Exercise and fluid challenge during right heart catheterisation for evaluation of dyspnoea
This prospective study compared exercise test and intravenous fluid challenge in a single right heart catheter procedure to detect latent diastolic heart failure in patients with echocardiographic heart failure with preserved ejection function. We included 49 patients (73% female) with heart failure with preserved ejection function and pulmonary artery wedge pressure ≤15 mmHg. A subgroup of 26 patients had precapillary pulmonary hypertension. Invasive haemodynamic and gas exchange parameters were measured at rest, 45° upright position, during exercise, after complete haemodynamic and respiratory recovery in lying position, and after rapid infusion of 500 mL isotonic solution. Most haemodynamic parameters increased at both exercise and intravenous fluid challenge, with the higher increase at exercise. Pulmonary vascular resistance decreased by –0.21 wood units at exercise and –0.56 wood units at intravenous fluid challenge (p = 0.3); 20% (10 of 49) of patients had an increase in pulmonary artery wedge pressure above the upper limit of 20 mmHg at exercise, and 20% above the respective limit of 18 mmHg after intravenous fluid challenge. However, only three patients exceeded the upper limit of pulmonary artery wedge pressure in both tests, i.e. seven patients only at exercise and seven other patients only after intravenous fluid challenge. In the subgroup of pulmonary hypertension patients, only two patients exceeded pulmonary artery wedge pressure limits in both tests, further five patients at exercise and four patients after intravenous fluid challenge. A sequential protocol in the same patient showed a significantly higher increase in haemodynamic parameters at exercise compared to intravenous fluid challenge. Both methods can unmask diastolic dysfunction at right heart catheter procedure, but in different patient groups.
COVID-19 and the pulmonary vasculature
Patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-related disease (COVID-19) present in a number of ways, from asymptomatic carriers to respiratory failure with acute respiratory distress syndrome (ARDS)-like features. Early observational studies documented that virtually all hospitalized patients had parenchymal abnormalities on computed chest tomography. Interestingly, vascular thickening was also shown to be a predominant imaging finding in COVID-19 compared to non-COVID-19 pneumonia (observed in 59% vs. 22%, p < 0.001),1 implying a potential tropism of the virus for the pulmonary vasculature. This is not surprising since its functional receptor from the host cells, the angiotensin-converting enzyme 2 receptor, is largely present on the surface of pulmonary vascular cells. Accordingly, diffuse endothelial inflammation, dysfunction and apoptosis resulting from direct viral infection of the endothelial cells have been reported within the lungs and other organs. Several lines of evidence also suggest that COVID-19 impacts the pulmonary circulation clinically. For example, patients with severe COVID-19 commonly present an atypical form of ARDS with significant dissociation between relatively well-preserved lung mechanics and severe hypoxemia for which the loss of hypoxic vasoconstriction lung perfusion regulation has been proposed as a possible explanation.2 Systematic assessment of thrombotic complications also revealed a high incidence of confirmed venous thromboembolic events amongst patients hospitalized in the ICU, likely exacerbating ventilation–perfusion mismatch.3 Disseminated intravascular coagulation, a condition characterized by the generation of microthrombi in different organs including the pulmonary circulation, was also diagnosed in 71% of the non-survivors of COVID-19, and pulmonary microthrombi were observed at lung dissection from critically ill COVID-19 patients. Consistently, high levels of D-dimers were repeatedly shown to be associated with mortality amongst COVID-19 patients in line with the immuno-thrombosis model of severe sepsis and ARDS, and anticoagulant therapy with heparin has been reported to be associated with decreased mortality, especially so in patients with significant sepsis-induced coagulopathy or markedly elevated D-dimer levels.4 Whether these observations could be related to the non-anticoagulant properties of heparin, including its anti-inflammatory, antiviral, and protective effects on the pulmonary endothelium remains elusive. Given the increased risk of bleeding and previous negative trials of endogenous anticoagulants in sepsis, this retrospective study requires further validation before the efficacy and best dosage, as well as characteristics of patients most suitable for systemic anticoagulation beyond the traditional prevention and management of venous thromboembolism are confirmed.
In the Eye of the Storm: The Right Ventricle in COVID-19
The COVID-19 pandemic caused by the SARS-CoV-2 virus continues to inflict significant morbidity and mortality around the globe. A variety of cardiovascular presentations of SARSCoV-2 infection have been described so far. However, the impact of SARS-CoV-2 on the right ventricle (RV) is largely unknown. Due to its pathophysiologic relevance, the RV finds itself in the eye of the storm of COVID-19, placing it at higher risk of failure. Increased afterload from acute respiratory distress syndrome (ARDS) and pulmonary embolism, negative inotropic effects of cytokines and direct ACE2-mediated cardiac injury from SARS-CoV-2 are potential mechanisms of RV dysfunction in COVID-19. Early detection and treatment of RV dysfunction can lead to decreased mortality and improved patient outcomes in COVID-19.
Long-term outcomes in pulmonary arterial hypertension by functional class: a metaanalysis of randomized controlled trials and observational registries
Limited data about the long-term prognosis and response to therapy in pulmonary arterial hypertension (PAH) patients with World Health Organization functional class (FC) I/II symptoms are available. PubMed and Embase were searched for publications of observational registries and randomized, controlled trials (RCTs) in PAH patients published between January 2001 and January 2018. Eligible registries enrolled PAH patients ≥18 years, N>30, and reported survival by FC. RCT inclusion criteria were PAH patients ≥18 years, ≥6 months of treatment, and morbidity, mortality, or time to worsening as end points reported by FC. The primary outcomes were survival for registries and clinical event rates for RCTs. Separate random effects models were calculated for registries and RCTs. Four RCTs (n=2,482) and 10 registries (n=6,580) were included. Registries enrolled 9%–47% FC I/II patients (the vast majority being FC II) with various PAH etiologies. Survival rates for FC I/II patients at 1, 2, and 3 years were 93% (95% confidence interval [CI]: 91%–95%), 86% (95% CI: 82%–89%), and 78% (95% CI: 73%–83%), respectively. The hazard ratio for the treatment effect in RCTs overall was 0.61 (95% CI: 0.51–0.74), 0.60 (95% CI: 0.44–0.82) for FC I/II patients, and 0.62 (95% CI: 0.49–0.78) for FC III/IV. The calculated risk of death of 22% within 3 years for FC I/II patients underlines the need for careful assessment and optimal treatment of patients with FC I/II disease. The RCT analysis demonstrates that current medical therapies have a beneficial treatment effect in this population.
Targeting translational read-through of premature termination mutations in BMPR2 with PTC124 for pulmonary arterial hypertension
Pulmonary arterial hypertension (PAH) is a fatal disorder of the lung circulation in which accumulation of vascular cells progressively obliterates the pulmonary arterioles. This results in sustained elevation in pulmonary artery pressure leading eventually to right heart failure. Approximately, 70% of familial and 20% of sporadic idiopathic PAH cases are caused by mutations in the bone morphogenetic protein receptor type 2 (BMPR2). Nonsense mutations in BMPR2 are amongst the most common mutations found, where the insertion of a premature termination codon (PTC) causes mRNA degradation via activation of the nonsense-mediated decay (NMD) pathway leading to a state of haploinsufficiency. Ataluren (PTC124), a compound that permits ribosomal read-through of premature stop codons, has been previously reported to increase BMPR2 protein expression in cells derived from PAH patients harbouring nonsense mutations. In this study, we characterized the effects of PTC124 on a range of nonsense BMPR2 mutations, focusing on the R584X mutation both in vitro and in vivo. Treatment with PTC124 partially restored BMPR2 protein expression in blood outgrowth endothelial cells (BOECs) isolated from a patient harbouring the R584X mutation. Furthermore, a downstream BMP signalling target, Id1, was rescued by PTC124 treatment. Mutant cells also exhibited increased LPS-induced permeability which was reversed by PTC124 treatment. Increased proliferation and apoptosis in R584C BOECs were also significantly reduced by PTC124. Moreover, oral PTC124 increased lung Bmpr2 protein expression in mice harbouring the R584X mutation (Bmpr2+/R584X). Our findings provide support for future experimental medicine studies of PTC124 in PAH patients with specific nonsense BMPR2 mutations.
Echocardiographic markers of pulmonary hemodynamics and right ventricular hypertrophy in rat models of pulmonary hypertension
Echocardiography is the gold standard non-invasive technique to diagnose pulmonary hypertension. It is also an important modality used to monitor disease progression and response to treatment in patients with pulmonary hypertension. Surprisingly, only few studies have been conducted to validate and standardize echocardiographic parameters in experimental animal models of pulmonary hypertension. We sought to define cut-off values for both invasive and non-invasive measures of pulmonary hemodynamics and right ventricular hypertrophy that would reliably diagnose pulmonary hypertension in three different rat models. The study was designed in two phases: (1) a derivation phase to establish the cut-off values for invasive measures of right ventricular systolic pressure, Fulton's index (right ventricular weight/left ventricle + septum weight), right ventricular to body weight ratio, and non-invasive echocardiographic measures of pulmonary arterial acceleration time, pulmonary arterial acceleration time to ejection time ratio and right ventricular wall thickness in diastole in the hypoxic and monocrotaline rat models of pulmonary hypertension and (2) a validation phase to test the performance of the cut-off values in predicting pulmonary hypertension in an independent cohort of rats with Sugen/hypoxia-induced pulmonary hypertension. Our study demonstrates that right ventricular systolic pressure ≥35.5 mmHg and Fulton's Index ≥0.34 are highly sensitive (>94%) and specific (>91%) cut-offs to distinguish animals with pulmonary hypertension from controls. When pulmonary arterial acceleration time/ejection time and right ventricular wall thickness in diastole were both measured, a result of either pulmonary arterial acceleration time/ejection time ≤0.25 or right ventricular wall thickness in diastole ≥1.03 mm detected right ventricular systolic pressure ≥35.5 mmHg or Fulton's Index ≥0.34 with a sensitivity of 88% and specificity of 100%. With properly validated non-invasive echocardiography measures of right ventricular performance in rats that accurately predict invasive measures of pulmonary hemodynamics, future studies can now utilize these markers to test the efficacy of different treatments with preclinical therapeutic modeling.