Pulmonary hypertension news

Br J Cardiol 2016;23:96–7 Leave a comment
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In this report we review two major American meetings: the 36th Annual Meeting and Scientific Sessions of the International Society for Heart and Lung Transplantation (ISHLT), held in Washington DC, USA, from 27th–30th April 2016; and the Annual Meeting of the American Thoracic Society (ATS), held in San Francisco, USA, from 13th–18th May 2016.

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ISHLT overview: advances in transplantation

Presenters shared the importance of increasing the source of hearts for transplantation through donation after cardiac death (DCD). “The lack of suitable donor hearts for transplantation has severely limited access to this life saving therapy for patients with advanced heart failure,” said Andrew Fisher (Professor of Respiratory Transplant Medicine, University of Newcastle). “The ability to safely perform DCD heart transplant together with improved overall management of potential heart donors represents a substantial step forward in addressing this clinical challenge,” he concluded.

40% increase in transplant activity

A study presented by Dr Simon Messer (Papworth NHS Trust Hospital, Cambridge) sought to discover if DCD hearts could help to increase the donor pool. Normothermic regional perfusion (NRP) was utilised to restore function to the DCD heart to allow robust assessment of heart function prior to proceeding to clinical transplantation (pictured). Over the last year, 10 patients were successfully transplanted thanks to this pioneering technique with 100% survival and a median five day intensive care stay.

Heart from the donor is removed after it stops beating and, depending on the transplant centre protocol, is reactivated and monitored for about 50 minutes before it is approved for transplantation. The restarted heart is then supplied with blood and nutrition in an “organ care system” (OCS™ Heart), for as long as needed to monitor and improve the state of the organ until it is transplanted. Supplying blood and nutrients inside the heart in the Organ Care System helps reduce the damage caused to the cardiac muscle compared with the traditional way of storing it in an ice box. The OCS™ Heart System is manufactured by TransMedics, Inc. in the United States. Each unit reportedly costs approximately £150,000 plus £25,000 per patient transplanted. (Photo courtesy of TransMedics, Inc.)
Heart from the donor is removed after it stops beating and, depending on the transplant centre protocol, is reactivated and monitored for about 50 minutes before it is approved for transplantation. The restarted heart is then supplied with blood and nutrition in an “organ care system” (OCS™ Heart), for as long as needed to monitor and improve the state of the organ until it is transplanted. Supplying blood and nutrients inside the heart in the Organ Care System helps reduce the damage caused to the cardiac muscle compared with the traditional way of storing it in an ice box. The OCS™ Heart System is manufactured by TransMedics, Inc. in the United States. Each unit reportedly costs approximately £150,000 plus £25,000 per patient transplanted. (Photo courtesy of TransMedics, Inc.)

Their proficiency with NRP has allowed practitioners to safely redefine the limits of DCD heart transplantation. Using both NRP and direct procurement, they have established a successful programme with 19 successful DCD heart transplants to date. This has resulted in an unprecedented 40% increase in their overall heart transplant activity. Their vision for the future is to share their expertise and replicate this programme for the global transplant community.

USA and European management consensus

Dr Kiran Khush (Stanford University, California, USA) discussed the standardisation of donor selection for heart transplantation. Altogether at the Consensus Conference, over 95 participants including cardiologists, cardiac surgeons, and transplant coordinators from over 40 transplant centres, participated in the discussion. A primary observation of the group was that donor heart management and selection criteria varied greatly across centres. Additionally, they prioritised the most important risk factors in donor selection, which included older age, left ventricular function, and distance from transplant centres.

A highlight of the European Consensus meeting was discussion of DCD and organ preservation (heart and lung) focused on how to select the candidates and manage end-of- life care, ex vivo preservation strategies, and the potential for ex vivo resuscitation of the organs.

ATS overview: higher rates of vitamin D deficiency…

All pulmonary hypertension (PH) patients should be screened for vitamin D deficiency, according to a study presented by Dr Basheer Tash and colleagues (Cleveland Clinic, Florida, USA). Vitamin D is known to have a protective immunomodulatory and antiproliferative effect on vascular smooth muscle. The retrospective study found a 22% prevalence of vitamin D deficiency among a group of 77 PH patients (mean age 63 years) who had levels measured within one month of their diagnostic right heart catheterisation (RHC).

The prevalence of sub-optimal (insufficient and deficient) levels was 53%. The deficiency rates are significantly higher compared to other USA national survey datasets and they appear to serve as a consistent marker of a significantly higher mean pulmonary artery pressure (PAP). But the authors suggest that larger prospective studies are needed to verify the prognostic implications of vitamin D deficiency in PH and the effect of replacement therapy on disease outcomes.

…and schizophrenia associated with pulmonary hypertension

Chronic thromboembolic pulmonary hypertension (CTEPH) is characterised by persistent thromboemboli in the pulmonary arteries, which cause pulmonary hypertension and resultant right heart failure and death. CTEPH has been reported to develop in approximately 2–4% of patients with acute pulmonary embolism (PE), suggesting a common pathophysiology between the two disorders. Several common risk factors for CTEPH and PE have been demonstrated, such as certain medical therapies, thrombophilia and a genetic predisposition. However, little is known about the possible association between CTEPH and schizophrenia, although the association between PE and schizophrenia has been suggested. Now a team from Tohoku University, Sendai, Japan, have reported a significantly higher prevalence of schizophrenia in CTEPH patients compared with those with pulmonary arterial hypertension (PAH) and the general population.

The prevalence of schizophrenia was 8/110 (7.3%) in CTEPH, 1/150 (0.7%) in PAH and 795,000/127,692,000 (0.6%) in the general population, respectively, and thus was significantly higher in CTEPH patients compared with the other two groups (both P<0.01). The Japanese workers propose two possible mechanisms involved in the increase of schizophrenia in CTEPH. First, CTEPH may be directly induced by activation of blood coagulation and enhanced blood clotting in schizophrenia. Second, such hypercoagulable states in schizophrenia may prevent thrombolysis and anticoagulation of PE with resultant development of CTEPH.

Right heart catheterisation safe in the elderly

RHC is the reference test in diagnosing PH. A study conducted by Dr Marylise Ginoux (Louis Pradel Hospital, Bron, France) questioned whether RHC is justified in very elderly patients. They retrospectively analysed 1,060 RHCs performed by a single operator over a four year period. 228 (21.5%) of the patients were >75 years and 832 (78.5%) were below 75 years. Nine procedures led to complications (0.9%) three in >75 year olds and six (0.7%) in those younger. Eight were related to femoral vein puncture; “which should be avoided whenever possible,” the authors suggest. Some 24 procedures (2.3%) could have been obviated as results did not influence management. The authors conclude however that RHC can be performed regardless of age, and complication rate is not increased in older patients.

‘Breath signature’ for PAH

In PAH and other diseases, cells/tissues produce a spectrum of volatile organic compounds (VOCs) that diffuse, eventually, from blood to exhaled breath. This way, the detection of exhaled VOCs could serve as a non-invasive diagnostic test, especially for respiratory diseases, due to their proximity to blood-air barrier. Dr Morad Nakhleh (Université Paris-Sud, France) and co-authors hypothesised that PAH-induced specific profiles of VOCs, (referred to as volatolomes) could serve for the non-invasive diagnosis of PAH.

Breath samples from 22 PAH patients, were compared to healthy controls as well as to over 1,380 samples obtained from patients diagnosed with 15 different diseases (including but not only, lung cancer, neurological disorders, inflammatory diseases, gastric cancer and others). They compared the breath composition of 22 PAH patients and 23 control subjects and discovered that the concentration of nine breath VOCs was significantly altered in association with PAH. The investigators then determined the collective PAH breath-signature, using the nano-arrays, discriminating PAH patients from controls with an accuracy of 92%. Based on the meta-analysis of 1,404 breath samples, they found that PAH-induced volatolome is unique and distinctive from the remaining 15 diseases with an accuracy of 86%, when blindly validated.

Targeting the prostacyclin pathway…

Despite available therapies, patients with connective tissue disease associated PAH (PAH-CTD) have a particularly poor prognosis. The global phase III GRIPHON (Prostacyclin [PGI2] Receptor Agonist In Pulmonary Arterial Hypertension) study investigated the use of the oral, selective IP receptor agonist, selexipag, which is pharmacologically distinct from prostanoids and which has recently become available for use in Europe. The study enrolled 1,156 PAH patients including 334 with PAH-CTD. Compared with placebo, selexipag significantly reduced the risk of the primary outcome composite of morbidity/mortality by 41% among patients with PAH-CTD.

Professor Sean Gaine (Mater Misericordiae Hospital, Dublin, Ireland) on behalf of the GRIPHON Investigators, presented findings on the effect of selexipag vs. placebo in patients with PAH associated with CTD subtypes, including systemic sclerosis (PAH-SSc), systemic lupus erythematous (PAH-SLE) and mixed CTD (PAH-MCTD).

Selexipag reduced the risk of morbidity/mortality events by 44% in PAH-SSc, by 34% in PAH-SLE, and by 53% in PAH-MCTD patients. The treatment effect was consistent across the PAH-CTD subgroups which suggests that targeting the prostacyclin pathway with selexipag is an effective therapeutic option in these difficult-to-treat patients, according to the investigators.

…and benefits of combination therapy

Combined targeted (CT) therapy is associated with a significant reduction in clinically relevant outcomes compared to monotherapy in PAH, according to a meta-analysis involving 4,095 patients.

The analysis was conducted by Dr Annie Lajoie, and co-investigators (Centre de Recherche de l’Institut Universitaire de Cardiologie et de Pneumologie de Québec, Quebec, Canada). The primary outcome in the trials was the risk of clinical worsening, and secondary outcomes included the components of the clinical worsening definition, functional class, exercise capacity and treatment discontinuation.

CT was associated with significant risk reduction for clinical worsening (P<0.00001), with treatment effect being consistent across subgroups. CT was also associated with a risk reduction for hospitalisation, treatment escalation and symptomatic progression. Moreover, all-cause (P=0.09) and PAH-related (P=0.06) mortality tended to be reduced by CT compared to monotherapy, whereas CT had no effect on lung transplantation. Finally, CT resulted in WHO functional class improvement and six-minute walked distance (+22.1 m; 95% CI 17.6–26.5 m; p<0.00001).

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