Arterial and pulmonary hypertension: risk assessment and current pharmacological and interventional management

For the podcast associated with this article, please visit https://academic.oup.com/eurheartj/pages/Podcasts. Arterial hypertension remains one of the most common and important cardiovascular risk factors.1 For its management, a series of old and novel antihypertensive drugs are at our disposal.2,3 However, more recently, renal denervation, which was sucessfully used surgically in the 1950s, and other interventional techniques has been rediscovered.4 Unfortunately, after exciting early trials,5 the neutral Symplicity HTN-3 trial brought this novel technique almost to an end,6,7 until a subanalysis demonstrated the relationship of its effectiveness to the number of properly performed ablations.8 This year, the Phoenix was re-born out of its ashes with three positive trials with novel devices based on radiofrequency or ultrasound energy (Figure 1), as outlined in the Viewpoint ‘Catheter-based renal denervation: the next chapter begins’ authored by Felix Mahfoud from the Universitätsklinikum des Saarlandes in Homburg, Germany and colleagues.9 Antihypertensive effectivness of renal denervation with radiofrequency (DENERHTN, SPYRAL HTN-OFF, and SPYRAL HTN-ON) or ultrasound energy (Radiance-HTN) in three major recent trials (from Lüscher TF. Cardiovasc Med 2018; 21(11):290–295). Adjusted hazard ratio of cardiovascular disease outcome as a function of clinic and ambulatory blood pressure. (A) Adjusted hazard ratio of cardiovascular disease outcome as a function of awake and asleep systolic blood pressure/diastolic blood pressure means. (B) Adjusted hazard ratio of cardiovascular disease as a function of office blood pressure measurements and awake plus asleep systolic blood pressure/diastolic blood pressure means. Awake systolic blood pressure/diastolic blood pressure mean was considered normal if <135/85 mmHg and high otherwise. Asleep systolic blood pressure/diastolic blood pressure mean was considered normal if <120/70 mmHg and high otherwise. Clinic systolic blood pressure/diastolic blood pressurewas considered normal if <140/90 mmHg and high otherwise. Adjustments were applied for the same variables as in Figure 1. Ref. means reference group for hazard ratio calculations (from Hermida RC, Crespo JJ, Otero A, Domínguez-Sardiña M, Moyá A, Ríos MT, Castiñeira MC, Callejas PA, Pousa L, Sineiro E, Salgado JL, Durán C, Sánchez JJ, Fernández JR, Mojón A, Ayala DE; for the Hygia Project Investigators. Asleep blood pressure: significant prognostic marker of vascular risk and therapeutic target for prevention. See pages 4159–4171). In-hospital (A) and 30-day (B) all-cause death in patients with or without syncope at acute pulmonary embolism presentation. (A) Absolute risk difference (95% confidence interval) was +7% (0% to +14%) in studies including mixed populations and −3% (−4% to −1%) in studies including haemodynamically stable patients (test for subgroup differences: P = 0.01). (B) Absolute risk difference (95% confidence interval) was +5% (−1% to +10%) in studies including mixed populations and −1% (−2% to −1%) in studies including haemodynamically stable patients (test for subgroup differences: P = 0.09) (from Barco S, Ende-Verhaar YM, Becattini C, Jimenez D, Lankeit M, Huisman MV, Konstantinides SV, Klok FA. Differential impact of syncope on the prognosis of patients with acute pulmonary embolism: a systematic review and meta-analysis. See pages 4186–4195). In their Review entitled ‘Epigenetics and precision medicine in cardiovascular patients: from basic concepts to the clinical arena’, Francesco Paneni and colleagues from the University of Zurich in Switzerland10 remind us that preventive medications improve vascular outcomes in less than half of patients. Thus, precision medicine is an unmet need which new genetic tools could help to address. Yet, the inherited genome determines only part of an individual’s risk profile. Indeed, standard genomic approaches do not take into account the extensive gene expression by epigenetic modifications—defined as heritable changes to the genome that do not involve changes in DNA sequence. These could advance individualized risk assessment, as well as devising and deploying tailored therapies. Hypertension is a known cardiovascular risk factor. However, it is less known that sleep-time blood pressure11 is a stronger risk factor for cardiovascular disease events than awake and 24-h blood pressure. Unfortunatly, the role of asleep blood pressure as a therapeutic target for diminishing cardiovascular diseases risk is uncertain. In their article ‘Asleep blood pressure: significant prognostic marker of vascular risk and therapeutic target for prevention’,12 Ramon C. Hermida on behalf of the Hygia Project Investigators prospectively evaluated 18 078 individuals with baseline 48-h ambulatory blood pressure ranging from normotension to hypertension. Over 5 years of follow-up, 13% had events, almost all of them experiencing either cardiovascular death, myocardial infarction, coronary revascularization, heart failure, or stroke, with asleep systolic blood pressure being most predictive (hazard ratio 1.29), regardless of office (hazard ratio 1.03) and awake systolic blood pressure (hazard ratio 1.02; Figure 2). Most importantly, progressive attenuation of asleep systolic blood pressure was the most significant marker of event-free survival, with a hazard ratio of 0.75, regardless of changes in office or awake systolic blood pressure. Thus, asleep systolic blood pressure is an under-recognized and most important risk factor. Furthermore, treatment-induced decrease of asleep, but not awake systolic blood pressure, a novel hypertension therapeutic target requiring periodic patient evaluation by ambulatory monitoring, is associated with significantly lower cardiovascular risk, a novel finding that is further discussed in a interesting Editorial by Stefano Taddei from the Università degli Studi di Pisa in Italy.13 Not only arterial, but also pulmonary hypertension is associated with a high morbidity and mortality independent of its cause.14–17 Guidelines recommend a goal-oriented treatment approach in such patients based on proper risk assessment.18 However, as this is not well evaluated, David Kylhammar and colleagues from the Lunds Universitet in Lund, Sweden investigated such a risk assessment and its benefit for reaching a low risk profile in their article entitled ‘A comprehensive risk stratification at early follow-up determines prognosis in pulmonary arterial hypertension’.14 They investigated 530 pulmonary arterial hypertension patients over a median of 4 months and classified them as ‘Low’, ‘Intermediate’, or ‘High risk’. Survival differed between the risk groups at baseline, while survival was similar for those remaining in or improved to the ‘Low risk’ group. Survival was similar for patients who remained in or worsened to the ‘Intermediate risk’ or ‘High risk’ groups. Irrespective of risk group, survival was better for patients with a higher proportion of variables at low risk. Patients in the ‘Low risk’ group at follow-up exhibited a markedly reduced mortality risk with an adjusted hazard ratio of 0.2, as compared with those in the ‘Intermediate risk’ or ‘High risk’ groups. Thus, comprehensive risk assessments with a strategy of reaching a low risk profile is a valid approach in pulmonary hypertension. The importance of these results for clinical practice are further discussed in an Editorial by Marc Humbert from the Université Paris-Sud in Paris, France.19 Pulmonary embolism is a cause of acute pulmonary hypertension and indeed may lead to syncopal events in such patients.20 In their article ‘Differential impact of syncope on the prognosis of patients with acute pulmonary embolism: a systematic review and meta-analysis’, Stefano Barco and colleagues from the Johannes Gutenberg Universität Mainz in Germany investigate the association between syncope and short-term outcomes in such patients.21 Of 1664 studies, 29 were included, yielding a total of 21 956 patients with pulmonary embolism of which 17% presented with syncope. Syncope was associated with higher prevalence of haemodynamic instability, with an odds ratio of 3.50, as well as with echocardiographic signs of right ventricular dysfunction (Figure 3). Patients with syncope had a higher risks of all-cause 30-day mortality and pulmonary embolism-related 30-day adverse outcomes. The absolute risk difference for all-cause death was +6% in studies of unselected patients, but was –1% in studies restricted to normotensive patients. Thus, acute pulmonary embolism presenting with syncope is associated with a higher prevalence of haemodynamic instability and right ventricular dysfunction, and an elevated risk for early pulmonary embolism-related adverse outcomes. The association with an increased risk of early death appeared more prominent in studies including unselected patients, as compared with those focusing on normotensive patients only. Haemodynamically unstable patients with pulmonary embolism have a grave outcome. The role of extracorporeal membrane oxygenation in such patients remains ill defined. In their article entitled ‘Outcomes after extracorporeal membrane oxygenation for the treatment of high-risk pulmonary embolism: a multicentre series of 52 cases’, Nicolas Meneveau and colleagues from the University Hospital Besancon in France investigated outcomes of such an intervention.22 A total of 128 patients were treated conservatively, while 52 underwent extracorporeal membrane oxygenation. Overall 30-day mortality was 48.3%. Of the conservatively treated patients, 43% died, while mortality in those receiving extracorporeal membrane oxygenation was 62%. At 30 days, mortality was 77% for those undergoing extracorporeal membrane oxygenation plus fibrinolysis, 29% for those undergoing extracorporeal membrane oxygenation plus surgical embolectomy, and 77.7% for those undergoing extracorporeal membrane oxygenation alone. Thus, in high-risk pulmonary embolism, those with extracorporeal membrane oxygenation have a more severe presentation and worse prognosis. Extracorporeal membrane oxygenation in those with failed fibrinolysis or no reperfusion seems to be associated with a particularly unfavourable outcome compared with extracorporeal membrane oxygenation with surgical embolectomy. As such, extracorporeal membrane oxygenation is not justified as a stand-alone strategy, but shows promise together with surgical embolectomy, a conclusion that is critically discussed in an Editorial by Nazzareno Galie from the University of Bologna in Italy.23 Venous thrombosis is the basis of pulmonary embolism. Its origin is often unclear, but involves immobility, coagulation disorders,24 and inflammation.25,26 The current knowledge is updated in a Current Opinion entitled ‘Diagnosis and management of acute deep vein thrombosis: a joint consensus document from the European Society of Cardiology working groups of aorta and peripheral circulation and pulmonary circulation and right ventricular function’, Lucia Mazzolai and colleagues from the Centre Hospitalier Universitaire Vaudois in Lausanne, Switzerland note that deep vein thrombosis represents an often neglected, by cardiologists, global disease burden affecting millions of individuals worldwide.27 Here they address current diagnosis and management of acute deep vein thrombosis according to a European Consensus. The document follows the 2014 ESC guidelines on diagnosis and management of acute pulmonary embolism, filling a gap for a comprehensive view on management of venous thrombo-embolism. The issue is complemented by a Discussion Forum related to the article ‘Blood pressure variability and risk of cardiovascular events and death in patients with hypertension and different baseline risks’ by Eivind Berge and colleagues from the Oslo University Hospital in Norway.28 In their letter ‘Blood pressure and the uncertainty of prediction using hazard ratio’, Christian Torp-Pedersen and colleagues from the Aalborg University and Aalborg University Hospital in Denmark comment on the paper.29 de Courson and colleagues from the University of Bordeaux in France provided a second Discussion Forum ‘Blood pressure variability and risk of cardiovascular event: is it appropriate to use the future for predicting the present?’,30 also commenting on the paper by Berges et al. The editors hope that this issue of the European Heart Journal will be of interest to its readers. With thanks to Amelia Meier-Batschelet for help with compilation of this article.