The prostacyclin pathway in pulmonary arterial hypertension: a clinical review.

INTRODUCTION: Prostacyclin is produced in vascular endothelial cells and acts via the IP prostacyclin receptor to cause vasodilation and inhibit smooth muscle cell proliferation and platelet aggregation. Prostacyclin production is reduced in pulmonary arterial hypertension (PAH), and drugs targeting the prostacyclin pathway are one of the pharmacotherapeutic options for PAH. Areas covered: The prostacyclin pathway and drugs that target it are discussed, including synthetic prostacyclin (epoprostenol), prostacyclin analogs (iloprost, treprostinil, beraprost) and selective prostacyclin IP receptor agonists (selexipag). An overview of the development of these therapies, from the earlier agents requiring parenteral administration, through inhaled formulations, to oral products, is provided, together with a summary of data from key clinical trials and registries. Expert commentary: Synthetic prostacyclin and prostacyclin analogs are beneficial for patients with PAH, but they tend to be underused, in part due to the difficulties associated with the administration of parenteral and inhaled formulations. Oral prostacyclin analogs have some limitations with regard to efficacy. The newest agent targeting the prostacyclin pathway, the selective prostacyclin receptor agonist selexipag, is administered orally, and has been shown to reduce a composite morbidity/mortality endpoint. Ongoing studies will help clarify how best to use it in the management of PAH.

Remodelado cardíaco inverso en pacientes con hipertensión pulmonar tras trasplante bipulmonar. Estudio con tomografía computarizada multidetector / Multidetector computed tomography shows reverse cardiac remodeling after double lung transplantation for pulmonary hypertension

Objetivo. Valorar mediante tomografía computarizada multidetector (TCMD) los cambios estructurales del corazón derecho y de las arterias pulmonares que se producen en los pacientes con hipertensión pulmonar (HP) grave tratados mediante trasplante bipulmonar (TxBP). Material y métodos. Estudio retrospectivo de 21 pacientes consecutivos diagnosticados de HP grave, a los que se realizó TxBP en nuestro centro hospitalario durante los años 2010-2014. Se analizó la TCMD realizada previa al trasplante pulmonar, y la primera disponible después. Se obtuvieron las siguientes variables: diámetro del tronco de la arteria pulmonar, relación diámetro tronco de la arteria pulmonar/diámetro de la aorta ascendente, diámetro del ventrículo derecho, relación diámetro ventrículo izquierdo/derecho e índice de excentricidad. Se realizó un análisis estadístico con comparación de medias de las diferentes variables recogidas. Resultados. En todos los casos analizados se observó, en la TCMD realizada, una media de 24±14 días post-TxBP, una reducción significativa del tamaño de las cavidades derechas, con mejoría de los índices de interdependencia ventricular y del tamaño del tronco de la arteria pulmonar (p<0,001 para todas las variables analizadas). Conclusión. Los pacientes con HP tratados mediante TxBP presentan un remodelado inverso precoz de los cambios estructurales cardíacos derechos y del árbol arterial pulmonar. La TCMD es útil para detectar dichos cambios (AU)

Objective. To use multidetector computed tomography (MDCT) to evaluate the structural changes in the right heart and pulmonary arteries that occur in patients with severe pulmonary hypertension treated by double lung transplantation. Material and methods. This was a retrospective study of 21 consecutive patients diagnosed with severe pulmonary hypertension who underwent double lung transplantation at our center between 2010 and 2014. We analyzed the last MDCT study done before lung transplantation and the first MDCT study done after lung transplantation. We recorded the following variables: diameter of the pulmonary artery trunk, ratio of the diameter of the pulmonary artery trunk to the diameter of the ascending aorta, diameter of the right ventricle, ratio of the diameter of the left ventricle to the diameter of the right ventricle, and eccentricity index. Statistical analysis consisted of the comparison of the means of the variables recorded. Results. In all cases analyzed, the MDCT study done a mean of 24±14 days after double lung transplantation showed a significant reduction in the size of the right heart chambers, with improved indices of ventricular interdependency index, and reduction in the size of the pulmonary artery trunk (p<0.001 for all the variables analyzed). Conclusion. Patients with pulmonary hypertension treated by double lung transplantation present early reverse remodeling of the changes in the structures of the right heart and pulmonary arterial tree. MDCT is useful for detecting these changes (AU)

Multidetector computed tomography shows reverse cardiac remodeling after double lung transplantation for pulmonary hypertension. / Remodelado cardíaco inverso en pacientes con hipertensión pulmonar tras trasplante bipulmonar. Estudio con tomografía computarizada multidetector.

OBJECTIVE: To use multidetector computed tomography (MDCT) to evaluate the structural changes in the right heart and pulmonary arteries that occur in patients with severe pulmonary hypertension treated by double lung transplantation. MATERIAL AND METHODS: This was a retrospective study of 21 consecutive patients diagnosed with severe pulmonary hypertension who underwent double lung transplantation at our center between 2010 and 2014. We analyzed the last MDCT study done before lung transplantation and the first MDCT study done after lung transplantation. We recorded the following variables: diameter of the pulmonary artery trunk, ratio of the diameter of the pulmonary artery trunk to the diameter of the ascending aorta, diameter of the right ventricle, ratio of the diameter of the left ventricle to the diameter of the right ventricle, and eccentricity index. Statistical analysis consisted of the comparison of the means of the variables recorded. RESULTS: In all cases analyzed, the MDCT study done a mean of 24±14 days after double lung transplantation showed a significant reduction in the size of the right heart chambers, with improved indices of ventricular interdependency index, and reduction in the size of the pulmonary artery trunk (p<0.001 for all the variables analyzed). CONCLUSION: Patients with pulmonary hypertension treated by double lung transplantation present early reverse remodeling of the changes in the structures of the right heart and pulmonary arterial tree. MDCT is useful for detecting these changes.

Management and outcomes in chronic thromboembolic pulmonary hypertension: From expert centers to a nationwide perspective.

BACKGROUND: The Spanish "Registry of Pulmonary Arterial Hypertension" (REHAP), started in 2007, includes chronic thromboembolic hypertension (CTEPH) patients. Based on data provided by this registry and retrospective data from patients diagnosed during 2006 (≤ 12 months since the registry was created), clinical management and long-term outcomes of CTEPH patients are analyzed nationwide for the first time in a scenario of a decentralized organization model of CTEPH management. METHODS AND RESULTS: A total of 391 patients (median [Q1:Q3] age 63.7 [48.0;73.3] years, 58% females) with CTEPH included during the period January 1, 2006-December 31, 2013 in the REHAP registry were analyzed. Rate of pulmonary endarterectomy (PEA) was 31.2%, and highly asymmetric among centers: rate was 47.9% at two centers designated as CTEPH expert centers, while it was 4.6% in other centers. Among patients not undergoing PEA, 82% were treated with therapies licensed for pulmonary arterial hypertension (PAH). Five-year survival rate was 86.3% for PEA patients, and 64.9% for non-PEA patients. Among non-PEA patients, presenting proximal lesions (42% of non-referred patients) was associated with a 3-fold increase in mortality. PEA patients achieved significantly better hemodynamic and clinical outcomes at one-year follow-up compared to non-PEA patients. Patients not being referred for PEA assessment were older and had a worse functional capacity. Older age was the most deterrent factor for non-operability. CONCLUSION: Despite the increase in diagnosis and expertise in PEA-specialized centers, an important percentage of patients do not benefit of PEA in a decentralized organization model of CTEPH management.

A founder EIF2AK4 mutation causes an aggressive form of pulmonary arterial hypertension in Iberian Gypsies.

Pulmonary arterial hypertension (PAH) is a pathological condition characterized by a persistent and progressive elevation of pulmonary vascular resistance with devastating consequences if untreated. In the past recent years, several genes have been related to PAH, however, the molecular defect remains unknown in a significant proportion of patients with familial PAH (∼20%). During the past few years, we have observed that PAH shows a particular behavior in Iberian Gypsies, with more aggressive course and frequently affecting multiple members of the same family. We studied five Gypsy families in whom at least one individual from each family developed a severe form of PAH and in whom no mutation had been identified in the common genes. We applied SNP-array-based homozygosity mapping in three families and obtained, among others, one of which included the gene EIF2AK4, recently reported in patients with PAH from group-1' pulmonary veno-occlusive disease (PVOD) and pulmonary capillary hemangiomatosis (PCH). Subsequently, we sequenced EIF2AK4 and found a homozygous mutation in all five families: c.3344C>T(p.P1115L). The majority of our patients required early lung transplantation. Hence, this mutation appeared with a more severe phenotype than previously reported for other EIF2AK4 mutations. The finding of this novel mutation is important for genetic counseling and calculation of population recurrence risks.

Effect of different pharmacologic agents to reverse severe pulmonary hypertension among end-stage heart failure patients.

OBJECTIVE: The goal of this study was to analyze the hemodynamic responses during vasoreactivity tests among candidates for heart transplantation who displayed severe pulmonary hypertension seeking to identify risk markers of nonresponse to the test. MATERIALS AND METHODS: In this observational retrospective study we evaluated demographic, clinical, echocardiographic, and hemodynamic variables. The target hemodynamic goal in the vasoreactivity test was to achieve a transpulmonary gradient (TPG) <12 mm Hg and/or pulmonary vascular resistances (PVR) <2.5 Wood Units (WU). RESULTS: We analyzed medical records from 79 patients. Inotropes (dopamine or dobutamine) were used to treat 33 patients, nonselective vasodilators (nitroglycerin or sodium nitroprusside) were used in 22 patients, and prostacyclin (PC) was used in 24 patients. The study observed a significant decrease in pulmonary pressures, PVR, and TPG, with increased cardiac output (CO) compared with baseline hemodynamics in all groups. No significant differences were observed between agents except for an increase in CO, which was greater in the PC group. Also, 49.4% of patients were considered responders to the vasoreactivity test without significant differences between groups. Risk markers for absence of a response to the vasoreactivity test were a CO <2.5 L/min (odds ratio [OR] = 2.1; confidence interval [CI] 95%, 1.1-3.9; P = .035) and a PVR >6 WU (OR = 3.7; CI 95%, 1.8-7.6; P < .001) in the baseline hemodynamic study. CONCLUSIONS: Inotropes, nonselective vasodilators, and prostacyclin produced effective vasodilator responses in the pulmonary vascular bed during the vasoreactivity test. The presence of a baseline high PVR or a low CO were predictors of nonresponse to the test.

[Sildenafil as a substitute for subcutaneous prostacyclin in pulmonary hypertension]. / Sildenafilo como sustituto de prostaciclina subcutánea en la hepertensión pulmonar.

Subcutaneous prostacyclin (treprostinil) is an effective short-term treatment for pulmonary hypertension. The most frequently described adverse effect-pain in the area of injection-rarely requires that treatment be withdrawn. Sildenafil is a selective fosfodiesterase-5 inhibitor with pulmonary vasodilating effects. We describe the use of sildenafil as a substitute for treprostinil in a patient with pulmonary hypertension associated with lupus erythematosus. Treatment with treprostinil was discontinued due to uncontrollable abdominal pain.

Sildenafilo como sustituto de prostaciclina subcutánea en la hipertensión pulmonar / Sildenafil as a substitute for subcutaneous prostacyclin in pulmonary hypertension

No disponible

Alternativas al trasplante cardíaco / Alternatives to heart transplantation

La incidencia y prevalencia de la insuficiencia cardíaca congestiva en fase terminal en la población mayor de 65 años es creciente y requiere un manejo terapéutico especifico. El trasplante cardíaco es una opción sólo para un reducido número, ya que la disponibilidad de donantes es limitada y la presencia de criterios de exclusión (patología vascular periférica severa, diabetes mellitus mal controlada...) es frecuente en esta población. Recientemente se han desarrollando nuevos tratamientos: 1) Resincronización cardíaca 2) Asistencia ventricular 3) Plasmaferesis e inmunoabsorción 4) Tratamiento quirúrgico. Estas modalidades terapéuticas están en fase de desarrollo, con resultados iniciales prometedores, pero la experiencia acumulada es pequeña y limitada, y no se dispone de datos fiables que valoren eficacia a medio-largo plazo. (AU)

[Diastolic dysfunction in human immunodeficiency virus infection]. / Disfunción diastólica en la infección por el virus de la inmunodeficiencia humana.

AIMS: We sought to determine the prevalence and characteristics of echocardiographic abnormalities (systolic and/or diastolic dysfunction, pericardial effusion) in patients with human immunodeficiency virus infection (HIV) with no symptoms or previous history of cardiac disease, and compare them with a healthy control group. PATIENTS AND METHOD: Transthoracic echocardiography was performed in 125 patients (73% male, mean age 33.2 +/- 6.6 years) with HIV infection without cardiac involvement and 47 age and sex-matched healthy volunteers (78% male, 31.6 +/- 7.3 years). The immunologic situation was determined by CD4 lymphocyte counts. RESULTS: Abnormal left ventricular relaxation and filling patterns (E/A relation 1.31 +/- 0.35 in HIV group, 1.66 +/- 0.38 in control group, p < 0.001; pressure half-time 57.5 +/- 13 in HIV group, 50.6 +/- 6.6 in control group, p < 0.001), segmental wall-motion abnormalities (15%) and pericardial effusion (7.2%) were found in patients with HIV infection. Systolic function (EF 64.8 +/- 8.3) and left ventricular dimension (diastolic diameter 4.94 +/- 0.55, systolic diameter 3.17 +/- 0.51) showed normal patterns and did not significantly differ from those of the control group. CONCLUSIONS: Silent echocardiographic abnormalities in patients with HIV infection are frequent suggesting a direct myocardial effect of the virus. The development of diastolic dysfunction is directly related to a worse immunologic situation. Prospective studies are needed to clarify the clinical prognosis of these asymptomatic abnormalities.

[Incidence and dynamic behavior of spontaneous echocardiographic contrast and atrial thrombi in the transplanted heart]. / Incidencia y comportamiento dinámico del contraste ecocardiográfico espontáneo y del trombo auricular en el corazón trasplantado.

BACKGROUND: Standard orthotopic heart transplantation produces important anatomic and functional atrial alterations with subsequent thrombotic risk. Therefore the aim of this study was to analyze the prevalence and evolution of spontaneous echocardiography, atrial thrombi and embolic events. PATIENTS AND METHOD: 52 consecutive transplanted patients were analyzed with transesophageal echocardiography and hemodynamic studies performed at 15 days and one year after transplantation. RESULTS: Spontaneous echocardiography contrast was present in 27 patients (52%). Ten atrial thrombi were observed (19.2%), 9 with spontaneous echocardiography contrast. Six atrial thrombi appeared on day 15 and 4 after one year (with spontaneous echocardiography contrast on the previous study). Using multiple logistic regression analysis left atrial size was the only independent predictor factor for spontaneous echocardiography contrast (OR = 1.27; 95% CI, 1.09-1.54) and was an important predictor factor of atrial thrombi formation (OR = 1.19; 95% CI, 1.04-1.42). Likewise, the main predictor of atrial thrombi was the presence of spontaneous echocardiography contrast (OR = 116; 95% CI, 8.4-999). The hemodynamic pattern did not predict either the presence of spontaneous echocardiography contrast or atrial thrombi. The global incidence of embolic events was 4% less than previously described. CONCLUSIONS: The incidence of atrial thrombi and spontaneous echocardiographic contrast after standard orthotopic heart transplantation was 19.2% and 52%, respectively. An enlarged atrium and/or spontaneous echocardiography contrast was found to increase the risk of atrial thrombi. Considering the dynamic nature of atrial thrombi formation, periodical transesophageal echocardiography studies are recommended after heart transplantation.

[Mycotic aneurysm caused by Aspergillus of the aortic suture line after heart transplantation]. / Aneurisma micótico por Aspergillus en la línea de sutura aórtica tras el trasplante cardíaco.

The first case of mycotic aneurysm of aorta by Aspergillus in a patient with heart transplantation is described, in which the infection was produced by direct surgical contamination of the aortic suture. The period of latency was of eight months. The unusualness of the case and its diagnostic difficulties, are is commented.

Manejo del enfermo con miocardiopatía dilatada y miocarditis / Management of the patient with dilated myocardiopathy and myocarditis

La miocardiopatía dilatada (MCD) es una enfermedad intrínseca del miocardio, caracterizada por la dilatación del ventrículo izquierdo o de ambos ventrículos, así como por la disminución de su contractilidad. Es más frecuente en varones en la edad media de la vida, pero debido a que en las fases iniciales suele cursar de forma asintomática, su incidencia puede estar infraestimada. Se han identificado múltiples etiologías causantes de MCD, y todo apunta a que diversos factores pueden influir conjuntamente en producirla. Con frecuencia no se encuentra el agente causal y entonces se denomina MCD idiopática. Su presentación clínica es muy variada, pero la manifestación más frecuente es la insuficiencia cardíaca (IC), que se agrava conforme evoluciona la enfermedad.El manejo de los pacientes con MCD consiste en retrasar la progresión hacia la IC y disminuir la morbimortalidad.La miocarditis es un proceso inflamatorio no isquémico del miocardio, debido a un amplio y heterogéneo grupo de agentes etiológicos con variada distribución geográfica, lo que afecta a la incidencia y prevalencia de la enfermedad. Existe una fase inicial de agresión al miocardio, que suele seguirse de curación o de una segunda fase de inflamación crónica mediada por mecanismos autoinmunes, asociados o no a la persistencia del agente causal. La clínica varía desde la curación completa hasta la evolución hacia MCD. Su tratamiento es sintomático incluyendo el manejo y prevención de las complicaciones. Actualmente se investiga con la terapia inmunosupresora, basándose en la posible perpetuación del daño miocárdico por mecanismos autoinmunes. (AU)

[Immediate hemodynamic response to atrioventricular+ stimulation in severe hypertrophic obstructive myocardiopathy]. / Respuesta hemodinámica inmediata a la estimulación bicameral en la miocardiopatía hipertrófica obstructiva severa.

INTRODUCTION AND OBJECTIVES: Atrial synchronized ventricular pacing has shown to be an alternative to surgery in the therapeutic management of obstructive hypertrophic cardiomyopathy. Our purpose is the analysis of the hemodynamic mechanisms associated with the reduction of left ventricular outflow tract gradient and the changes in left ventricular diastolic function induced by dual-chamber pacing. PATIENTS AND METHODS: We studied twenty patients (age range 40-78 years; mean 63 +/- 10), who were evaluated while receiving their current medication with cardiac catheterization and angiography, at baseline and under dual-chamber pacing. RESULTS: The atrioventricular delay was 127 +/- 26 ms. The subaortic gradient was reduced from 96 +/- 38 to 36 +/- 28 mmHg (p < 0.001), the ejection period index was shortened from 523 +/- 26 to 491 +/- 30 ms (p < 0.001) and the left ventricular end-diastolic pressure fell from 22 +/- 6 to 13 +/- 5 mmHg (p < 0.001). There was no remarkable change in cardiac output. The median wedge pressure decreased from 17 +/- 5 to 12 +/- 2.5 mmHg (p < 0.01), the pulmonary systolic pressure from 39 +/- 15 to 30 +/- 10 mmHg (p < 0.01), the pulmonary diastolic pressure from 19 +/- 5 to 13 +/- 4 mmHg (p < 0.01) and the right ventricular end-diastolic pressure from 7 +/- 3 to 5 +/- 3 mmHg (p < 0.05). The left ventricular ejection fraction was reduced from 79 +/- 6 to 72 +/- 6 per cent (p < 0.001). The initial ejection fraction diminished from 49 +/- 13 to 34 +/- 13 per cent (p < 0.01), the early diastolic filling increased from 39 +/- 11 to 52 +/- 10 per cent (p < 0.001) and the atrial contribution was reduced from 36 +/- 10 to 24 +/- 10 per cent (p < 0,001). The degree of mitral regurgitation changed from 1.4 +/- 1.2 to 0.7 +/- 0.9 (p < 0.01). CONCLUSIONS: There is an obstruction in the left ventricular outflow tract in patients with obstructive hypertrophic cardiomyopathy that is relieved with dual-chamber pacing. The reduction in the intraventricular pressure seems to improve the ventricular relaxation and the diastolic function. The decrease in the degree of mitral regurgitation and the improvement in diastolic function diminish pulmonary capillary and right circuit pressures.