European Heart Journal

Crea, Filippo

doi: 10.1093/eurheartj/ehac203pmid: 35523427

Nagai, Michiaki; Dote, Keigo; Ishihara, Masaharu; Kurisu, Satoshi

doi: 10.1093/eurheartj/ehac146pmid: 35323897

A pioneer of Japanese reperfusion therapy for acute myocardial infarction, the discoverer and outstanding researcher of ‘Takotsubo syndrome’ passed away on 10 November 2021 Dr. Hikaru Sato graduated from Kobe University in 1963. Immediately after becoming a physician, he became interested in the electrocardiographic (ECG) transformation of subarachnoid haemorrhage (SAH), and he speculated that it might be possible to diagnose SAH based on ECG findings.1 Post-university: Coronary angiography examinations of acute myocardial infarction initiated at Hiroshima City Hospital Dr. Sato moved from Kobe University to Hiroshima City Hospital in 1978 (Figure 1). Cardiac surgeons at Hiroshima City Hospital had been performing angiocardiography since the early 1960s for patients in the chronic phase of heart disease,1 and Dr. Sato was enthusiastic about studying acute myocardial infarction (AMI) patients in the coronary care unit (CCU). He suspected that the pivotal pathological condition of myocardial infarction (MI) could not be elucidated without performing coronary angiography (CAG) for patients in the acute MI phase. At that time, CAG performed in the acute phase of MI had been investigated in only a few foreign studies, and Dr. Sato’s colleagues in the hospital objected based on concerns about its safety.1 Figure 1 Open in new tabDownload slide Hiroshima City Hospital in 1978, and Dr. Hikaru Sato. Figure 1 Open in new tabDownload slide Hiroshima City Hospital in 1978, and Dr. Hikaru Sato. In 1979–80, Dr. Sato conducted research examining whether single blood clots in a test tube would dissolve following the addition of the thrombolytic agent urokinase. The blood clots did not dissolve, but Dr. Sato persisted; he compiled all of the existing literature on urokinase to determine why the blood clots did not dissolve. He speculated that if urokinase was infused intravenously, the presence or absence of the effect could be evaluated by CAG or by left ventriculography (LVG). In 1979, Dr. Klaus Peter Rentrop at Göttingen University succeeded in the recanalization of AMI patients’ occluded coronary arteries by applying a selective intracoronary administration of streptokinase under angiography.2 In light of that report, Dr. Sato realized that the solution to his above-mentioned in vitro research might be obtained if he performed CAG and LVG before and after an intracoronary administration of urokinase in a patient with AMI. He had been informed that Dr. Masakiyo Nobuyoshi at Kokura Memorial Hospital injected urokinase into a patient’s aortic bulb for the first time in Japan, and he decided to try infusing urokinase directly into a coronary artery, in 1981. In the first case, 480 000 units of urokinase were infused; the thrombosis dissolved as he watched (Figure 2).3 His further results demonstrated that conducting CAG and LVG in patients in the acute phase of MI was safe and effective as long as the procedures were performed carefully. Dr. Keigo Dote, the president of Hiroshima City Asa Hospital, later presented an introduction to intracoronary thrombolytic therapy in AMI at an annual meeting of the American College of Cardiology. Figure 2 Open in new tabDownload slide The first use of emergency coronary angiography for acute myocardial infarction at Hiroshima City Hospital, on 26 May 1981. Control contrast shows complete occlusion of the left anterior descending artery (left). After an intracoronary infusion of urokinase, recanalization was observed without contrast delay (right). Reconstructed from Ishihara and Sato3. Figure 2 Open in new tabDownload slide The first use of emergency coronary angiography for acute myocardial infarction at Hiroshima City Hospital, on 26 May 1981. Control contrast shows complete occlusion of the left anterior descending artery (left). After an intracoronary infusion of urokinase, recanalization was observed without contrast delay (right). Reconstructed from Ishihara and Sato3. Encounters with Dr. Hirofumi Yasue and Dr. Saichi Hosoda, and the discovery of Takotsubo syndrome A few years later, Dr. Hirofumi Yasue, who worked to reveal the pathophysiology of vasospastic angina in the 1970s at Shizuoka Municipal Hospital, came to Hiroshima to give a lecture. Dr. Yasue was the clinician that Dr. Sato admired most because Dr. Yasue had shown the importance of work outside the university, and Dr. Sato was greatly influenced by Dr. Yasue’s stance regarding clinical investigations. Dr. Saichi Hosoda, who established the Japanese CCU system at Tokyo Women’s Medical University, taught medical statistics for clinical research and greatly encouraged Dr. Sato.1 During the many years that Dr. Sato pursued his passion to determine the pathophysiology of AMI, he encountered a patient with left ventricular (LV) apical ballooning shown by LVG, without coronary artery stenosis. Surprisingly, the LVG revealed akinesis in the mid- to the apical portion of the LV with vigorous contraction of the basal segment, which could not be explained by a single branch lesion. Soon after, Dr. Sato discussed the case with Dr. Dote, and Dr. Sato named the syndrome ‘Takotsubo cardiomyopathy’ (Takotsubo syndrome: TTS) because on LVG, the patient’s end-systolic LV apical ballooning resembled a Japanese traditional octopus trap, i.e. a takotsubo. In 1983, the first case of TTS at Hiroshima City Hospital was documented (Figure 3),1,4 and three and five additional cases were reported in 19905 and 1991,6 respectively. Figure 3 Open in new tabDownload slide The first diagnosed case of Takotsubo syndrome (23 September 1983). No stenosis or occlusion was observed in coronary angiography after an intracoronary nitroglycerin infusion (left). Left ventriculography revealed a characteristic ‘takotsubo’-like end-systolic LV morphology (right); with permission from Sato and Yamashina1. Figure 3 Open in new tabDownload slide The first diagnosed case of Takotsubo syndrome (23 September 1983). No stenosis or occlusion was observed in coronary angiography after an intracoronary nitroglycerin infusion (left). Left ventriculography revealed a characteristic ‘takotsubo’-like end-systolic LV morphology (right); with permission from Sato and Yamashina1. Although the peculiar wall motion of the LV in Dr. Sato’s initial TTS patient disappeared within about 2 weeks, the coronary vasospasm was considered the pivotal pathophysiology in the acute phase of the patient’s TTS. At the first annual meeting of the Japanese Coronary Association, Dr. Dote explained the case and presented a cine film of the CAG and LVG results. Dr. Sato felt that Dr. Dote’s explanation was excellent and quite memorable, as he clearly remembers that the large audience seemed taken aback when the coronary artery was projected with a thin thread-like image under a load of ergometrine in the acute phase of TTS. As shown by subsequent reports, a load of ergometrine present in the acute phase is extremely rare, while the results in the chronic phase of TTS denied a coronary artery spasm. In his following extensive research regarding TTS, Dr. Sato was blessed with the cooperation of excellent physicians such as Dr. Hironobu Tateishi, Dr. Dote, Dr. Takuji Kawagoe, Dr. Masaharu Ishihara, and Dr. Satoshi Kurisu, who are part of the younger generation leading the Japanese Society of Cardiology. Takotsubo syndrome is now known worldwide as a transient weakening of the LV, triggered by emotional or physical stress such as a sudden illness, the loss of a loved one, a serious accident, or a natural disaster such as an earthquake.4,7–9 On 10 November 2021, we received a message that Dr. Hikaru Sato, the discoverer of TTS who had been a leader in TTS research for many years, passed away peacefully. As his pupils, we are profoundly saddened by his death. We seek to carry on Dr. Sato’s seminal research. In his later years, he mentioned that the ECG change of SAHs had suddenly come to his attention when he thought about TTS. Inspired by the mentorship of Dr. Hikaru Sato, we have taken a group oath to pursue the elucidation of the pathophysiology of TTS from the viewpoint of the brain–heart axis.10 We regret that he did not live to see this discovery, and we very much miss our discussions on his original ideas. Acknowledgements We thank Toshiaki Sato at the Division of Advanced Arrhythmia Management, Kyorin University Hospital, and Masaya Kato at the Department of Cardiology, Hiroshima City Asa Hospital for information collection, and for the interpretation of the information presented in this manuscript. Conflict of interest: None declared. References 1 Sato H , Yamashina A. Discovery of Takotsubo cardiomyopathy: interview with Dr. Hikaru Sato . Heart 2006 ; 38 : 872 – 881 . Google Scholar OpenURL Placeholder Text WorldCat 2 Rentrop KP , Blanke H, Karsch KR, Wiegand V, Köstering H, Oster H, et al. Acute myocardial infarction: intracoronary application of nitroglycerin and streptokinase . Clin Cardiol 1979 ; 2 : 354 – 363 . Google Scholar Crossref Search ADS PubMed WorldCat 3 Ishihara M , Sato H. Thirty years trend in acute myocardial infarction undergoing coronary angiography at a tertiary emergency center in Japan . J Cardiol 2012 ; 59 : 243 – 248 . Google Scholar Crossref Search ADS PubMed WorldCat 4 Ghadri JR , Wittstein IS, Prasad A, Sharkey S, Dote K, Akashi YJ, et al. International expert consensus document on Takotsubo syndrome (Part I): clinical characteristics, diagnostic criteria, and pathophysiology . Eur Heart J 2018 ; 39 : 2032 – 2046 . Google Scholar Crossref Search ADS PubMed WorldCat 5 Sato H . Tako-tsubo-like left ventricular dysfunction due to multivessel coronary spasm . In: Kodama K, Haze K, Hori M, eds. Clinical Aspect of Myocardial Injury: From Ischemia to Heart Failure . Tokyo : Kagakuhyoronsha Publishing Co ; 1990 . p 56 – 64 . Google Scholar Google Preview OpenURL Placeholder Text WorldCat COPAC 6 Dote K , Sato H, Tateishi H, Uchida T, Ishihara M. Myocardial stunning due to simultaneous multivessel coronary spasms: a review of 5 cases . J Cardiol 1991 ; 21 : 203 – 214 . Google Scholar PubMed OpenURL Placeholder Text WorldCat 7 Kurisu S , Sato H, Kawagoe T, Ishihara M, Shimatani Y, Nishioka K, et al. Tako-tsubo-like left ventricular dysfunction with ST-segment elevation: a novel cardiac syndrome mimicking acute myocardial infarction . Am Heart J 2002 ; 143 : 448 – 455 . Google Scholar Crossref Search ADS PubMed WorldCat 8 Kurisu S , Inoue I, Kawagoe T, Ishihara M, Shimatani Y, Nishioka K, et al. Myocardial perfusion and fatty acid metabolism in patients with tako-tsubo-like left ventricular dysfunction . J Am Coll Cardiol 2003 ; 41 : 743 – 748 . Google Scholar Crossref Search ADS PubMed WorldCat 9 Kurisu S , Inoue I, Kawagoe T, Ishihara M, Shimatani Y, Nakamura S, et al. Time course of electrocardiographic changes in patients with tako-tsubo syndrome: comparison with acute myocardial infarction with minimal enzymatic release . Circ J 2004 ; 68 : 77 – 81 . Google Scholar Crossref Search ADS PubMed WorldCat 10 Nagai M , Förster CY, Dote K. Sex hormone-specific neuroanatomy of Takotsubo syndrome: is the insular cortex a moderator? Biomolecules 2022 ; 12 : 110 . Google Scholar Crossref Search ADS PubMed WorldCat Published by Oxford University Press on behalf of European Society of Cardiology 2022. This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model)

Braunwald, Eugene

doi: 10.1093/eurheartj/ehac058pmid: 35165710

Introduction Seventy years ago, in the spring of 1952, as a medical student at New York University and Bellevue Hospital, I was given the opportunity to assist in the management of patients with heart failure (HF). Treatment was quite limited at the time, consisting of a low salt diet (which was rarely followed), digitalis (now of questionable value), and meralluride (mercuhydrin), a relatively weak organomercurial diuretic which required painful intramuscular injection. Following hospital discharge patients with HF returned to the outpatient clinic for weekly injections of meralluride. Because of chronic nursing shortages, I volunteered to make the injections, which allowed me to establish personal relationships with HF patients, observe their suffering with severe dyspnoea and get a sense of the natural history of this condition. Few patients survived for more than 3 months after hospital discharge, and the patients ‘drowning’ in their pulmonary oedema often caused death. This experience, while sobering, awoke my interest in cardiology, and more specifically in HF. After completing my clinical training, I served a fellowship in the cardiopulmonary laboratory at Bellevue under the direction of Nobel laureate André Cournand, where I participated in some of the early studies on the hemodynamics of HF. I then moved to the cardiovascular physiology laboratory of the National Heart Institute (now the NHLBI) in Bethesda Maryland, where my work focused on the control of contraction of intact ventricles as well as isolated cardiac muscles. We studied the inverse relationship between afterload and the extent and velocity of shortening in muscle obtained from normal and failing feline hearts, and developed two techniques to assess ventricular function in patients; the left ventricular ejection fraction1 and the rate of ventricular pressure rise during isometric contraction (dP/dT).2 There have, of course, been enormous improvements in the management of HF since 1952 (Figure 1), four of which I consider to be so important that I have designated them as ‘breakthrough’ advances. The first of these occurred in the early 1960s when a new class of orally active diuretics—the thiazides—was discovered, which were orally active and more potent than meralluride. I was delighted to note in my small HF clinic at the Institute that both dyspnoea and oedema improved, as did the patients’ morale. Two other important advances occurred in the late 1960s. The first was the development of even more powerful ‘loop’ diuretics, which received little public attention but had a profoundly positive impact on the care of hundreds of thousands of patients with HF. The other was a report of a single patient in South Africa who had undergone the first successful human heart transplantation,3 which made international headlines. However, the limited supply of human donor hearts has severely curtailed this mode of therapy. Nonetheless, cardiac transplantation served to stimulate the more rapid development of devices that provide mechanical support to advanced HF (see below). Importantly, it also set the stage for current research on xenotransplantation of genetically altered donors. Figure 1 Open in new tabDownload slide Timeline for major advances for the treatment of heart failure. Dig, digitalis; Mer, meralluride; Tx, transplantation; Vasodil, vasodilator; ACEi, angiotensin-converting enzyme inhibitor; β Block, beta blockade; ARB, angiotensin receptor blocker; LVAD, left ventricular assist device; MRA, mineralocorticoid receptor antagonist; ICD, implanted cardioverter/defibrillator; CRD, cardiac resynchronization device; ARNi, angiotensin receptor neprilysin inhibitor; SGLT2i, sodium-glucose cotransporter inhibitor. ‘Breakthrough drugs’ as designated by the author are noted by red ellipses. Figure 1 Open in new tabDownload slide Timeline for major advances for the treatment of heart failure. Dig, digitalis; Mer, meralluride; Tx, transplantation; Vasodil, vasodilator; ACEi, angiotensin-converting enzyme inhibitor; β Block, beta blockade; ARB, angiotensin receptor blocker; LVAD, left ventricular assist device; MRA, mineralocorticoid receptor antagonist; ICD, implanted cardioverter/defibrillator; CRD, cardiac resynchronization device; ARNi, angiotensin receptor neprilysin inhibitor; SGLT2i, sodium-glucose cotransporter inhibitor. ‘Breakthrough drugs’ as designated by the author are noted by red ellipses. Blockade of neurohormonal stimulation The concept that excessive neurohormonal stimulation could play a role in the pathophysiology of HF was an important one. Our group described excessive activation of the adrenergic nervous system in patients with severe HF,4 leading to systemic vasoconstriction and an increased left ventricular afterload. The latter reduced the extent and velocity of myocardial shortening, just as had been observed in isolated heart muscle. In the 1970s, vasodilators such as nitroprusside, nitroglycerine, and hydralazine reduced left ventricular afterload, increased cardiac output while reducing pulmonary artery pressure.5 Blocking the beta-adrenergic blockers was shown to be very beneficial in the treatment of HF as well.6 This class has been observed repeatedly to improve survival and deserves ‘breakthrough’ status. Activation of the renin-angiotensin system (RAS) in HF became apparent in the 1980s. While angiotensin-converting enzyme inhibitors (ACEi) lowered blood pressure modestly, the drugs in this class were not simple vasodilators, but by preventing the formation of angiotensin II they blocked myocyte hypertrophy and ventricular remodelling. A series of clinical trials showed that ACEi enhanced survival and reduced symptoms in patients with chronic HF,7 in what I consider another ‘breakthrough’ therapy of HF. Next came the observation that a mineralocorticoid receptor antagonist (MRA) was also beneficial in patients with severe HF.8 Thus, by the end of the 20th century, the four classes of drugs were widely employed in the management of patients with HF: (i) loop diuretics; (ii) beta blockers; (iii) RAS inhibitors; and (iv) MRAs. Although we had come a long way in the second half of the twentieth century, advances continued. The 21st century The REMATCH trial, published in 2001, was a turning point for left ventricular assist devices (LVADs), since it clearly demonstrated improved survival when added to guideline-directed care in patients with far advanced HF who were ineligible for cardiac transplantation and it led to regulatory approval.9 Left ventricular assist devices are now implanted in more than 5000 such patients around the world each year, primarily as either destination therapy or as a bridge to cardiac transplantation. Implanted cardioverter/defibrillators are increasingly employed in HF patients at a risk of sudden death, as are cardiac resynchronization devices in patients with prolonged ventricular depolarization. Two important new pharmacologic classes were introduced during the second decade. In 2014 sacubitril/valsartan, the first angiotensin receptor/neprilysin inhibitor (ARNi), was shown to be superior to ACEi, improving survival and reducing symptoms of HF.10 In 2015, the first large sodium-glucose cotransporter 2 inhibitor (SGLT2i) trial showed striking reductions in hospitalization for HF and cardiovascular mortality in patients with type 2 diabetes.11 This observation has been confirmed repeatedly and extended to HF patients with and without diabetes and across a wide range of ejection fractions. Consequently, the population that can be helped by SGLT2 is has expanded considerably, qualifying these as HF ‘breakthrough’ agents. Conclusions Despite the enormous progress summarized above, HF remains an important cause of death or disability. HF has changed considerably in the past seven decades. It has become a victim of our therapeutic successes. Patients in the mid-20th century who would have succumbed to a myocardial infarction, cancer, or an infection in their 40s or 50s, now often survive into their 80s and beyond, when they develop HF. Approximately half of all patients with HF in industrially developed nations now have preserved ejection fraction, a condition that was not clearly recognized before 1975. The advances described above must be made available to the entire global population; this is certainly not the case today. Since arteriosclerotic heart disease remains the most common cause of HF, the tools of modern biology, population science, and artificial intelligence should begin early in life to reduce and ultimately eliminate the development of coronary risk factors. I have been very fortunate during the past 70 years to have had the opportunity to have a ‘ringside seat’ to view these exciting advances, and occasionally to enter the ring. It really has been a combination of being in the right place, at the right time, with the right mentors and mentees. Conflict of interest: Research grant support through Brigham and Women’s Hospital from: AstraZeneca, Daiichi-Sankyo, Merck, and Novartis; consulting for: Amgen, Boehringer-Ingelheim/Lilly, Bristol Myers Squibb (MyoKardia), Cardurion, NovoNordisk, and Verve. References 1 Folse R , Braunwald E. Determination of fraction of left ventricular volume ejected per beat and of ventricular end-diastolic and residual volumes: experimental and clinical observations with a precordial dilution technique . Circulation 1962 ; 25 : 674 – 685 . Google Scholar Crossref Search ADS PubMed WorldCat 2 Gleason WL , Braunwald E. Studies on the first derivative of the ventricular pressure pulse in man . J Clin Invest 1962 ; 41 : 80 – 91 . Google Scholar Crossref Search ADS PubMed WorldCat 3 Barnard CS . Heart transplantation: an experimental review and preliminary research . S Afr Med J 1967 ; 41 : 1260 – 1262 . Google Scholar PubMed OpenURL Placeholder Text WorldCat 4 Chidsey CA , Harrison DC, Braunwald E. Augmentation of the plasma nor-epinephrine response to exercise in patients with congestive heart failure . N Engl J Med 1962 ; 267 : 650 – 654 . Google Scholar Crossref Search ADS PubMed WorldCat 5 Cohn JN , Franciosa JA. Vasodilator therapy of cardiac failure . N Engl J Med 1977 ; 297 : 27 – 31 . Google Scholar Crossref Search ADS PubMed WorldCat 6 Waagstein F , Bristow MR, Swedberg K, Bristow MR, Gilbert EM, Camerini F, et al. Beneficial effects of metoprolol in idiopathic dilated cardiomyopathy. Metoprolol in Dilated Cardiomyopathy (MDC) Trial Study Group . Lancet 1993 ; 342 : 1441 – 1446 . Google Scholar Crossref Search ADS PubMed WorldCat 7 SOLVD Investigators . Effect of enalapril on survival in patients with reduced left ventricular ejection fractions and congestive heart failure . N Engl J Med 1991 ; 325 : 293 – 302 . Crossref Search ADS PubMed WorldCat 8 Pitt B , Zannad F, Remme WJ, Cody R, Castaigne A, Perez A, et al. The effect of spironolactone on morbidity and mortality in patients with severe heart failure . N Engl J Med 1999 ; 341 : 709 – 717 . Google Scholar Crossref Search ADS PubMed WorldCat 9 Rose EA , Gelijns AC, Moskowitz AJ, Heitjan DF, Stevenson LW, Dembitsky W, et al. Long-term use of a left ventricular assist device for end-stage heart failure . N Engl J Med 2001 ; 345 : 1435 – 1443 . Google Scholar Crossref Search ADS PubMed WorldCat 10 McMurray JJV , Packer M, Desai AS, Gong J, Lefkowitz MP, Rizkala AR, et al. Angiotensin–neprilysin inhibition versus enalapril in heart failure . N Engl J Med 2014 ; 371 : 993 – 1004 . Google Scholar Crossref Search ADS PubMed WorldCat 11 Zinman B , Wanner C, Lachin JM, Fitchett D, Bluhmki E, Hantel S, et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes . N Engl J Med 2015 ; 373 : 2117 – 2128 . Google Scholar Crossref Search ADS PubMed WorldCat Author notes † Inaugural Victor J. Dzau Distinguished Lecture in Cardiovascular Medicine, Stanford University, Palo Alto, CA, USA, 8 December 2021. © The Author(s) 2022. Published by Oxford University Press on behalf of European Society of Cardiology. All rights reserved. For permissions, please e-mail: [email protected] This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model)

Volpe, Massimo; Liuzzo, Giovanna

doi: 10.1093/eurheartj/ehac127pmid: 35325080

Comment on ‘Atrial shunt device for heart failure with preserved and mildly reduced ejection fraction (REDUCE LAP-HF II): a randomized, multicentre, blinded, sham-controlled trial’ which was published in The Lancet, doi: 10.1016/S0140-6736(22)00016-2. Key Points The REDUCE elevated Left Atrial Pressure in patients with Heart Failure II (REDUCE LAP-HF II)1 is a randomized, blinded, sham-controlled trial performed at 89 international centres, which included patients aged ≥40 years with symptomatic heart failure (HF), an ejection fraction (EF) of ≥40%, pulmonary capillary wedge pressure during exercise ≥25 mmHg while exceeding right atrial pressure by at least 5 mmHg. Patients were randomly assigned (1:1) to receive either an interatrial shunt device (Corvia atrial) or sham procedure.2 The primary efficacy endpoint was a hierarchical composite of cardiovascular (CV) death or non-fatal ischaemic stroke up to 12 months post-randomization; rate of total (first plus recurrent) HF events (defined as admissions to hospital or urgent visits) up to 24 months post-randomization; and change in Kansas City Cardiomyopathy Questionnaire (KCCQ) overall summary score between baseline and 12 months. Secondary efficacy endpoints included 24-month total HF events; change in New York Heart Association (NYHA) functional class between baseline and 12 months; and change in KCCQ score. The pre-specified safety endpoint was a composite of CV death; non-fatal ischaemic stroke; new-onset or worsening kidney dysfunction (defined as an estimated glomerular filtration rate decrease of >20 mL/min per 1.73 m2); major adverse cardiac events, defined as cardiac death, myocardial infarction (MI), cardiac tamponade, or emergency cardiac surgery; thrombo-embolic complications (transient ischaemic attack, systemic embolization); atrial fibrillation or atrial flutter; and at least a 30% increase in right ventricular size or at least a 30% decrease in tricuspid annular plane systolic excursion between baseline and 12 months post-randomization. Between May 2017 and July 2020, 1072 participants were enrolled, of whom 626 were assigned to either the atrial shunt device (n = 314) or sham procedure (n = 312) (median age 72 years, 62% female, most were NYHA Class III, median ejection fraction was 60%). The primary efficacy endpoint did not differ between the groups (win ratio 1.0, 95% confidence interval 0.8–1.2; P = 0.85), and there were no differences between groups in the individual components of the primary endpoint. Cardiovascular death and non-fatal ischaemic stroke were uncommon in both groups (1% vs. an expected 5%). The 21% of patients in the shunt device group and 19% in the sham group had at least one HF event. The KCCQ overall summary score improved to a similar extent in both groups at 1 year. Patients with right atrial volume index in the highest tertile (>29.7 mL/m²) (P for interaction = 0.012), and patients with pulmonary artery systolic pressure at 20 W of exercise in the highest tertile (>70 mmHg) (P for interaction = 0.002) had worse HF event outcomes with the device, as did men (P for interaction = 0.02). There were no differences in the composite safety endpoint between the two groups [n = 116 (38%) for shunt device vs. n = 97 (31%) for sham procedure; P = 0.11]. However, patients treated with the shunt device showed more major adverse events (cardiac death, MI, cardiac tamponade, or emergency cardiac surgery) in the 12 months following the procedure than the sham-treated patients (4 vs. 1%, P = 0.025). Comment Heart failure with preserved EF (HFpEF) causes approximately 5 million cases of HF and a yearly incidence of more than 650 000 new diagnoses in US, thus representing a major public health issue.3 However, there are no therapies specifically recommended for the treatment of HFpEF, since all candidate therapies tested including angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, angiotensin receptor/neprilysin inhibitors, beta-blockers, and mineralocorticoid receptor antagonists failed to demonstrate significant benefits in clinical studies. An evident trend towards a reduction in hospitalization and mortality, however, was consistently documented in the individual studies and confirmed in meta-analyses.4,5 Consequently, the current therapeutic approach is mostly based on the principle of unloading the heart with diuretics and treating the underlying condition associated with HFpEF. Recently, in the EMPEROR-Preserved (Empagliflozin in Heart Failure with a Preserved Ejection Fraction) study, empagliflozin produced significant improvement of the composite primary endpoint in HFpEF patients with EF ≥ 40%.6 Indeed, HFpEF must be viewed as a heterogeneous condition featuring distinct phenotypes7,8 and the substantial failure of all randomized trials was repeatedly attributed to the heterogeneity of the recruited study population. In such a context, the REDUCE LAP-HF II trial1 tested an interatrial shunt procedure as a potential tool to improve both the prognosis and quality of life of patients with normal or near-normal central venous pressure but marked elevation of left atrial pressure with exercise. In the overall study population, those subjects who received the experimental procedure showed no clinical benefits over the patients who underwent the sham control procedure. The negative results might be related to the inadequate statistical power of the study, as the event rate was much lower than expected: 1 vs. 5% (CV death or non-fatal ischaemic stroke); 0.25 vs. 0.5 (HF events). Patients with major risk factors for increased mortality in HFpEF and HFmrEF (such as right ventricular dysfunction, pulmonary vascular disease, and inability to exercise) were excluded, which could have led to the lower-than-expected mortality rate. The peak exercise pulmonary vascular resistance (PVR) post hoc subgroup analyses should be considered exploratory at most. However, the results of these analyses suggest that the presence of exercise-induced pulmonary arterial hypertension may represent a fundamental parameter to evaluate the eligibility to unload the left atrium. Indeed, in many HFpEF patients, PVR is normal at rest, displaying elevation during exercise and resulting in increased right ventricle afterload, impaired right-sided ventricular–arterial coupling, accelerated development of right ventricular dysfunction, and elevated right atrial pressure.9 In fact, pulmonary hypertension is a strong predictive factor of increased mortality and morbidity in HFpEF.10 It is interesting that individuals with a peak exercise PVR of <1.74 Wood units (upper limit of normal) appeared to benefit from the shunt in terms of HF events and KCCQ score. In turn, patients with pulmonary artery pressures exceeding 70 mmHg at exercise or with a right atrial volume index in the upper tertile showed increased incidence rate of the primary endpoint. Finally, safety concerns need to be considered as patients treated with the shunt were more likely to have a major adverse cardiac event (cardiac death, MI, cardiac tamponade, or emergency cardiac surgery). Although the results of this study are frankly negative, they support the concept that to be beneficial interatrial shunting requires a specific phenotype (e.g. elevated left atrial pressure in the absence of right-sided HF or significant pulmonary vascular disease) and that an invasive exercise evaluation may be highly important to individualize the management of HFpEF. It is unclear whether non-invasive tests, including measurement of biomarkers (e.g. natriuretic peptides), performance to cardiopulmonary exercise testing, and exercise echocardiography may be equally effective in selecting HFpEF patients eligible to the shunt device. The potential beneficial role of interatrial shunts as an innovative approach in specific HFpEF clinical phenotypes remains to be defined. Conflict of interest: Prof Massimo Volpe reports personal fees for speaker bureau and/or consulting in Advisory Board from Amarin, Amgen, Astra Zeneca, Kalos Medical, Menarini Int, Novartis Pharma, Novo Nordisk, outside the submitted work. Prof Giovanna Liuzzo received grant support (to the Institution) for investigator-initiated research from American Heart Association, Italian National Health Service and Italian Minister of Education, University and Research. She is currently involved in the Research Programs of the Italian Cardiovascular Network. References 1 Shah SJ , Borlaug BA, Chung ES, Cutlip DE, Debonnaire P, Fail PS, et al. Atrial shunt device for heart failure with preserved and mildly reduced ejection fraction (REDUCE LAP-HF II): a randomised, multicentre, blinded, sham-controlled trial . Lancet 2022 : S0140–6736(22)00016-2 . Google Scholar OpenURL Placeholder Text WorldCat 2 Yancy CW , Jessup M, Bozkurt B, Butler J, Casey DE Jr, Drazner MH, et al. 2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines . J Am Coll Cardiol 2013 ; 62 : e147 – e239 . Google Scholar Crossref Search ADS PubMed WorldCat 3 Berry N , Mauri L, Feldman T, Komtebedde J, van Veldhuisen DJ, Solomon SD, et al. Transcatheter interAtrial shunt device for the treatment of heart failure: rationale and design of the pivotal randomized trial to REDUCE elevated Left Atrial Pressure in patients with Heart Failure II (REDUCE LAP-HF II) . Am Heart J 2020 ; 226 : 222 – 231 . Google Scholar Crossref Search ADS PubMed WorldCat 4 Gallo G , Tocci G, Fogacci F, Battistoni A, Rubattu S, Volpe M. Blockade of the neurohormonal systems in heart failure with preserved ejection fraction: a contemporary meta-analysis . Int J Cardiol . 2020 ; 316 : 172 – 179 . Google Scholar Crossref Search ADS PubMed WorldCat 5 McDonagh TA , Metra M, Adamo M, Gardner RS, Baumbach A, Böhm M, et al. 2021 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure . Eur Heart J . 2021 ; 42 : 3599 – 3726 . Google Scholar Crossref Search ADS PubMed WorldCat 6 Anker SD , Butler J, Filippatos G, Ferreira JP, Bocchi E, Böhm M, et al. Empagliflozin in heart failure with a preserved ejection fraction . N Engl J Med 2021 ; 385 : 1451 – 1461 . Google Scholar Crossref Search ADS PubMed WorldCat 7 Gallo G , Volpe M, Battistoni A, Russo D, Tocci G, Musumeci MB. Sacubitril/valsartan as a therapeutic tool across the range of heart failure phenotypes and ejection fraction spectrum . Front Physiol 2021 ; 12 : 652163 . Google Scholar Crossref Search ADS PubMed WorldCat 8 Shah SJ , Kitzman DW, Borlaug BA, et al. Phenotype-specific treatment of heart failure with preserved ejection fraction: a multiorgan roadmap . Circulation 2016 ; 134 : 73 – 90 . Google Scholar Crossref Search ADS PubMed WorldCat 9 Borlaug BA , Kane GC, Melenovsky V, Olson TP. Abnormal right ventricular–pulmonary artery coupling with exercise in heart failure with preserved ejection fraction . Eur Heart J 2016 ; 37 : 3293 – 3302 . Google Scholar Crossref Search ADS PubMed WorldCat 10 Lam CSP , Roger VL, Rodeheffer RJ, Borlaug BA, Enders FT, Redfield MM. Pulmonary hypertension in heart failure with preserved ejection fraction: a community-based study . J Am Coll Cardiol 2009 ; 53 : 1119 – 1126 . Google Scholar Crossref Search ADS PubMed WorldCat © The Author(s) 2022. Published by Oxford University Press on behalf of European Society of Cardiology. All rights reserved. For permissions, please e-mail: [email protected] This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model)

Lu, Xiangfeng; Liu, Zhongying; Cui, Qingmei; Liu, Fangchao; Li, Jianxin; Niu, Xiaoge; Shen, Chong; Hu, Dongsheng; Huang, Keyong; Chen, Jichun; Xing, Xiaolong; Zhao, Yingxin; Lu, Fanghong; Liu, Xiaoqing; Cao, Jie; Chen, Shufeng; Ma, Hongxia; Yu, Ling; Wu, Xianping; Wu, Xigui; Li, Ying;

Kavousi, Maryam; Schunkert, Heribert

doi: 10.1093/eurheartj/ehab923pmid: 35211747

This editorial refers to ‘A polygenic risk score improves risk stratification of coronary artery disease: a large-scale prospective Chinese cohort study’, by X. Lu et al., https://doi.org/10.1093/eurheartj/ehac093 Graphical Abstract Open in new tabDownload slide The figure shows two individuals with their risk profile and predicted 10-year CVD risk (lower arrow). The predicted CVD risk is based on SCORE2 (the European man)15 and the recalibrated China-PAR model for ASCVD (Chinese woman).9 A low (bottom 20%) or high (top 20%) PRS may shift risk into neighbouring categories (upper arrow). The thresholds for risk categories and medical treatment differ slightly between the Chinese (used in the figure) and European guidelines. Risk estimates are based on Chinese10 and European (UK Biobank)6 datasets. Effects of the PRS on CVD risk may differ between populations, given the differences in the genetic architecture of the diseases and the fact that stroke is relatively more prevalent in individuals with East Asian ancestry as compared with Europeans. This highlights that neither risk prediction by traditional cardiovascular risk algorithms nor risk prediction by a CVD PRS can simply be transferred across populations. The impact of PRS may be more pronounced if the outer 5% of the distribution curve is considered. Graphical Abstract Open in new tabDownload slide The figure shows two individuals with their risk profile and predicted 10-year CVD risk (lower arrow). The predicted CVD risk is based on SCORE2 (the European man)15 and the recalibrated China-PAR model for ASCVD (Chinese woman).9 A low (bottom 20%) or high (top 20%) PRS may shift risk into neighbouring categories (upper arrow). The thresholds for risk categories and medical treatment differ slightly between the Chinese (used in the figure) and European guidelines. Risk estimates are based on Chinese10 and European (UK Biobank)6 datasets. Effects of the PRS on CVD risk may differ between populations, given the differences in the genetic architecture of the diseases and the fact that stroke is relatively more prevalent in individuals with East Asian ancestry as compared with Europeans. This highlights that neither risk prediction by traditional cardiovascular risk algorithms nor risk prediction by a CVD PRS can simply be transferred across populations. The impact of PRS may be more pronounced if the outer 5% of the distribution curve is considered. In today’s outpatient clinic, you expect to see two patients; an apparently healthy 60-year-old woman and an apparently healthy 51-year-old man, asking for cardiovascular risk assessment (Graphical Abstract). In agreement with major prevention guidelines, your plan is to determine the probability of a future cardiovascular event based on their physical fitness and measurement of classical risk factors. You ask yourself whether it is possible to improve clinical decision-making by adding a polygenic risk score (PRS). In fact, your patients might be informed about such PRSs by direct-to-consumer genetic testing companies. Estimates suggest that globally 100 million people will have used online genetic tools from Ancestry.com or others by the end of 2021.1 Some sites including 23andMe, Impute.me, MyHeritage, and Allelica.com already allow users to calculate their PRS for some conditions.2 Over the last 15 years substantial progress has been made in identifying genetic variants associated with common diseases. Since the first meta-analysis of genome-wide association studies (GWAS) for coronary artery disease (CAD) in 2007,3 hundreds of variants met the stringent threshold of genome-wide significant association for many conditions.4 Subsequently, the use of a PRS has been proposed to help personalize preventive measures. Yet, the clinical utility of a PRS to further improve CAD risk prediction, beyond standard clinical risk factors, and to define clinical action thresholds based on the PRS results is subject to substantial debate.5,6 To be more specific, this debate is not about the reproducibility of genetic–epidemiological findings. In fact, dense genetic arrays studied in large populations have revealed ever-improving estimates for risk mediated by common risk alleles for common diseases.5,7,8 Thus, the PRS result can be expected to be precise in a given population. In numbers, the risk increase per standard deviation (SD) of the PRS can be expected to be between a factor of 1.3 and 1.7 for people of European descent.5,7 The issue is, rather, what is the clinical benefit? One important point in this respect is the genetic sampling theory, which proposes that alleles under small evolutionary pressure are fairly evenly distributed within a population. Accordingly, roughly two-thirds of the population fall within ±1 SD from the mean of the PRS for CAD and 95% within ±2 SD. In other words, the majority of the population carry a rather similar PRS—without allowing good discrimination of the genetic risk which is carried by all. Based on these facts, you may inform your patients that the chances to identify a substantial deviation from average risk are relatively small. On the other hand, having a PRS at the extreme ends (e.g. top 5–10%) could make a substantial difference.6 Secondly, you may inform your patients that, even with the advent of PRSs, an assessment of traditional risk factors will be non-replaceable. Indeed, the study published in the current issue of the European Heart Journal by Lu et al.9 clearly shows, like others before,10 that the PRS in principle multiplies the risk based on traditional risk factors, which thereby remain to be indispensable for risk prediction. Specifically, the authors document that a high (as compared with a low) PRS in a person with otherwise low risk increases the 10-year CAD risk by only 0.8% (from 0.5% for low PRS to 1.3% for high PRS). On the other hand, if a person carries an intermediate risk, not only is the conventionally predicted risk several fold higher, but so is the additional effect of a high PRS (2.5% increase in 10-year CAD risk—from 2.1% for low PRS to 4.6% for high PRS). If a person carries multiple traditional risk factors, e.g. a diabetic smoker with elevated blood pressure, a high PRS increases the 10-year risk by 6% (from 4.9% for low PRS to 10.9% for high PRS in the very high 10-year CAD risk category). Lu et al.9 also evaluated the potential clinical utility of their metaPRS for primary prevention for the first time in the Chinese population. Addition of the metaPRS to the clinical risk model improved the c-statistic by 0.01 (P = 7.72 × 10−7) and resulted in a modest two-category net reclassification improvement index (NRI) of 3.5% [95% confidence interval (CI) 1.2–6.0%] in the total population. The modest increment in the c-statistic and NRI in the total population obtained by addition of a CAD PRS is similar to what has been observed for other cardiovascular biomarkers.11 This study by Lu et al.9 thereby once more demonstrates an only weak clinical utility of a CAD PRS at the population level above the established clinical risk prediction tools. Nevertheless, among individuals at intermediate clinical risk, a significant number passed the threshold of high CAD risk (10-year CAD risk of >4.6%) when taking into account their high polygenic risk. Thus, the study also highlights the potential of a CAD PRS to further improve risk stratifications among groups of individuals at high polygenic risk but categorized at intermediate CAD risk by the clinical risk prediction tools. CAD is a complex, multifactorial disease. Lu et al.9 constructed a metaPRS for CAD by also incorporating variants associated with CAD-related traits, using the effect sizes of the selected variants in East Asian ancestry. These CAD-related traits included stroke, blood pressure, type 2 diabetes, total, LDL, and HDL cholesterol levels, triglycerides, and body mass index. Of note, there was a low genetic overlap between PRSs constructed for each of these conditions. The metaPRS had greater association with CAD risk than any other individual (CAD or CAD-related) PRS. While the mechanisms of CAD associations are unknown for the majority of identified CAD loci, the metaGRS by Lu et al. includes (a subset of) genetic variants that modify CAD risk based on their associations with traditional cardiovascular risk factors.9 Interestingly, comprehensive inclusion of genetic variants associated with CAD-related traits in the metaPRS improved its performance for CAD prediction. The observed interplay between a PRS and clinical risk in the current study also poses new questions. For example, among individuals in the high clinical risk category, the 10-year absolute CAD risk varied from 3.3% (low genetic risk) to 7.1% (high genetic risk). Considering the clinical actionable high-risk threshold defined to be at 4.6% in this study, the question arises as to whether to withhold preventive treatment among those with a low genetic risk but deemed to be at high risk based on clinical prediction tools. Along the same lines, reduction to three classes of genetic risk (low, medium, and high) artificially affects the precision of the score. In clinical practice, it might be better to replace this rather crude distinction with the effects related to each percentile of the distribution curve. An important novel aspect of the present study is that it went beyond individuals of European ancestry and evaluated a PRS for CAD incidence based on prospective cohorts of East Asian ancestry.9 The PRS, comprising only 540 genetic variants, showed better performance than the two genome-wide PRSs derived from the European studies.9 The less optimal performance of the European ancestry-based PRS in East Asian populations was expected and could be due to differences in variant frequencies and linkage disequilibrium patterns between populations as well as differences in heritability for the same trait across populations.12 This underscores the need for improved treatment of linkage disequilibrium and variant frequencies, for application of polygenic scoring to cohorts of non-European ancestry, and calls for large-scale GWAS in diverse human populations. Genetic contributions to sex differences in CAD risk have not been widely investigated.13 Using a CAD PRS in the UK Biobank, higher genetic risk for CAD in men than in women has been observed.14 In the study by Lu et al.,9 the relative and absolute risks of incident CAD according to the metaPRS categories were again stronger among men compared with women. Moreover, the added value of a CAD PRS for further risk stratifications among individuals at high polygenic risk but at intermediate CAD risk by the clinical risk prediction tools was only evident among men. Sex differences in genetic predisposition to CAD should be considered in future studies and a PRS should not be assumed to perform equally well in men and women for CAD prediction. In conclusion, meta-analyses of large CAD GWAS have allowed the identification of many common genetic variants with very small effects. In young people, in the absence of later life risk factors, a PRS might be the best tool for cardiovascular risk stratification, but indications of preventive treatment early in life still need a better definition. Likewise, when cardiovascular risk is high or a person has already suffered from an event, the CAD PRS offers little information for stratification of medical treatment. On the other hand, among middle-aged subjects with mild risk factors, a CAD PRS yields additional clinical benefit in ∼10% of those being tested. If a person decides to have a genetic test, such arrays also cover genes implicated in a variety of other common conditions including cancers of the prostate, breast, and colon, and thus may yield predictive information beyond CAD risk. This complex situation should be explained to the patient asking for genotyping (Graphical Abstract). Acknowledgements The authors wish to thank Dr Fabian Starnecker for help with the figure. M.K. acknowledges support from the Dutch Heart Foundation (Senior Scientist grant: 03-004-2021-T050). H.S. acknowledges support from the Foundation Leducq (PlaqueOmics: Novel Roles of Smooth Muscle and Other Matrix Producing Cells in Atherosclerotic Plaque Stability and Rupture,18CVD02; CADgenomics: Understanding CAD Genes, 12CVD02) and the European Union under grant agreement HEALTH-F2-2013-601456 (CVgenes-at-target). He received grants for a British Heart Foundation (BHF)–German Center of Cardiovasular Research (DZHK) collaboration and the ERA-NET (Druggable-MI-Genes: 01KL1802), and was also supported by grants from the Federal German Ministries (AbCD-Net, grant 01ZX1706C; BLOCK-CAD, grant 16GW0198K; ModulMax, grant ZF4590201BA8), and the DFG as part of the Sonderforschungsbereich CRC 1123 (B2), the Transregio TRR 267 (B05), as well as the DigiMed Bayern project (DBM-1805-0001). Conflict of interest: none declared. References 1 MIT Technology Review . More than 26 million people have taken an at-home ancestry test . https://www.technologyreview.com/s/612880/more-than-26-million-people-have-taken-an-at-home-ancestry-test/. 2 Lewis CM , Vassos E. Polygenic risk scores: from research tools to clinical instruments . Genome Med 2020 ; 12 : 44 . Google Scholar Crossref Search ADS PubMed WorldCat 3 Samani NJ , Erdmann J, Hall AS, Hengstenberg C, Mangino M, Mayer B, et al. Genomewide association analysis of coronary artery disease . N Engl J Med 2007 ; 357 : 443 – 453 . Google Scholar Crossref Search ADS PubMed WorldCat 4 Chen Z , Schunkert H. Genetics of coronary artery disease in the post-GWAS era . J Intern Med 2021 ; 290 : 980 – 992 . Google Scholar Crossref Search ADS PubMed WorldCat 5 Elliott J , Bodinier B, Bond TA, Chadeau-Hyam M, Evangelou E, Moons KGM, et al. Predictive accuracy of a polygenic risk score-enhanced prediction model vs a clinical risk score for coronary artery disease . JAMA 2020 ; 323 : 636 – 645 . Google Scholar Crossref Search ADS PubMed WorldCat 6 Khera AV , Chaffin M, Aragam KG, Haas ME, Roselli C, Choi SH, et al. Genome-wide polygenic scores for common diseases identify individuals with risk equivalent to monogenic mutations . Nat Genet 2018 ; 50 : 1219 – 1224 . Google Scholar Crossref Search ADS PubMed WorldCat 7 Aragam KG , Jiang T, Goel A, Kanoni S, Wolford BN, Weeks EM, et al. Discovery and systematic characterization of risk variants and genes for coronary artery disease in over a million participants . MedRxiv doi: 10.1101/2021.05.24.21257377. 8 Hughes MF , Saarela O, Stritzke J, Kee F, Silander K, Klopp N, et al. Genetic markers enhance coronary risk prediction in men: the MORGAM prospective cohorts . PLoS One 2012 ; 7 : e40922 . Google Scholar Crossref Search ADS PubMed WorldCat 9 Lu X , Liu Z, Cui Q, Liu F, Li J, Niu X, et al. A polygenic risk score improves risk stratification of coronary artery disease: a large-scale prospective Chinese cohort study . Eur Heart J 2022 ; 43 : ehac093 . Google Scholar OpenURL Placeholder Text WorldCat 10 Hindy G , Aragam KG, Ng K, Chaffin M, Lotta LA, Baras A, et al. Genome-wide polygenic score, clinical risk factors, and long-term trajectories of coronary artery disease . Arterioscler Thromb Vasc Biol 2020 ; 40 : 2738 – 2746 . Google Scholar Crossref Search ADS PubMed WorldCat 11 Kavousi M , Elias-Smale S, Rutten JHW, Leening MJG, Vliegenthart R, Verwoert GC, et al. Evaluation of newer risk markers for coronary heart disease risk classification: a cohort study . Ann Intern Med 2012 ; 156 : 438 – 444 . Google Scholar Crossref Search ADS PubMed WorldCat 12 Gola D , Erdmann J, Läll K, Mägi R, Müller-Myhsok B, Schunkert H, et al. Population bias in polygenic risk prediction models for coronary artery disease . Circ Genom Precis Med 2020 ; 13 : e002932 . Google Scholar Crossref Search ADS PubMed WorldCat 13 Kavousi M , Bielak LF, Peyser PA. Genetic research and women’s heart disease: a primer . Curr Atheroscler Rep 2016 ; 18 : 67 . Google Scholar Crossref Search ADS PubMed WorldCat 14 Huang Y , Hui Q, Gwinn M, Hu YJ, Quyyumi AA, Vaccarino V, et al. Sexual differences in genetic predisposition of coronary artery disease . Circ Genom Precis Med 2021 ; 14 : e003147 . Google Scholar PubMed OpenURL Placeholder Text WorldCat 15 SCORE2 working group and ESC Cardiovascular risk collaboration . SCORE2 risk prediction algorithms: new models to estimate 10-year risk of cardiovascular disease in Europe . Eur Heart J 2021 ; 42 : 2439 – 2454 . Crossref Search ADS PubMed WorldCat Author notes The opinions expressed in this article are not necessarily those of the Editors of the European Heart Journal or of the European Society of Cardiology. © The Author(s) 2022. Published by Oxford University Press on behalf of European Society of Cardiology. All rights reserved. For permissions, please e-mail: [email protected] This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model)

Hageman, Steven H J; McKay, Ailsa J; Ueda, Peter; Gunn, Laura H; Jernberg, Tomas; Hagström, Emil; Bhatt, Deepak L; Steg, Ph. Gabriel; Läll, Kristi; Mägi, Reedik; Gynnild, Mari Nordbø; Ellekjær, Hanne; Saltvedt, Ingvild; Tuñón, José;

Sattar, Naveed; Welsh, Paul

doi: 10.1093/eurheartj/ehac125pmid: 35265991

This editorial refers to ‘Estimation of recurrent atherosclerotic cardiovascular event risk in patients with established cardiovascular disease: the updated SMART2 algorithm’, by S.H.J. Hageman et al., https://doi.org/10.1093/eurheartj/ehac056. Graphical Abstract Open in new tabDownload slide Multiple reasons to adopt residual risk scoring in the secondary prevention setting. A conceptual outline for why residual risk scoring is now important to undertake. Aggressive new targets for established risk factors allied to a widening choice of expensive newer therapies means that not all health systems or patients can affordably take on all new therapies and not all patients would be convinced of the merits of additional medications, especially if they are already on several. A formal calculation of residual risk that is well calibrated to each region will help in making informed decisions. The therapeutic armoury with which to treat patients in secondary prevention, whether or not they have diabetes, is likely to expand even further in the next few years, so that the need for a risk score may become even more important over time. Secondary prevention risk scores should improve over time as additional data become available, and newer methods are adopted. Attention to how well the current score is used will be important, with the aim of continuous improvement. Graphical Abstract Open in new tabDownload slide Multiple reasons to adopt residual risk scoring in the secondary prevention setting. A conceptual outline for why residual risk scoring is now important to undertake. Aggressive new targets for established risk factors allied to a widening choice of expensive newer therapies means that not all health systems or patients can affordably take on all new therapies and not all patients would be convinced of the merits of additional medications, especially if they are already on several. A formal calculation of residual risk that is well calibrated to each region will help in making informed decisions. The therapeutic armoury with which to treat patients in secondary prevention, whether or not they have diabetes, is likely to expand even further in the next few years, so that the need for a risk score may become even more important over time. Secondary prevention risk scores should improve over time as additional data become available, and newer methods are adopted. Attention to how well the current score is used will be important, with the aim of continuous improvement. Risk scoring in the primary prevention setting is well established in many parts of the world to guide allocation of therapies, initially statins but more recently antihypertensives, to those at highest risk. Such scores have evolved over time in generally overlapping ways in many regions or countries. A very similar core set of risk predictors (age, sex, smoking, blood pressure, cholesterol and HDL-cholesterol levels, and diabetes) are included in most primary prevention scores. In some countries, risk scores have expanded to more predictors. In the UK, for example, the QRISK3 risk score includes ethnicity, socioeconomic status as assessed by post code, and several chronic conditions beyond diabetes (specifically rheumatoid arthritis, atrial fibrillation, systemic lupus erythematosus, erectile dysfunction, and major psychiatric illness) that improve prediction models without substantially increasing time or costs associated with scoring.1 Other developments in primary prevention scoring are likely to follow, such as better determination of the lifetime benefits of therapies for 1:1 conversations with patients, and, potentially, the subsequent addition of risk factors such as lipoprotein(a) [Lp(a)]2 or high-sensitivity cardiac troponin,3 in selected individuals dependent on determined risk. However, access to a simple risk score that is pragmatic, discriminatory, calibrated, and equitable is valuable to aid treatment decisions. The recent SCORE2 risk score4 for use in primary prevention comes in an electronic interactive version, has been tested thoroughly with European data from many countries, and is based on cardiovascular death as the main ‘hard’ endpoint, though risk of heart disease and stroke death can also be derived. This improved functionality is a welcome development and, as statins and many antihypertensives are cheap, improving identification of people who would benefit will help reduce the incidence of primary cardiovascular disease (CVD), perhaps particularly in regions at higher cardiovascular risk. A consequence of better risk factor management and better clinical care following an index event is that an ever-increasing number of people are living with vascular disease, particularly in high-income countries. The issue of clinical management of these patients is therefore an escalating and important component of healthcare. Historically, guidelines have not invoked risk scoring to make clinical decisions in secondary prevention. For instance, the 2007 ESC guidelines advocates risk scoring in primary prevention, but notes that ‘In all patients with an acute coronary syndrome, statin treatment should be initiated while the patients are in the hospital’.5 However, this simple clinical picture has become more complex over time. Indeed, in the 2021 ESC guidelines,6 it is recommended that all patients living with atherosclerotic cardiovascular disease (ASCVD) should be offered lifestyle advice and target LDL-cholesterol (to <1.8 mmol/L) and systolic blood pressure (SBP) (to <140 mmHg), as well as antithrombotic therapy (STEP 1). However, in those with higher residual 10-year CVD risk determined from the SMART risk score (and taking into account patient circumstances and preferences), more aggressive risk reduction therapy including lower LDL-cholesterol and SBP targets, dual antiplatelet therapy, and emerging medications, such as colchicine and the omega-3 fatty acid, eicosapentaenoic acid (EPA), may also be considered (STEP 2). However, there is likely to be a further expansion of pharmacological options in the next few years. Of note, the choice of additional lipid-lowering agents beyond statins has already expanded to include ezetimibe, plus the currently expensive PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibitors, and recently introduced bempedoic acid. The latter two are likely to be needed in many patients if recently introduced lower LDL-cholesterol targets are to be reached, therefore leading to even more polypharmacy. Looking to the future, Lp(a)-lowering drugs may come into play if relevant outcomes trials are supportive. Similarly, following the Canakinumab Antiinflammatory Thrombosis Outcome Study (CANTOS) trial of interleukin- IL-1β (IL-1β) blockade in secondary prevention,7 trials are now ongoing for IL-6 inhibition.8 Sodium–glucose co-transporter 2 (SGLT2) inhibitors are options in patients living with diabetes or heart failure, and ongoing trials are testing their worth in patients post-myocardial infarction whether or not they have diabetes.9,10 Glucagon-like-1 (GLP-1) receptor agonists reduce weight and lower risk in patients with diabetes, but are also now being tested in the secondary prevention setting outside of diabetes.11 The implication of the current and potentially further expansion in therapeutic riches is a widening suite of cardiovascular preventative options. However, more treatment options bring greater costs, polypharmacy, side effects, and drug interactions, and enhance the complexity of clinical decision-making. In most areas of medicine, including CVD, drugs have been simply initiated in the order that they were put through clinical trials.12,13 This has benefits in terms of minimizing costs, and leads to clear clinical decisions when there are relatively few proven therapies. However, with more aggressive risk factor targets and widening treatment options, the need for a more systematic approach to residual risk reduction increases, and to do that we need a framework for clinical decision-making. Residual risk scoring also recognizes markedly varied absolute risk in patients with established vascular disease, an observation perhaps not well recognized. In the present issue of the European Heart Journal, Hageman and colleagues present a much-improved version of the SMART risk score; SMART2.14 Intended for use in patients with a history of prior coronary artery disease, cerebrovascular disease, peripheral artery disease, or abdominal aortic aneurysms, it predicts fatal CVD and non-fatal myocardial infarction or stroke. The new score includes the clinical risk predictors age, sex, current smoking, SBP, non-HDL cholesterol, diabetes, type of ASCVD, years since first ASCVD diagnosis, estimated glomerular filtration rate, and C-reactive protein (CRP). In the same manner as SCORE2,4 SMART2 recalibrates risk to local populations, thus ensuring that the score provides good estimates of absolute risks across many regions of the world. The study reports external validation across seven cohorts (>360 000 people) and, importantly, the methods account for competing mortality risks. This is potentially important since preventative therapies can only yield meaningful benefits if people live long enough to gain from them. The authors also tested the clinical utility of this score against potentially actionable risk thresholds that may signal further therapy interventions; they report potential benefits of the SMART2 risk being used to intensify therapy at a threshold of between 20% and 40% 10-year risk. Further work in defining optimal STEP2 thresholds is therefore required. However, as the authors recognize,14 there are some limitations to the SMART2 score. Any risk score can only be as good as the data from which it is derived and, though the study captures multiple cohorts, healthy selection bias is always a concern. In addition, several regions had only sparse data so that additional validation and calibration in some regions would be useful. For this reason, it is likely that investigators will try to collect better patient data across Europe (and elsewhere) going forwards. It is also well established that traditional cardiovascular risk factors offer less discrimination of CVD risk in secondary prevention (and in older cohorts) than they do in primary prevention. Even so, the C-statistics of SMART2 in the validation cohorts could be considered modest; 0.62 in the Clinical Practice Research Database (CPRD) and 0.69 in SWEDEHEART (the two largest studies), and so there is room for improvement in discrimination. Whether future addition of other comorbidities (probably common in patients with established vascular disease) or use of cardiac biomarkers, or other risk factors, could improve such risk scores requires assessment. Certainly, troponin and N-terminal probrain natriuretic peptide (NT-proBNP) have the potential to outperform high-sensitivity CRP in risk prediction,15 and NT-proBNP measurement would also aid screening for emergent heart failure, which is rising in prevalence. If there is any way to capture social class or ethnicity in wider settings this could also help but, of course, each additional measurement might make risk scores more costly (e.g. cardiac biomarkers) and/or less pragmatic. That noted, with better statistical methods (e.g. artifical intelligence [AI]) or expertise, future scores could improve and could also include ‘optional’ extra predictors for doctors working in regions where these are more easily, or affordably, measured. By providing a framework and an ‘objective’ identification of patients at highest residual risk, and who stand to benefit most from aggressive risk management, SMART2 provides an important basis for future clinical decisions. Whether this tool can be used to improve adherence, or could be further improved over time with better quality data or statistical methods, or cost-effectively expanded to include new risk factors for prediction gains, requires ongoing work. These limitations will doubtless be worked on in the future so that secondary prevention risk scores will continue to mature over time. For now, however, most cardiovascular specialists would do well to familiarize themselves with SMART2 as its use has the potential to improve care. Acknowledgements Thanks to Liz Coyle, University of Glasgow, for her assistance in the preparation of this article. Funding This work was supported by the British Heart Foundation Research Excellence Award (RE/18/6/34217). Conflicts of interest: N.S. reports personal fees from Afimmune, Amgen, Eli Lilly, Hanmi Pharmaceuticals, Merck Sharp & Dohme, Novo Nordisk, Pfizer, and Sanofi; grants and personal fees from AstraZeneca, Boehringer Ingelheim, and Novartis; and a grant from Roche Diagnostics, outside the submitted work. P.W. reports grant income from Roche Diagnostics, AstraZeneca, Boehringer Ingelheim, and Novartis; and personal fees from Novo Nordisk, outside the submitted work. References 1 Hippisley-Cox J , Coupland C, Brindle P. Development and validation of QRISK3 risk prediction algorithms to estimate future risk of cardiovascular disease: prospective cohort study . BMJ 2017 ; 357 : j2099 . Google Scholar OpenURL Placeholder Text WorldCat 2 Welsh P , Welsh C, Celis-Morales CA, Brown R, Ho FK, Ferguson LD, et al. Lipoprotein(a) and cardiovascular disease: prediction, attributable risk fraction, and estimating benefits from novel interventions . Eur J Prev Cardiol 2022 ; 28 : 1991 – 2000 . 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Zeng, Chao; Rosenberg, Lynn; Li, Xiaoxiao; Djousse, Luc; Wei, Jie; Lei, Guanghua; Zhang, Yuqing

doi: 10.1093/eurheartj/ehac059pmid: 35201347

AimsPrevious studies have found high sodium intake to be associated with increased risks of cardiovascular disease (CVD) and all-cause mortality among individuals with hypertension; findings on the effect of intake among individuals without hypertension have been equivocal. We aimed to compare the risks of incident CVD and all-cause mortality among initiators of sodium-containing acetaminophen with the risk of initiators of non-sodium-containing formulations of the same drug according to the history of hypertension.Methods and resultsUsing The Health Improvement Network, we conducted two cohort studies among individuals with and without hypertension. We examined the relation of sodium-containing acetaminophen to the risk of each outcome during 1-year follow-up using marginal structural models with an inverse probability weighting to adjust for time-varying confounders. The outcomes were incident CVD (myocardial infarction, stroke, and heart failure) and all-cause mortality. Among individuals with hypertension (mean age: 73.4 years), 122 CVDs occurred among 4532 initiators of sodium-containing acetaminophen (1-year risk: 5.6%) and 3051 among 146 866 non-sodium-containing acetaminophen initiators (1-year risk: 4.6%). The average weighted hazard ratio (HR) was 1.59 [95% confidence interval (CI) 1.32–1.92]. Among individuals without hypertension (mean age: 71.0 years), 105 CVDs occurred among 5351 initiators of sodium-containing acetaminophen (1-year risk: 4.4%) and 2079 among 141 948 non-sodium-containing acetaminophen initiators (1-year risk: 3.7%), with an average weighted HR of 1.45 (95% CI 1.18–1.79). Results of specific CVD outcomes and all-cause mortality were similar.ConclusionThe initiation of sodium-containing acetaminophen was associated with increased risks of CVD and all-cause mortality among individuals with or without hypertension. Our findings suggest that individuals should avoid unnecessary excessive sodium intake through sodium-containing acetaminophen use.

Schutte, Aletta E; Neal, Bruce

doi: 10.1093/eurheartj/ehab888pmid: 35201343

Graphical AbstractGraphical AbstractSodium hidden in medication warrants warning labels by drug companies.