Unravelling the role of the left and right ventricles in pulmonary arterial hypertension: patient and small animal cardiac MRI studies

The definite hemodynamic diagnosis of pulmonary hypertension (PH) requires direct measurement of the pulmonary artery pressure by right heart catheterisation. As right heart catheterisation is an invasive test with a small risk of associated morbidity and mortality, diagnostic algorithms have been devised that combines clinical history and examination, cardio- respiratory assessment by non-imaging techniques and subsequently imaging techniques in patients suspected of having PH. The aim of these initial investigations is to establish a tentative diagnosis of PH, help identify the underlying aetiology and to provide information regarding disease severity and determine response to treatment. Although PH is a disease of the pulmonary vasculature, it is the subsequent right ventricular (RV) failure that is the main cause of morbidity and mortality in PH patient. Thus, RV is the most widely studied of the chambers in PH, however focus has started to move to the left ventricle (LV). Although a disease of the pulmonary circulation and the RV, there is now evidence demonstrating LV abnormalities in PH. Further to this, the atrial chambers offer valuable information when measuring cardiac function as well as in identifying the aetiology of PH. Small animal (rodent) models are increasingly used to identify pathophysiology as well as therapies for PH with the intention of translating the findings to humans. Accurate monitoring of disease in rodents with emphasis on ventricular function and the ability to monitor the disease state without killing the animal is needed

Exploring the failing right ventricle in pulmonary hypertension by cardiac magnetic resonance: an in vivo study utilizing Macitentan

Cardiac magnetic resonance (CMR) imaging is used to assess the right ventricle (RV) of pulmonary hypertensive (PH) patients and more recently to track changes in response to therapy. We wished to investigate if repeat CMRs could be used to assess ventricular changes in the Sugen 5416 hypoxic (Su/Hx) rat model of PH treated with the dual endothelin receptor antagonist Macitentan. Male Sprague Dawley Su/Hx rats were dosed for 3 weeks with either vehicle or Macitentan (30 mg/kg) daily, control rats received only vehicle. All rats underwent three CMR scans; before treatment, 2 weeks into treatment, and end of the study. A separate group of Su/Hx and control rats, treated as above, underwent terminal hemodynamic measurements. Using terminal and CMR measurements, Macitentan was found to lower RV systolic pressure pulmonary artery remodeling and increase RV ejection fraction but not change RV hypertrophy (RVH). Repeat CMRs determined that Su/Hx rats treated with Macitentan had significantly reversed RVH via reducing RV mass as well as reducing elevated left ventricular eccentricity index; reductions in RV mass were also observed in Su/Hx vehicle rats exposed to normoxic conditions. We have demonstrated that repeat CMRs can be used to assess the volume and structural changes in the ventricles of the Su/Hx rat model. Using repeat CMRs has allowed us to build a more complete picture of the response of the RV and the left ventricle to treatment. It is unknown if these effects are a consequence of direct action on the RV or secondary to improvements in the lung vasculature

Dobutamine stress MRI in pulmonary hypertension: relationships between stress pulmonary artery relative area change, RV performance, and 10-year survival

In pulmonary hypertension (PH), right ventricular (RV) performance determines survival. Pulmonary artery (PA) stiffening is an important biomechanical event in PH and also predicts survival based on the PA relative area change (RAC) measured at rest using magnetic resonance imaging (MRI). In this exploratory study, we sought to generate novel hypotheses regarding the influence of stress RAC on PH prognosis and the interaction between PA stiffening, RV performance and survival. Fifteen PH patients underwent dobutamine stress-MRI (ds-MRI) and right heart catheterization. RACREST, RACSTRESS, and ΔRAC (RAC STRESS – RAC REST) were correlated against resting invasive hemodynamics and ds-MRI data regarding RV performance and RV-PA coupling efficiency (n’vv [RV stroke volume/RV end-systolic volume]). The impact of RAC, RV data, and n’vv on ten-year survival were determined using Kaplan–Meier analysis. PH patients with a low ΔRAC (<−2.6%) had a worse long-term survival (log-rank P = 0.045, HR for death = 4.46 [95% CI = 1.08–24.5]) than those with ΔRAC ≥ −2.6%. Given the small sample, these data should be interpreted with caution; however, low ΔRAC was associated with an increase in stress diastolic PA area indicating proximal PA stiffening. Associations of borderline significance were observed between low RACSTRESS and low n’vvSTRESS, Δη’VV, and ΔRVEF. Further studies are required to validate the potential prognostic impact of ΔRAC and the biomechanics potentially connecting low ΔRAC to shorter survival. Such studies may facilitate development of novel PH therapies targeted to the proximal PA

Near infrared spectroscopy for the assessment of peripheral tissue oxygenation in pulmonary arterial hypertension

Pulmonary arterial hypertension (PAH) is characterised by increased pulmonary vascular resistance and results in increased morbidity and mortality due to right heart failure and a progressive decline in cardiac output [1, 2]. The latter disturbs oxygen delivery to the periphery and may lead to pathological changes in tissue oxygenation. The balance between global oxygen supply and demand is reflected in mixed venous oxygen saturation (SvO2), an index that is generally reduced in patients with PAH [3]. SvO2 at baseline is one of the strongest predictors of survival in PAH [4–6]; this is also true for changes in SvO2 during follow-up [5]. Cut-off values of 60% [7] and 65% [5] have been used to distinguish between prognostic groups suggesting that these may be suitable treatment goals. SvO2 is measured invasively in the pulmonary artery, where venous blood mixes after circulating through the superior and inferior vena cava, coronary sinuses and the right-heart chambers

Asbestos accelerates disease onset in a genetic model of malignant pleural mesothelioma

Hypothesis: Asbestos-driven inflammation contributes to malignant pleural mesothelioma beyond the acquisition of rate-limiting mutations. Methods: Genetically modified conditional allelic mice that were previously shown to develop mesothelioma in the absence of exposure to asbestos were induced with lentiviral vector expressing Cre recombinase with and without intrapleural injection of amosite asbestos and monitored until symptoms required euthanasia. Resulting tumours were examined histologically and by immunohistochemistry for expression of lineage markers and immune cell infiltration. Results: Injection of asbestos dramatically accelerated disease onset and end-stage tumour burden. Tumours developed in the presence of asbestos showed increased macrophage infiltration. Pharmacological suppression of macrophages in mice with established tumours failed to extend survival or to enhance response to chemotherapy. Conclusion: Asbestos-driven inflammation contributes to the severity of mesothelioma beyond the acquisition of rate-limiting mutations, however, targeted suppression of macrophages in established epithelioid mesothelioma showed no therapeutic benefit

Asbestos accelerates disease onset in a genetic model of malignant pleural mesothelioma

Hypothesis: Asbestos-driven inflammation contributes to malignant pleural mesothelioma beyond the acquisition of rate-limiting mutations.Methods: Genetically modified conditional allelic mice that were previously shown to develop mesothelioma in the absence of exposure to asbestos were induced with lentiviral vector expressing Cre recombinase with and without intrapleural injection of amosite asbestos and monitored until symptoms required euthanasia. Resulting tumours were examined histologically and by immunohistochemistry for expression of lineage markers and immune cell infiltration.Results: Injection of asbestos dramatically accelerated disease onset and end-stage tumour burden. Tumours developed in the presence of asbestos showed increased macrophage infiltration. Pharmacological suppression of macrophages in mice with established tumours failed to extend survival or to enhance response to chemotherapy.Conclusion: Asbestos-driven inflammation contributes to the severity of mesothelioma beyond the acquisition of rate-limiting mutations, however, targeted suppression of macrophages in established epithelioid mesothelioma showed no therapeutic benefit

Advanced imaging in pulmonary hypertension

Pulmonary hypertension is a pathophysiological state defined as mean pulmonary artery pressure ≥ 25 mmHg at rest determined by right heart catheterization. Various non-invasive imaging modalities have been used to not only establish a tentative diagnosis of pulmonary hypertension but to assess its severity, to identify underlying etiology, to monitor disease progression and response to treatment. Continuous wave Doppler measurements of peak velocity of the tricuspid regurgitant jet is used to determine systolic pulmonary artery pressure non invasively but has various shortcomings when describing the complex right ventricle. Chest radiography may give the first clue to the presence of pulmonary hypertension with information about the cardiac size and pulmonary vasculature. The role of ventilation-perfusion scintigraphy is in the highly sensitive detection of pulmonary embolism which may indicate chronic thromboembolic pulmonary hypertension. Various features of pulmonary hypertension in the main and peripheral pulmonary arteries as well as the lung parenchyma are well visualised by computed tomography. Measures of right ventricular function have been shown to be prognostic in pulmonary hypertension and cardiac magnetic resonance imaging provides accurate information regarding biventricular mass, volume and function. New advances in imaging techniques such as Positron Emission Tomography will give us greater insight into the basic pathobiology of pulmonary vascular remodeling and RV dysfunction

Pulmonary hypertension and severe right heart failure following lumbar spinal surgery

Pulmonary hypertension is a disease process affecting the pulmonary circulation and is defined by an increase in pulmonary artery pressure subsequently causing right ventricular failure. Vascular complications, including arteriovenous fistulae, are recognised, but are uncommon complications of spinal surgery. Arteriovenous fistulae increase venous return to the right heart and can induce a high-output cardiac state, mimicking pulmonary arterial hypertension and right heart failure. We present a 47-year-old man with a 1 year history of worsening dyspnoea, exertional pre-syncope and leg swelling presenting with severe right heart failure. The previous year, he had complex spinal surgery, which included discectomy, laminectomy and bilateral nerve reconstruction at L5-S1 level. Initial non-invasive investigations including echocardiography and chest imaging raised the possibility of right heart failure presumed secondary to pulmonary vascular disease. Clinical examination and right heart catheterisation were in keeping with a high cardiac output state, and invasive saturation monitoring was suggestive of a sub-diaphragmatic shunt. Subsequent imaging confirmed the presence of an iatrogenic ilio-iliac arteriovenous fistula. The patient underwent urgent endovascular repair, which resulted in resolution of his symptoms and haemodynamics. We describe the case and present a review of the relevant literature