Peripheral and pulmonary artery disease: an update on under-regognized cardiovascular issues

For the podcast associated with this article, please visit https://academic.oup.com/eurheartj/pages/Podcasts. Cardiologists are focused on the heart; rightly so, but possibly too much. Indeed, cardiovascular issues outside the heart also affect cardiac patients. One such issue is peripheral artery disease that often co-exists with coronary artery disease and, importantly, affects outcomes of such patients.1,2 The most recent developments are summarized in the ‘The Year 2018 in Cardiology: aorta and peripheral circulation’ contribution by Victor Aboyans from Dupuytren University Hospital in Limoges, France, and colleagues.3 They review groundbreaking studies and trials opening up new perspectives and affecting our clinical practice for the management of aortic and peripheral arterial diseases, as well as venous thrombo-embolic disease. Although peripheral artery disease focuses on the cerebrovascular circulation and that of the legs, the renal circulation also plays an important role in cardiovascular patients, in particular in those undergoing procedures,4,5 those who receive arteriovenous fistulas,6 in diabetics,7 or in those develop heart failure.8 Unfortunately, most cardiovascular trials have excluded patients with advanced chronic kidney disease who are at greatest risk. Moreover, the few major outcome trials that have been conducted in such patients have not demonstrated a treatment benefit. In a Current Opinion entitled ‘Cardiovascular outcome trials in patients with chronic kidney disease: challenges associated with selection of patients and endpoints’, Patrick Rossignol and colleagues from the INSERM and Centre Hospitalier Universitaire de Nancy and colleagues from tht Université de Lorraine, France address some of these problems.9 Of note, several factors contribute to both the paucity of trials and the lack of an observed treatment effect in completed studies. Challenges in conducting trials in this population include patient heterogeneity, complexity of renal pathophysiology and its interaction with cardiovascular disease, and competing risks for death. The Investigator Network Initiative Cardiovascular and Renal Clinical Trialists (INI-CRCT) identified several research priorities that should be pursued to advance the field. Importantly, cardiovascular and renal trialists must partner to address the uncertainties in the field through collaborative research and design clinical trials that reflect the specific needs of the chronic and end-stage kidney disease populations, with the shared goal of generating robust evidence to guide the management of cardiovascular disease in patients with kidney disease. This issue is further pursued in the original research article ‘Cause of kidney disease and cardiovascular events in a national cohort of US patients with end-stage renal disease on dialysis: a retrospective analysis’ by Michelle O’Shaughnessy and colleagues from the Stanford University School of Medicine in Palo Alto, California, in the USA, who determined the contribution of kidney disease to cardiovascular risk using 658 168 patients of a national US end-stage renal disease registry.10 After adjusting for confounders, cardiovascular hazard ratios differed significantly by cause of renal disease. Compared with IgA nephropathy, the adjusted hazard ratio was highest for diabetic nephropathy with 2.97, followed by lupus nephritis with 1.86, and finally 1.67 in membranous nephropathy and 1.29 in autosomal dominant polycystic kidney disease (Figure 1). The authors conclude that high cardiovascular event rates in dialysis patients vary considerably by cause of end-stage renal disease. Thus, determining the underlying reasons for end-stage renal disease might provide new insights into mechanisms and future trial designs and drug treatment coming out of these. These findings are put into context in an Editorial by Emaad M. Abdel-Rahman from the University of Virginia in Charlottesville, Virginia, USA. 11 Prognostic value of imaging and laboratory indicators of right ventricular dysfunction or myocardial injury for early all-cause mortality in low-risk patients. CTPA, computed tomography pulmonary angiography; RV, right ventricular; 95% CI, 95% confidence interval (from Barco S, Mahmoudpour SH, Planquette B, Sanchez O, Konstantinides SV, Meyer G. Prognostic value of right ventricular dysfunction or elevated cardiac biomarkers in patients with low-risk pulmonary embolism: a systematic review and meta-analysis. See pages 902–910). Patients with acute pulmonary embolism classified as low risk by the Pulmonary Embolism Severity Index (PESI), its simplified version (sPESI), or the Hestia criteria may be considered for early discharge. In their FAST TRACK ‘Prognostic value of right ventricular dysfunction or elevated cardiac biomarkers in patients with low-risk pulmonary embolism: a systematic review and meta-analysis’, Stefano Barco and colleagues from the Johannes Gutenberg Universität Mainz in Rheinland-Pfalz, Germany performed a systematic review and meta-analysis of 22 studies including 3295 low-risk patients with acute pulmonary embolism to investigate the prognostic value of right ventricular (RV) dysfunction.12 Early all-cause mortality rates of those with or without RV dysfunction were 1.8% and 0.2%, respectively (Figure 2). For troponins, rates were 3.8% and 0.5%. Thus, in low-risk patients with acute pulmonary embolism, the presence of RV dysfunction increased the risk of early mortality. As such patients who appear at low risk based on clinical criteria alone may have RV dysfunction and may should be re-classified based on imaging and biomarker findings. These clinical important findings are further discussed in a thoughtful editorial by Adam Torbicki from the National Institute for Lung Diseases in Warsaw, Poland13 Cumulative incidence plots, stratified by cause of ESRD, showing 5-year cumulative incidences of first occurring cardiovascular or competing events among US patients who initiated and received at least 90 days of dialysis for treatment of ESRD, 19972014. ADPKD, autosomal dominant polycystic kidney disease; CV, cardiovascular; DN, diabetic nephropathy; FSGS, focal segmental glomerulosclerosis; IgAN, IgA nephropathy; LN, lupus nephritis; MI, myocardial infarction; MN, membranous nephropathy; MPGN, membranoproliferative GN (from O'Shaughnessy MM, Liu S, Montez-Rath ME, Lafayette RA, Winkelmayer WC. Cause of kidney disease and cardiovascular events in a national cohort of US patients with end-stage renal disease on dialysis: a retrospective analysis. See pages 887–898). Stroke is an important complication of cerebrovascular disease.14 Unlike myocardial infarction, the cardiovascular causes of stroke are many, including hypertension,15 atrial fibrillation,16–18 an open foramen ovale,19,20 aortic and cerebrovascular disease, and as a complication of cardiac procedures.21 The foramen ovale has been recognized as an important cause by a solid number of trials and meta-analyses.22 However, thus far, the role of an open foramen ovale diagnosed pre-operatively for pos-toperative ischaemic strokes is not well established. In their article entitled ‘Patent foramen ovale and long-term risk of ischaemic stroke after surgery’ Matthias Eikermann and colleagues from the Harvard Medical School in Boston, Massachusetts (USA) assessed the patent foramen ovale-attributable ischaemic stroke risk beyond the peri-operative period.23 Of the 144 563 patients, 1.1% and 1.6% experienced ischaemic strokes occurring within 1 and 2 years after surgery. This occurred in 4.7% and 6.6% with patent foramen ovale, but only in 1.1% and 1.6% among those without it, respectively. As a consequence, the odds of ischaemic stroke within 1 and 2 years after surgery were increased two-fold in patients with patent foramen. Among those undergoing contrast transoesophageal echocardiography (TEE), a patent foramen ovale was found in 27%, and stroke risk was even more pronounced with an odds ratio of 3.80. Of note, the patent foramen ovale-attributable risk was mitigated by post-operative prescription of antithrombotic therapy. Thus, as patients with patent foramen ovale are vulnerable to ischaemic stroke for an extended period of time after surgery, screening protocols should be implemented in patients scheduled for major non-cardiac surgery. This recommendation is further discussed in a balanced Editorial by David R. Holmes from the Mayo Clinic in Rochester, Minnesota, USA.24 Atherosclerosis is the common denominator of coronary, cerebrovascular, and peripheral artery disease. Inflammatory mediators, including blood cells and their products,25–27 contribute critically to the process, but the triggers remain elusive. Atherosclerosis-prone sites such as bifurcation lead to flow perturbation and accumulation of erythrocytes and granulocytes, suggesting that the entry of these blood cells through intimal arterial breaches, caused by haemodynamic stress, may initiate the inflammation and atherosclerotic plaque formation. In their Basic Science article ‘Haemodynamic stress-induced breaches of the arterial intima trigger inflammation and drive atherogenesis’ Giuseppina Caligiuri and colleagues from INSERM in Paris, France evaluated this concept in human and experimental atherogenesis.28 Human coronary samples isolated from human hearts and carotid arteries from ApoE–/– mice were subjected to haemodynamic stress. Under these conditions, most human coronary arteries accumulated iron and CD66b+ granulocytes in the subintimal space, an event that mainly occurred at sites of flow disturbance. Mouse carotid arteries also displayed intimal erythrocyte accumulation in the region of flow perturbation, after 3 days of haemodynamic stress exacerbation via endothelial breaches. After 7 days, abundant Ly6G+ inflammatory cells accumulated in the subendothelial layer at sites of pathological thickening, with extensive erythrocyte-derived iron and lipid deposition. Depletion of Ly6G+ leucocytes did not prevent endothelial layer disruption, but effectively protected against fatty streak formation, suggesting that haemodynamic stress-induced breaches can drive atherogenesis by triggering local inflammation. Thus, haemodynamic-driven breaches of the arterial intima provoke local mechanical injury, which triggers the recruitment of granulocytes and the formation of fatty streaks at sites of disturbed arterial flow. The manuscript is accompanied by a thought-provoking Editorial by Peter Libby from Brigham and Women's Hospital in Boston, Massachusetts (USA).29 The issue is further complemented by two Discussion Forums related to a recent retraction of one of our papers.30 In their contribution, Ricky Daniel Turgeon from the University of British Columbia in Vancouver, Canada, along with Andrew Althouse from the University of Pittsburgh School of Medicine in Pennsylvania, USA commented on several errors they identified that produced inaccurate results.31 After further investigation among the editors, the decision was taken to retract the contribution and, together with Allan Davies from the Royal Brompton and Harefield Hospitals, I have produced a response.32 The editors hope that readers of this issue of the European Heart Journal will find it of interest. With thanks to Amelia Meier-Batschelet for help with compilation of this article.

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