MK-5475, an inhaled soluble guanylate cyclase stimulator, for treatment of pulmonary arterial hypertension: the INSIGNIA-PAH study.

BACKGROUND: MK-5475 is an investigational inhaled soluble guanylate cyclase stimulator hypothesised to avoid most side-effects of systemic vasodilation. METHODS: The phase 2 INSIGNIA-PAH (NCT04732221) trial randomised adults with pulmonary arterial hypertension (PAH) on stable background therapy 1:1:1:1 to once-daily dosing with placebo, MK-5475 32 µg, 100 µg or 380 µg via dry powder inhalation for 12 weeks. OBJECTIVES: The objectives were to evaluate pulmonary vascular resistance (PVR; primary), 6-min walk distance (6MWD; secondary), additional selected haemodynamic parameters, and safety and tolerability in participants with PAH. RESULTS: 168 participants were randomised to placebo (n=41), MK-5475 32 µg (n=42), 100 µg (n=44), and 380 µg (n=41). Median age was 51 years. Most participants were female (73.8%), diagnosed with idiopathic PAH (63.7%), receiving concomitant phosphodiesterase type 5 inhibitors (PDE5i; 93.5%), and treated with double or triple combination therapy (85.1%). At week 12, the placebo-corrected changes in PVR by least-squares means were -9.2% (95% CI -21.3%, 2.9%; p=0.068) with 32 µg, -22.0% (95% CI -33.7%, -10.3%; p<0.001) with 100 µg, and -19.9% (95% CI -33.4%, -6.4%; p=0.002) with 380 µg MK-5475. No treatment differences versus placebo were observed in 6MWD. Treatment-related adverse events and serious adverse events were similar across treatment groups. Three participants died: two on placebo and one on MK-5475 100 µg. One participant had symptomatic hypotension and one had haemoptysis (both on MK-5475 100 µg). CONCLUSIONS: In participants with PAH on stable background therapy, including PDE5i, inhaled MK-5475 reduced PVR and was well tolerated, without evidence of systemic side-effects such as hypotension, suggesting a pulmonary selective pharmacodynamic effect.

[SPCCTV and SPC Recommendations Related to the Waiting Times for Cardiac Surgery]. / Recomendações da Sociedade Portuguesa de Cirurgia Cardiotorácia e Vascular (SPCCTV) e da Sociedade Portuguesa de Cardiologia (SPC) sobre os Tempos de Espera para Cirurgia Cardíaca.

Appointed jointly by the Portuguese Society for Cardiothoracic and Vascular Surgery (SPCCTV) and by the Portuguese Society of Cardiology (SPC), the Working Group related to the Waiting Times for Cardiac Surgery was created with the aim of developing practical recommendations about clinically acceptable waiting times for the three critical phases of the care of adults with a cardiac disease that require surgery or an intervention: cardiology appointments; diagnostic process and invasive therapy. Cardiac surgery has its own characteristics, not comparable to other surgical specialties and, therefore, it is important to reduce its maximum waiting times and, also, increase the efficacy of the systems which are responsible to monitor and trace the patient. The information given in this document was based, mostly, in available clinical information. The methodology used to establish the criteria was based on studies regarding disease's natural history, clinical studies that compared medical treatment with intervention, retrospective and prospective analysis of patients included on a waiting list, and experts or working groups' opinions. After this first step, marked by this publication, the SPCCTV and the SPC PSC should be considered as natural interlocutors about this matter and they are committed to decisively contribute to the definition of operational strategies through the adaption of the clinical evidence with reality and with the available resources.

Clinical applications of exercise stress echocardiography in the treadmill with upright evaluation during and after exercise.

Exercise stress echocardiography is the most frequently used stress test in our laboratory. Exercise echocardiography is used mainly in the study of patients with coronary artery disease. However, the technique is increasingly being used to study other diseases. In our centre, we use an original methodology, published by us in 2000, in which we evaluate heart function during exercise in the treadmill. After the exercise, patients are maintained in orthostatic position when appropriate or lying down in left lateral decubitus for further evaluation. Since this method seems to increase the quality and the quantity of information obtained in so many clinical arenas, we now present a detailed review of this methodology and its applications.

Blueprint for developing an effective pulmonary embolism response network.

INTRODUCTION: Acute pulmonary embolism (PE) is a major cause of morbidity and mortality in Portugal. It is the third most common cause of cardiovascular death after stroke and myocardial infarction. However, the management of acute PE remains poorly standardized, and there is a lack of access to mechanical reperfusion when indicated. METHODS AND RESULTS: This working group analyzed the current clinical guidelines for the use of percutaneous catheter-directed treatment in this setting and proposed a standardized approach for severe forms of acute PE. This document also proposes a methodology for the coordination of regional resources in order to create an effective PE response network, based on the hub-and-spoke organization design. CONCLUSION: This model can be applied at the regional level, but it is desirable to extend it to the national level.

[Takotsubo cardiomyopathy in a cardiology department]. / Miocardiopatia de takotsubo num serviço de Cardiologia.

Takotsubo cardiomyopathy, also known as transient left ventricular apical ballooning syndrome, stress-induced cardiomyopathy and broken heart syndrome, is characterized by transient left ventricular dysfunction in the absence of obstructive coronary artery disease. It was first described in 1990 in Japan, and gained worldwide recognition following the publication of several series of case reports. Its prevalence is estimated to be 1.7-2.2% of suspected acute coronary syndromes. Although takotsubo cardiomyopathy has been progressively better characterized, certain aspects remain to be clarified, and it is still under study. In this article, we report a series of ten cases of takotsubo cardiomyopathy admitted to a cardiology department, and compare the clinical, laboratory, electrocardiographic and imaging characteristics, therapeutic regimens and follow-up of these patients with those described in the latest scientific reviews.

Severe and Apparently Irreversible Pulmonary Arterial Hypertension in a Patient with Ostium Secundum Atrial Septal Defect - A Successful Case of Treat and Close Strategy.

Irreversible pulmonary arterial hypertension is considered a contraindication for surgical or percutaneous closure of atrial septal defects (ASD) due to risk of right heart failure. We present a case of 37 years-old woman who was referred to our center due to progressive worsening fatigue and high probability of pulmonary hypertension on a transthoracic echocardiogram. The diagnostic work-up revealed the presence of an ostium secundum atrial septal defect and severe pre-capillary pulmonary hypertension on right heart cathetherization (RHC). The patient was considered inoperable and started medical therapy with sildenafil and bosentan. After one year of treatment, she repeated RHC that showed a significant reduction in pulmonary vascular resistance making her eligible for closure. Surgical closure of ASD with a fenestra was performed with success. Our case emphasizes the importance of individual assessment even if cases where initial evaluation is unfavorable to closure in accordance with the guidelines.

Continuous Aspiration Mechanical Thrombectomy for the management of intermediate- and high-risk pulmonary embolism: Data from the first cohort in Portugal.

INTRODUCTION: This study describes the experience of a reference center using continuous aspiration mechanical thrombectomy for acute high- and intermediate-high-risk pulmonary embolism (PE). METHODS: Twenty-nine consecutive patients with acute central PE (48.3% high-risk PE; 82.8% in class >III from the original Pulmonary Embolism Severity Index score; median Charlson Comorbidity Index of 4) were treated with the Indigo® Mechanical Thrombectomy System between March 2018 and March 2020. Technical success was defined as successful placement of the device and initiation of aspiration thrombectomy. Clinical success was defined as any improvement in hemodynamic and/or oxygenation parameters, pulmonary hypertension or right heart strain at 48 hours, and survival to hospital discharge. Safety was defined as freedom from severe adverse events potentially related to the procedure. Three-month follow-up results were collected. RESULTS: Technical success was 96.6%. Miller index and systolic pulmonary arterial pressure were significantly reduced after the procedure (-5.5±3.0, and -10.2±11.5 mmHg, respectively, both p<0.001). There was a significant improvement in mean paO2/FiO2 ratio (+77.1±103.2; p=0.001), shock index (-0.4±0.4; p<0.001), need for aminergic support at 48 h after the procedure (-75.0%, p=0.006) and improvement in right ventricular function in 66.6% (p=0.008). Clinical success was 75.9%. Severe adverse event rate was 10.3%: two deaths during the procedure and one pulmonary macroembolization during device progression. In-hospital and three-month survival rates were 82.8% and 72.4%, respectively. CONCLUSIONS: Aspiration thrombectomy for acute high- and intermediate-high-risk PE is feasible with a high technical and clinical success rate. Nevertheless, all-cause mortality is still high, probably related to the baseline high-risk features of the studied population and associated comorbidities.

Safety and efficacy of balloon pulmonary angioplasty in a Portuguese pulmonary hypertension expert center.

INTRODUCTION: Balloon pulmonary angioplasty (BPA) is an alternative therapy in patients with inoperable chronic thromboembolic pulmonary hypertension (CTEPH) or residual/recurrent pulmonary hypertension (PH) after surgery. The aim of this study was to assess the short-term efficacy and safety of a BPA program. METHODS: This prospective single-center study included all BPA sessions performed in CTEPH patients between 2017 and 2019. Clinical assessment including WHO functional class, plasma biomarkers, 6-min walk test (6MWT) and right heart catheterization was performed at baseline and six months after the last BPA session. RESULTS: A total of 57 BPA sessions were performed in 11 CTEPH patients (64% with inoperable disease, 82% under pulmonar vasodilator therapy). Nine patients completed both the BPA program and a minimum six-month follow-up period. There were significant improvements in WHO functional class (p=0.004) and 6MWT (mean increase of 42 m; p=0.050) and a trend for significant hemodynamic improvement: 25% decrease in mean pulmonary artery pressure (mPAP) (p=0.082) and 42% decrease in pulmonary vascular resistance (PVR) (p=0.056). In the group of patients with severely impaired hemodynamics (three patients with mPAP >40 mmHg), the reduction was significant: 51% in mPAP (p=0.013) and 67% in PVR (p=0.050). Prostacyclin analogs and long-term oxygen therapy were withdrawn in all patients. Minor complications were recorded in 25% of patients. There were no major complications or deaths. CONCLUSIONS: A BPA strategy on top of pulmonary vasodilator therapy further improves symptoms, exercise capacity and hemodynamics with an acceptable risk-benefit ratio in patients with inoperable CTEPH or residual/recurrent PH after surgery.

Balloon pulmonary angioplasty protocol in a Portuguese pulmonary hypertension expert center.

INTRODUCTION: Balloon pulmonary angioplasty (BPA) has emerged as a promising therapeutic option for patients with chronic thromboembolic pulmonary hypertension (CTEPH) who are not eligible for pulmonary thromboendarterectomy (PEA) or who have recurrent or persistent pulmonary hypertension after surgery. There is no standardized technique for BPA and, its complexity and high risk of severe complications, requires skills and appropriate training and should be reserved for expert CTEPH centers, as a complementary intervention to medical and surgical therapy. OBJECTIVE: The purpose of this document is to describe the BPA protocol used at a high-volume center nationwide, validated by its results. METHODS: The present protocol includes technical details, definition of outcomes and complications, as well as patient full diagnostic work-up and treatment algorithm, before and after BPA. RESULTS: The technical, hemodynamic, and clinical results of the application of this protocol will be subject of a later publication where they will be described in detail. In conclusion, we present a percutaneous intervention protocol in the treatment of pulmonary hypertension in the context of chronic pulmonary thromboembolism, validated by its clinical, hemodynamic, and technical results.

Safety and efficacy of balloon pulmonary angioplasty in a Portuguese pulmonary hypertension expert center. / Segurança e eficácia da angioplastia pulmonar por balão em Portugal num centro de referência em hipertensão pulmonar.

INTRODUCTION: Balloon pulmonary angioplasty (BPA) is an alternative therapy in patients with inoperable chronic thromboembolic pulmonary hypertension (CTEPH) or residual/recurrent pulmonary hypertension (PH) after surgery. The aim of this study was to assess the short-term efficacy and safety of a BPA program. METHODS: This prospective single-center study included all BPA sessions performed in CTEPH patients between 2017 and 2019. Clinical assessment including WHO functional class, plasma biomarkers, 6-min walk test (6MWT) and right heart catheterization was performed at baseline and six months after the last BPA session. RESULTS: A total of 57 BPA sessions were performed in 11 CTEPH patients (64% with inoperable disease, 82% under pulmonary vasodilator therapy). Nine patients completed both the BPA program and a minimum six-month follow-up period. There were significant improvements in WHO functional class (p=0.004) and 6MWT (mean increase of 42 m; p=0.050) and a trend for significant hemodynamic improvement: 25% decrease in mean pulmonary artery pressure (mPAP) (p=0.082) and 42% decrease in pulmonary vascular resistance (PVR) (p=0.056). In the group of patients with severely impaired hemodynamics (three patients with mPAP >40mmHg), the reduction was significant: 51% in mPAP (p=0.013) and 67% in PVR (p=0.050). Prostacyclin analogs and long-term oxygen therapy were withdrawn in all patients. Minor complications were recorded in 25% of patients. There were no major complications or deaths. CONCLUSIONS: A BPA strategy on top of pulmonary vasodilator therapy further improves symptoms, exercise capacity and hemodynamics with an acceptable risk-benefit ratio in patients with inoperable CTEPH or residual/recurrent PH after surgery.

Intraventricular gradients and acute coronary syndromes: a case report.

Left ventricular outflow tract obstruction (LVOTO) has traditionally been associated with hypertrophic obstructive cardiomyopathy, but can occur in other clinical scenarios such as acute myocardial infarction (AMI). In some patients, LVOTO is absent at rest, being detectable only with provocation tests such as stress echocardiography. Timely diagnosis of this phenomenon is very important, as it has therapeutic implications, and relies on clinical suspicion and on recognizing substrates in which LVOTO can occur. We report a case of syncope and AMI associated with LVOTO with systolic anterior motion of the mitral valve and a significant intraventricular gradient.

[Value of exercise echocardiography in aortic recoarctation--case report]. / Utilidade da ecocardiografia de esforço na recoarctação da aorta--caso clínico.

In this article the authors present a case study of a young man with coarctation of the aorta that underwent surgical correction at 4 months old, for whom the exercise echocardiogram was important in determining the functional importance of recoarctation and the decision of the timing for re-intervention, demonstrating the importance of this technique to discriminate the functional significance of this pathology.

Neurofibromatosis-associated pulmonary hypertension: an ominous duo.

The authors report a rare clinical case of a patient with neurofibromatosis type 1 (NF1) complicated by pulmonary hypertension (PH), which presents with rapid progression. An exhaustive investigation was performed to identify the main aetiology of the PH. It was concluded that the PH could be associated with NF1, and so belonged in group 5 of the clinical classification of PH. In general, such patients have a poor long-term prognosis due to the inexistence of proven, effective treatment. Further studies are needed to better understand the mechanisms of NF1-associated PH.

Pulmonary veno-occlusive disease: a probably underdiagnosed cause of pulmonary hypertension in systemic sclerosis.

Pulmonary hypertension is a serious complication of systemic sclerosis and remains one of the leading causes of mortality. Pulmonary veno-occlusive disease (PVOD), recently reclassified as pulmonary arterial hypertension (PAH) with overt features of venous/capillaries involvement, is a subgroup of group 1 pulmonary hypertension, which has been rarely reported in systemic sclerosis patients. It is symptomatically indistinguishable from idiopathic pulmonary arterial hypertension and should be suspected in those with manifestations of pulmonary arterial hypertension who have evidence of pulmonary venous congestion in the absence of left-sided heart disease. Thoracic high-resolution computed tomography can give important hints for the diagnosis, such as ground-glass opacities/nodules, mediastinal lymph node enlargement and interlobular septal thickening. Patients with PVOD usually have a poor prognosis and might experience acute pulmonary oedema after introduction of pulmonary vasodilators. Due to clinical similarities between scleroderma-related PAH and PVOD, some patients are misdiagnosed and this could explain, in part, the worse prognosis associated with this clinical condition, when compared with idiopathic PAH. We report the case of a 72-year-old woman with limited systemic sclerosis, who was initially diagnosed with systemic sclerosis-related pulmonary arterial hypertension. However, after introduction of sildenafil and bosentan, the patient developed acute pulmonary oedema, and findings from complementary exams were suggestive of PVOD.

Chronic thromboembolic pulmonary hypertension secondary to implantable cardioverter defibrillator lead thrombus in a patient with Brugada syndrome: a rare complication requiring a multidisciplinary approach.

We report the case of a 57-year-old male patient with prior syncope associated with sustained ventricular tachycardia in the setting of Brugada syndrome, who was submitted to implantation of a cardioverter defibrillator for secondary prevention. During follow-up, he presented a significant increase in lead impedance, and a transthoracic echocardiogram showed a mass attached to the lead. He was started on oral anticoagulation after infective endocarditis was excluded but nevertheless suffered repeated episodes of pulmonary embolism that led to severe chronic thromboembolic pulmonary hypertension. After heart team discussion, he was referred to pulmonary endarterectomy and replacement of the implantable cardioverter defibrillator with a subcutaneous device. This led to significant improvement of functional class and normalisation of pulmonary haemodynamics. More recently, he suffered syncope in the setting of ventricular fibrillation with appropriate shocks and was started on quinidine without further recurrence of arrhythmic episodes.

Dyspnea in antiphospholipid syndrome: Beyond pulmonary embolism.

Pulmonary embolism due to primary antiphospholipid syndrome is rarely associated with chronic thromboembolic pulmonary hypertension, and therefore according to the latest guidelines on pulmonary hypertension, routine screening is not recommended. We describe a young patient with a late diagnosis of chronic thromboembolic pulmonary hypertension in the context of pulmonary embolism, primary antiphospholipid syndrome and suboptimal anticoagulation. Of note, mild cardiopulmonary symptoms were consistently misattributed to a depressive disorder because physical examination was normal, serial Doppler echocardiography failed to show pulmonary hypertension, and all other diagnostic tests were normal. Once symptoms became severe, positive screening tests led to the correct diagnosis and surgical referral, and bilateral pulmonary endarterectomy was successfully performed. This case demonstrates the need for extra awareness in patients with antiphospholipid syndrome and pulmonary embolism.

A pregnant woman with a mechanical prosthetic valve.

A 24-year-old woman who was 11 weeks pregnant and had a mechanical mitral valve presented at the emergency department with ischemic stroke. Although treatment with aspirin and unfractionated heparin was initially successful, subsequent management was almost impossible, as she eventually suffered a right hemispheric stroke, requiring percutaneous intervention and an emergency cesarian; prosthetic valve thrombosis with hemodynamic instability; and multiple bleeding complications. This case demonstrates how difficult it can be to select the appropriate treatment strategy for prosthetic valve thrombosis.

Three-vessel myocardial bridging: A possible cause of myocardial stunning.

The authors report a rare clinical case of myocardial bridging of the three major coronary arteries, which manifested in an unusual way with severe biventricular dysfunction in the context of tachycardia. For the diagnosis, the authors relied on non-invasive multimodality cardiac imaging, including cardiac magnetic resonance, computed tomography angiography and myocardial perfusion scintigraphy. The implementation of targeted medical and neurohormonal therapy resulted in the recovery of ventricular function and clinical improvement.

Evaluation of left ventricular outflow tract gradient during treadmill exercise and in recovery period in orthostatic position, in patients with hypertrophic cardiomyopathy.

BACKGROUND: Left ventricular outflow tract obstruction is an independent predictor of adverse outcome in hypertrophic cardiomyopathy (HCM). The classical quantification of intraventricular obstruction is performed in resting conditions in supine position, but this assessment does not reflect what happens in HCM patients (pts) in their daily activities, neither during effort nor during orthostatic recovery. AIM: To assess intraventricular gradients with echocardiography during treadmill exercise and in the recovery period in upright position, in HCM pts. METHODS: We studied 17 HCM pts (9 males, mean age 53 +/- 16 years, 11 with obstructive HCM). Each pt had 2 echocardiographic evaluations at rest (left lateral decubitus (LLD) and orthostatic position). The pts then underwent a treadmill exercise test and intraventricular gradients were measured at peak exercise and during recovery in orthostatic position. RESULTS: 3 pts with non-obstructive HCM at rest developed intraventricular gradients during exercise. 1 pt developed this gradient only during orthostatic recovery. The mean intraventricular gradient in LLD was 49 +/- 24 mmHg; in orthostatic position was 62 +/- 29 mmHg (p < 0.001 versus in LLD); at peak exercise was 83 +/- 35 mmHg (p < 0.001 versus supine rest); during recovery it was 96 +/- 35 mmHg (p < 0.001 versus peak exercise) CONCLUSION: In HCM pts the intraventricular gradient increases in orthostatic position, increases significantly during treadmill exercise and continues increasing in the recovery period in orthostatic position. This type of evaluation can help us to better understand the physiopathology, the symptoms and the efficacy of different therapeutic modalities in this disease and should be routinely used in the assessment of HCM pts.

Syncope caused by severe hypotension and intraventricular gradient during dobutamine stress echocardiography.

Dobutamine stress echocardiography is widely used for the evaluation of coronary artery disease. This form of stress echocardiography is safe but not without complications. We report a case of hypotension and syncope during dobutamine stress echocardiography in which a severe intraventricular gradient of over 200 mmHg and systolic anterior movement of the mitral valve were observed.