drug target in pulmonary arterial hypertension.

BACKGROUND: Inflammation and dysregulated immunity are important in the development of pulmonary arterial hypertension (PAH). Compelling preclinical data supports the therapeutic blockade of interleukin-6 (IL-6) signalling. METHODS: We conducted a phase 2 open-label study of intravenous tocilizumab (8 mg·kg-1) over 6 months in patients with group 1 PAH. Co-primary end-points were safety, defined by incidence and severity of adverse events, and change in pulmonary vascular resistance. Separately, a mendelian randomisation study was undertaken on 11 744 individuals with European ancestry including 2085 patients with idiopathic/heritable disease for the IL-6 receptor (IL6R) variant (rs7529229), known to associate with circulating IL-6R levels. RESULTS: We recruited 29 patients (male/female 10/19; mean±sd age 54.9±11.4 years). Of these, 19 had heritable/idiopathic PAH and 10 had connective tissue disease-associated PAH. Six were withdrawn prior to drug administration; 23 patients received at least one dose of tocilizumab. Tocilizumab was discontinued in four patients owing to serious adverse events. There were no deaths. Despite evidence of target engagement in plasma IL-6 and C-reactive protein levels, both intention-to-treat and modified intention-to-treat analyses demonstrated no change in pulmonary vascular resistance. Inflammatory markers did not predict treatment response. Mendelian randomisation did not support an effect of the lead IL6R variant on risk of PAH (OR 0.99, p=0.88). CONCLUSION: Adverse events were consistent with the known safety profile of tocilizumab. Tocilizumab did not show any consistent treatment effect.

Balloon pulmonary angioplasty for inoperable chronic thromboembolic pulmonary hypertension: the UK experience.

Objective: Inoperable chronic thromboembolic pulmonary hypertension (CTEPH) managed medically has a poor prognosis. Balloon pulmonary angioplasty (BPA) offers a new treatment for inoperable patients. The national BPA service for the UK opened in October 2015 and we now describe the treatment of our initial patient cohort. Methods: Thirty consecutive, inoperable, anatomically suitable, symptomatic patients on stable medical therapy for CTEPH were identified and offered BPA. They initially underwent baseline investigations including Cambridge Pulmonary Hypertension Outcome Review (CAMPHOR) quality of life (QoL) questionnaire, cardiopulmonary exercise test, 6 min walk distance (6MWD), transthoracic echocardiography, N-terminal probrain natriuretic peptide (NT pro-BNP) and right heart catheterisation. Serial BPA sessions were then performed and after completion, the treatment effect was gauged by comparing the same investigations at 3 months follow-up. Results: A median of 3 (IQR 1-6) BPA sessions per patient resulted in a significant improvement in functional status (WHO functional class ≥3: 24 vs 4, p<0.0001) and QoL (CAMPHOR symptom score: 8.7±5.4 vs 5.6±6.1, p=0.0005) with reductions in pulmonary pressures (mean pulmonary artery pressure: 44.7±11.0 vs 34.4±8.3 mm Hg, p<0.0001) and resistance (pulmonary vascular resistance: 663±281 vs 436±196 dyn.s.cm-5, p<0.0001). Exercise capacity improved (minute ventilation/carbon dioxide production: 55.3±12.2 vs 45.0±7.8, p=0.03 and 6MWD: 366±107 vs 440±94 m, p<0.0001) and there was reduction in right ventricular (RV) stretch (NT pro-BNP: 442 (IQR 168-1607) vs 202 (IQR 105-447) pg/mL, p<0.0001) and dimensions (mid RV diameter: 4.4±1.0 vs 3.8±0.7 cm, p=0.002). There were no deaths or life-threatening complications and the mild-moderate per-procedure complication rate was 10.5%. Conclusions: BPA is safe and improves the functional status, QoL, pulmonary haemodynamics and RV dimensions of patients with inoperable CTEPH.

Initial combination therapy of ambrisentan and tadalafil in connective tissue disease-associated pulmonary arterial hypertension (CTD-PAH) in the modified intention-to-treat population of the AMBITION study: post hoc analysis.

OBJECTIVES: To evaluate initial combination therapy with ambrisentan plus tadalafil (COMB) compared with monotherapy of either agent (MONO), and the utility of baseline characteristics and risk stratification in predicting outcomes, in patients with connective tissue disease-associated pulmonary arterial hypertension (CTD-PAH) and the systemic sclerosis (SSc)-pulmonary arterial hypertension (PAH) subpopulation. METHODS: This post hoc analysis of the Ambrisentan and Tadalafil in Patients with Pulmonary Arterial Hypertension (AMBITION) study included patients with CTD-PAH from the modified intention-to-treat population. Time to clinical failure (TtCF) was assessed by baseline characteristics, treatment assignment and risk group (low, intermediate and high) at baseline and week 16. TtCF was compared between groups using Kaplan-Meier curves and Cox proportional hazards regression modelling. RESULTS: The analysis included 216 patients (COMB, n=117; MONO, n=99). The risk of clinical failure was lower with COMB versus MONO (risk reduction: CTD-PAH 51.7%, SSc-PAH 53.7%), particularly in patients with haemodynamic parameters characteristic of typical PAH without features of left heart disease and/or restrictive lung disease at baseline. The risk of clinical failure was lower with COMB versus MONO in the baseline low-risk group (HR not calculated due to no events in COMB), baseline intermediate-risk group (HR 0.519, 95% CI 0.297 to 0.905) and in the week 16 low-risk group (HR 0.069, 95% CI 0.009 to 0.548). CONCLUSIONS: The benefit of COMB over MONO was demonstrated in patients with CTD-PAH, particularly in those with typical PAH haemodynamic characteristics at baseline. COMB is appropriate for patients categorised as low risk and intermediate risk at baseline and low risk at follow-up. TRIAL REGISTRATION NUMBER: NCT01178073.

Balloon Pulmonary Angioplasty: State of the Art.

Balloon pulmonary angioplasty (BPA) is a novel technique for the treatment of chronic thromboembolic pulmonary hypertension. While cardiologists need no introduction to the concept of balloon angioplasty, BPA has its own particular challenges. This article aims to provide the reader with an overview of BPA, starting with an introduction to chronic thromboembolic disease (CTED), the standard management of chronic thromboembolic pulmonary hypertension (CTEPH), technical challenges faced when performing BPA and the evidence base supporting its use. The second part of the article will focus on the future of BPA, in particular the areas where research is required to establish an evidence base to justify the role of BPA in CTEPH and CTED treatment.

Genetic determinants of risk in pulmonary arterial hypertension: international genome-wide association studies and meta-analysis.

BACKGROUND: Rare genetic variants cause pulmonary arterial hypertension, but the contribution of common genetic variation to disease risk and natural history is poorly characterised. We tested for genome-wide association for pulmonary arterial hypertension in large international cohorts and assessed the contribution of associated regions to outcomes. METHODS: We did two separate genome-wide association studies (GWAS) and a meta-analysis of pulmonary arterial hypertension. These GWAS used data from four international case-control studies across 11 744 individuals with European ancestry (including 2085 patients). One GWAS used genotypes from 5895 whole-genome sequences and the other GWAS used genotyping array data from an additional 5849 individuals. Cross-validation of loci reaching genome-wide significance was sought by meta-analysis. Conditional analysis corrected for the most significant variants at each locus was used to resolve signals for multiple associations. We functionally annotated associated variants and tested associations with duration of survival. All-cause mortality was the primary endpoint in survival analyses. FINDINGS: A locus near SOX17 (rs10103692, odds ratio 1·80 [95% CI 1·55-2·08], p=5·13 × 10-15) and a second locus in HLA-DPA1 and HLA-DPB1 (collectively referred to as HLA-DPA1/DPB1 here; rs2856830, 1·56 [1·42-1·71], p=7·65 × 10-20) within the class II MHC region were associated with pulmonary arterial hypertension. The SOX17 locus had two independent signals associated with pulmonary arterial hypertension (rs13266183, 1·36 [1·25-1·48], p=1·69 × 10-12; and rs10103692). Functional and epigenomic data indicate that the risk variants near SOX17 alter gene regulation via an enhancer active in endothelial cells. Pulmonary arterial hypertension risk variants determined haplotype-specific enhancer activity, and CRISPR-mediated inhibition of the enhancer reduced SOX17 expression. The HLA-DPA1/DPB1 rs2856830 genotype was strongly associated with survival. Median survival from diagnosis in patients with pulmonary arterial hypertension with the C/C homozygous genotype was double (13·50 years [95% CI 12·07 to >13·50]) that of those with the T/T genotype (6·97 years [6·02-8·05]), despite similar baseline disease severity. INTERPRETATION: This is the first study to report that common genetic variation at loci in an enhancer near SOX17 and in HLA-DPA1/DPB1 is associated with pulmonary arterial hypertension. Impairment of SOX17 function might be more common in pulmonary arterial hypertension than suggested by rare mutations in SOX17. Further studies are needed to confirm the association between HLA typing or rs2856830 genotyping and survival, and to determine whether HLA typing or rs2856830 genotyping improves risk stratification in clinical practice or trials. FUNDING: UK NIHR, BHF, UK MRC, Dinosaur Trust, NIH/NHLBI, ERS, EMBO, Wellcome Trust, EU, AHA, ACClinPharm, Netherlands CVRI, Dutch Heart Foundation, Dutch Federation of UMC, Netherlands OHRD and RNAS, German DFG, German BMBF, APH Paris, INSERM, Université Paris-Sud, and French ANR.

Author Correction: Major lung complications of systemic sclerosis.

Corrections: Table 2: the text 'Also licensed for CTEPH; cannot be combined with a PDE5 inhibitor' has been moved to a different row; reference for this moved statement updated.

Major lung complications of systemic sclerosis.

Systemic sclerosis (SSc) is associated with high mortality owing to internal organ complications, and lung disease is the leading cause of SSc-associated death. The most notable lung complications in SSc are fibrosis and pulmonary arterial hypertension (PAH). A major challenge for the management of lung disease in SSc is detecting those patients with severe pathology and those patients who are likely to benefit from available treatments. In the past few years, strategies for managing lung fibrosis and pulmonary hypertension, including PAH, have greatly progressed. For lung fibrosis, the tools to assess risk of progression and severity of the disease have been refined. Clinical trial results support the use of immunosuppression, including high-intensity regimens with autologous stem cell transplantation. New trials are underway to test other potential therapies including treatments that are approved for use in idiopathic lung fibrosis. For PAH, identifying individuals at high risk of disease development is critical. In addition, individuals who have borderline elevation of pulmonary arterial pressure need to be appropriately managed and followed up. Many approved drugs targeting PAH are now available, and results from large-scale clinical trials provide robust evidence that various treatments for SSc-associated PAH are associated with good long-term outcomes.

Daily remote ischaemic conditioning following acute myocardial infarction: a randomised controlled trial.

BACKGROUND: Remote ischaemic conditioning (rIC) is a cardioprotective tool which has shown promise in preclinical and clinical trials in the context of acute ischaemia. Repeated rIC post myocardial infarction may provide additional benefits which have not previously been tested clinically. METHODS: The trial assessed the role of daily rIC in enhancing left ventricular ejection fraction (LVEF) recovery in patients with impaired LVEF (<45%) after ST segment elevation myocardial infarction (STEMI) treated with primary percutaneous coronary intervention (P-PCI). Patients were recruited from four UK hospitals and randomised to receive either 4 weeks of daily rIC or sham conditioning using the autoRIC Device (CellAegis) starting on day 3 post P-PCI. The primary endpoint was the improvement in LVEF over 4 months assessed by cardiac MRI (CMR). Seventy-three patients (38 cases, 35 controls) completed the study. RESULTS: The treatment and control groups were well matched at baseline including for mean LVEF (42.8% vs 44.3% respectively, p=0.952). There was no difference in the improvement in LVEF over 4 months between the treatment and control groups (4.8%±7.8% vs 4.6%±5.9% respectively, p=0.924). No differences were seen in the secondary outcome measures including changes in infarct size and left ventricular end-diastolic and systolic volumes, major adverse cardiac and cerebral event, mean Kansas City Cardiomyopathy Questionnaire score and change in N-terminal pro-brain natriuretic peptide levels. CONCLUSIONS: Daily rIC starting on day 3 and continued for 4 weeks following successful P-PCI for STEMI did not improve LVEF as assessed by CMR after 4 months when compared with a matched control group. TRIAL REGISTRATION NUMBER: NCT0166461.

Grossly Abnormal Ventilation/Perfusion SPECT Study in Idiopathic Pulmonary Arterial Hypertension Without Thromboembolism.

Pulmonary hypertension is a serious condition with multiple underlying aetiologies which require different treatment strategies. We present a case of severe idiopathic pulmonary arterial hypertension in a 20-year-old patient with ongoing breathlessness. She was initially diagnosed with asthma and panic attacks in community care. As the symptoms became progressively worse, she was referred for pulmonary hypertension clinic assessment. Ventilation/perfusion single-photon emission computed tomography (V/Q SPECT) showed grossly abnormal perfusion defects which were mismatched to the ventilation scan, suggestive of chronic thromboembolic disease. However, corroborating computed tomographic (CT) pulmonary angiogram and invasive pulmonary angiography showed no thromboembolic disease. Histological examination of the pulmonary arteries post-mortem showed changes consistent with idiopathic pulmonary arterial hypertension. This case highlighted the clinical challenges in interpreting the investigation results and phenotyping pulmonary hypertension. V/Q SPECT might have a role in visualising the extent of vasculopathies in pulmonary arterial hypertension.

Pulmonary Arterial Hypertension With Abnormal V/Q Single-Photon Emission Computed Tomography.

OBJECTIVES: This study aimed to evaluate the incidence and clinical outcomes of abnormal ventilation/perfusion (V/Q) single-photon emission computed tomography (SPECT) without thromboembolism, especially in patients with group I pulmonary arterial hypertension (PAH). BACKGROUND: American Heart Association/American College of Cardiology and European Society of Cardiology guidelines recommend V/Q scan for screening for chronic thromboembolic pulmonary hypertension. The significance of patients with abnormal V/Q SPECT findings but no thromboembolism demonstrated in further investigations remained unclear. A distinct pattern of global patchy changes not typical of thromboembolism is recognized, but guidelines for reporting these in the context of PAH are lacking. METHODS: A total of 136 patients who underwent V/Q SPECT and right-sided heart catheterization showing mean pulmonary arterial pressure ≥25 mm Hg were included. V/Q SPECT findings were reported using European Association of Nuclear Medicine criteria for pulmonary embolism followed by computed tomography pulmonary angiography screening for positive thromboembolism and further invasive pulmonary angiography for distal thromboembolism. The abnormal V/Q SPECT images were further analyzed according to perfusion pattern into focal or global perfusion defects. RESULTS: V/Q SPECT showed thromboembolic disease in 44 patients, but 19 of these patients had no thromboembolism demonstrated by pulmonary angiography. Among these patients, 15 of 19 (78.9%) had group I PAH, and the majority had diffuse, patchy perfusion defects. After redefining V/Q SPECT images according to the perfusion pattern, those patients with global perfusion defects had higher mean pulmonary arterial pressure compared with patients with focal perfusion defects and normal scans (mean difference +13.9 and +6.2 mm Hg, respectively; p = 0.0002), as well as higher pulmonary vascular resistance (mean difference +316.6 and +226.3 absolute resistance units, respectively; p = 0.004). Among patients with PAH, global perfusion defects were associated with higher all-cause mortality with a hazard ratio of 5.63 (95% confidence interval: 1.11 to 28.5) compared with patients with focal or no perfusion abnormalities. CONCLUSIONS: There is a high incidence of abnormal V/Q SPECT scans in nonthromboembolic PAH. Further studies are needed to investigate the poor outcome associated with abnormal V/Q SPECT findings in the context of PAH.

Two-dimensional knowledge-based volumetric reconstruction of the right ventricle documents short-term improvement in pulmonary hypertension.

BACKGROUND: Data are scarce about short-term right ventricular changes in pulmonary hypertension. Two-dimensional knowledge-based reconstruction of the right ventricle with 2D echocardiography (2DKBR) has been shown to be a valid alternative to Cardiac MRI. PATIENTS AND METHODS: In this longitudinal study 25 pulmonary hypertension patients underwent 2DKBR of the right ventricle, assessment of NT-proBNP levels and functional class at baseline and after a mean follow-up of 6.1 months. Patients were followed up clinically for a further mean of 8.2 months. The majority of patients had connective tissue disease (CTD) associated pulmonary arterial hypertension (n=15) or chronic thromboembolic pulmonary hypertension (CTEPH; n=6). A total of 15 patients underwent an intervention, either new targeted therapy, escalation of targeted therapy or pulmonary endarterectomy. A total of 10 clinically stable patients were routinely followed up without any change in therapy. RESULTS: There were significant improvements in the right ventricular end-diastolic volume index (111±29 mL/m² vs 100±36 mL/m²; P=.038), end-systolic volume index (72±23 mL/m² vs 61±25 mL/m²; P=.001), and ejection fraction (35±10% vs 40±9%; P=.030). Changes in NT-proBNP levels correlated strongest with changes in end-systolic volume index (r=-.77; P=<.0001). Four patients experienced clinical worsening during extended follow-up, dilatation of the right ventricle was associated with clinical worsening. CONCLUSION: In a CTD and CTEPH dominated patient population significant reverse remodeling and improvement of ejection fraction occurred despite a short follow-up and was paralleled by significant changes in NT-proBNP levels. Further right ventricular dilatation was associated with worse clinical outcome. 2DKBR is a feasible substitute for Cardiac MRI to follow-up right ventricular indices in pulmonary hypertension.

Optical coherence tomography evaluation of pulmonary arterial vasculopathy in Systemic Sclerosis.

Our current understanding of the pathophysiology of pulmonary vascular disease is incomplete, since information about alterations of the pulmonary vasculature in pulmonary arterial hypertension (PAH) is primarily provided by autopsy or tissue specimens. The aim of this study was to compare the distal pulmonary vasculature of <2 mm in diameter in Systemic Sclerosis (SSc) patients with (n = 17) and without (n = 5) associated PAH using Optical Coherence Tomography during Right Heart catheterization. SSc-PAH patients showed significant thickening of Intima Media Thickening Area compared to patients without PAH (27 +/- 5.8% vs. 21 +/- 1.4%, p = 0.024). A good haemodynamic response to previous targeted PAH treatment was associated with a significantly greater number of small pulmonary artery side branches <300 µm per cm vessel (3.8 +/- 1.1 vs. 1.8 +/- 1.1; p = 0.010) and not associated with Intima Media thickening Area (26 +/- 5.4% vs. 28 +/- 6.7%; p = 0.6). Unexpected evidence of pulmonary artery thrombus formation was found in 19% of SSc-PAH patients. This is the first in-vivo study demonstrating a direct link between a structural abnormality of pulmonary arteries and a response to targeted treatment in PAH. Intravascular imaging may identify subgroups that may benefit from anticoagulation.