European Heart Journal (2014) 35, 403–409 doi:10.1093/eurheartj/eht573

Nobel Prize winner joins European Heart Journal International Board The Journal welcomes Evgeny L. Chazov from Russia as a member of the International Board, bringing with him the experience of a long and distinguished career in cardiology

Dr Evgeny L. Chazov MD

ESC Gold Medal


Andros Tofield

Nobel Prize Medal

Published on behalf of the European Society of Cardiology. All rights reserved. & The Author 2014 . For permissions please email: [email protected]

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Academician Evgeny Chazov is a prominent scientist, physician, public health administrator and currently, chief cardiologist of the Russian Ministry of Health. His medical career started in 1953 at the Sechenov First Medical Institute of Moscow under the supervision of the prominent Soviet cardiologist Prof. A.L. Myasnikov who was awarded the Golden Stethoscope by the International Society of Cardiology in 1964. Dr Chazov’s professional interests have concentrated on basic research and the clinical aspects of atherosclerosis and acute myocardial infarction. He has been particularly interested in the treatment of myocardial infarction. His main contribution to cardiology has been in the development of thrombolytic therapy for myocardial infarction, particularly when applied in a pre-hospital setting. In 1956, he received his first scientific degree as Candidate of Medical Sciences and in 1963, Doctor of Medical Sciences. From 1959 to 1963, Dr Chazov worked as a senior researcher at the Institute of Therapy, USSR Academy of Medical Sciences and from 1963 to 1965 he was Deputy Director of the Institute. In 1965, he was appointed Director of the USSR Ministry of Health, then in 1987 became Minister of Health of the USSR until 1990. During those years much of his professional activities were devoted to the problems of prevention and rehabilitation as well as healthcare organization. From 1975 until now, Dr Chazov has been General Director of the Russian Cardiology Research and Production Complex with a staff of .1500. As Director of this huge clinical and research medical institution, he supervises all studies carried out at the Institute of Clinical Cardiology and Institute of Experimental Cardiology. Studies are conducted in a number of problem areas including atherosclerosis,

arterial hypertension, acute coronary syndrome, electrophysiology, genetics, immunology, and cellular biology. For 37 years, Dr Chazov has coordinated collaboration programmes in biomedical science with the USA within agreements between the former Soviet Union and lately, the Russian Federation. He has also supervised coordinated programmes in cardiology with Australia, France, Germany, and other nations. He has .1000 publications to his name including 11 monographs in English, German, and Polish. The most known are Experimental Necrosis of the Myocardium, 1963; Thrombosen und Embolien in der Klinik innerer Krankheiten (Thrombosis and Embolism in Internal Medicine), 1966; Myocardial Infarction, 1971; and Essays of Urgent Cardiology. Dr Chazov has been recognized nationally and internationally, however and above all, he is a practicing physician. During the 60 years of his medical career, he has treated .20,000 patients including leaders of 14 foreign states. Since 1971, he has been a full Member of the Russian Academy of Medical Sciences and since 1979 a full Member of the Russian Academy of Sciences. He has been awarded many honorary memberships including the American Heart Association. For many years, Dr Chazov was a Member of the WHO Expert Advisory Panel for Cardiovascular Diseases. In 1996, he was awarded the Leon Bernard Foundation Prize and Medal by WHO. Among his honours are several State Prizes, the Botkin Health Prize, the Myasnikov Health Prize, Albert Schweitzer Gold Medal in 2001, The Ordre des Palmes Academiques, France, and Order of Merit, first Degree (Russian Federation, 2009). Almost 30 years ago, in 1985, he received the Nobel Peace Prize jointly with Dr Bernard Lown, USA, for founding the organization: International Physicians for the Prevention of Nuclear War. Recently, in 2013, Dr Chazov was awarded the Gold Medal of the European Society of Cardiology.



Eleventh International Symposium on the Mechanisms of Vasodilation The latest developments were presented by an international panel of scientists last October in Zu¨rich, Switzerland

The sympathetic system in hypertension and heart failure Prof. Murray Esler, Melbourne, Australia, held the John T. Shepherd Lecture. He has contributed enormously to the understanding of neuronal control of the circulation using microneurography and norepinephrine spill over in humans in vivo. Prof. Esler has shown that the sympathetic nervous system is a crucial regulator of the circulation

Murray Esler (R) and Richard A. Cohen (L)

Clinton R. Webb (R) and Virginia Miller (L)

Novel vasoactive peptides Novel vasoactive peptides are currently of high interest, particularly in patients with heart failure. To that end, the Symposium on Vasodilator and Natriuretic Peptides was held with a particular focus on heart failure. Mario Bigazzi, Florence, Italy, one of the first cardiovascular scientists to study relaxin, gave an impressive overview of the importance of this peptide for the adaptation of the circulation in pregnancy. The physiological properties of relaxin lend themselves to therapeutic applications that eventually led to the development of serelaxin, as a novel treatment for acute heart failure. Marco Metra, Brescia, Italy, reviewed the current evidence in heart failure showing an impressive reduction in mortality in patients presenting to the emergency department with acute dyspnoea and other signs of acute cardiac decompensation.

Ernesto L. Schiffrin (R) and Paul M. Vanhoutte (L)

Zvonimir S. Katusic (R) and (L) Hiroaki Shimokawa

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Changes in vasomotor tone led Paul M. Vanhoutte, MD, PhD to initiate an International Symposium on the Mechanisms of Vasodilatation in Antwerp in 1970 which has continued every 3–4 years. The latest 3-day Symposium was in October 2013 at the University Hospital in Zu¨rich, with an international audience of over 100 scientists from Australia, Canada, China, Europe, Japan, and the USA. In the 1986, 4th Symposium, Robert R. Furchgott made a major impact on cardiovascular control. He proposed in a few handwritten transparencies that endothelium-derived relaxing factor released by acetylcholine was nitric oxide (NO). Simultaneously, Louis Ignarro demonstrated that this free radical is a potent vasodilator of arteries and veins. Salvador Moncada attended that meeting and returned home to perform crucial experiments, demonstrating that the hypothesis was true. Later the enzymes producing NO, the family of NO synthases, were discovered.

and contributes to hypertension and heart failure. His experiments, particularly in the renal circulation, have led to the development of renal nerve ablation as a novel and promising strategy to treat resistant hypertension. Uta Hoppe, Salzburg, Austria, reported on novel technologies for renal nerve ablation from the Simplicity Single Electrode Systemw to multi-electrode baskets, multi-electrode wires, and balloons using radiofrequency energy, neurotoxins, or ultrasound. Christian Templin, Zu¨rich, Switzerland, demonstrated that pathological renal lesions are induced with available technologies, e.g. endothelial oedema, endothelial detachment, thrombus formation, and diffuse vasospasm. Based on these results, it has been recommended to pre-treat patients with aspirin and/or ADP receptor antagonists to avoid thrombus formation during the procedure. Felix Mahfoud, Homburg, Germany, reviewed the clinical effectiveness of renal nerve ablation, which is already convincing based on the available data. In patients with severe or treatment-resistant hypertension, ablation results in a blood pressure reduction of 30/10 mmHg after 3–12 months.



Lastly, Stefan Anker Berlin, Germany, discussed a new peptide, ularitide, a synthetic analogue of urodilatin, a naturally occurring natriuretic and vasodilator hormone produced by the kidneys. Ularitide has been developed based on the exciting results with urodilatin in uncontrolled trials and is currently being tested in a Phase III multicentre study enrolling patients with acute heart failure. The session on novel vasoactive peptides was complemented by the David Bohr Lecture held by Clinton R. Webb, Augusta, USA, who gave a talk on ‘Mitochondria-derived Peptides: Novel Mediators of Vasodilation’. Mitochondria contain N-formyl peptides activating specific receptors leading to profound vasodilatation. This mechanism appears to be important in septic shock and the discovery of this pathway, which is inhibited by cyclosporine-H, is likely to provide novel opportunities to treat this devastating condition, which still has a mortality rate of 30– 50%.

Ernesto L. Schiffrin, Montreal, Canada, gave the Bjo¨rn Folkow Lecture on growth and remodelling. Bjo¨rn Folkow, Professor of Physiology at Go¨teborg University in Sweden, was an eminent physiologist who discovered the importance of structural changes in the resistance arteries during the development of hypertension. Ernesto L. Schiffrin spoke about the ‘Effects of Immune Mechanisms on the Vasculature in Hypertension’ and demonstrated in his elegant talk that T reg lymphocytes contribute to inflammatory responses in small resistance arteries in hypertension and, therefore, may aggravate and/ or sustain hypertension by interfering with the L-arginine/NO pathway and by expressing endothelin. The role of endothelin in the control of vascular tone was then reviewed by both Paul M. Vanhoutte and Thomas F. Lu¨scher, emphasizing, that this peptide normally suppressed by biologically active NO via a cyclic GMP-dependent mechanism, is widely expressed in situations of endothelial dysfunction. Endothelin contributes to different forms of hypertension, in particular DOCA-salt hypertension, DAHL-salt hypertension, and angiotensin II-induced hypertension. Angiotensin II stimulates endothelin production and endothelin markedly contributes to any condition where the renin–angiotensin system is activated. Although, bosentan has been shown by Henry Krum to lower blood pressure similar to enalapril, bosentan and other molecules interfering with endothelin receptors have not been further developed in hypertension for several reasons. One is that malformations develop in endothelin receptor knockout animals in the jaw and throat. This precludes the use of such molecules in women of childbearing age. Headaches associated with the drugs, particularly in hypertensive patients, also made development of these drugs less attractive. However, the endothelin system is markedly elevated in patients with heart failure, especially those with cardiogenic shock. Furthermore, in patients after acute myocardial infarction, often leading to heart failure, baseline endothelin levels are highly predictive of future outcome. In spite of that, and although endothelin receptor antagonists had very favourable haemodynamic effects in patients with heart

Endothelial function in the cerebral circulation On the last day, Zvonimir S. Katusic Mayo Clinic, MN, USA, presented the 4th Paul M. Vanhoutte Lecture on vascular pathology. His lecture on ‘Endothelial Nitric Oxide in Cerebrovascular Disease’ revealed truly novel aspects of the role of NO in Alzheimer disease as a regulator processing the APP-protein to ab3, a crucial pathway in the development of Alzheimer disease. Of note, endothelial NO knockout mice do develop neurological alterations compatible with a certain form of Alzheimer disease, suggesting that also in vivo this mechanism may be operative and important. Whether such mechanisms are important in humans prone to or those who have already developed Alzheimer disease remains to be determined. Thus, the 11th International Symposium on Mechanisms of Vasodilation provided again vascular science of the highest level and allowed insights into the current state-of-the-art of this important field of vascular biology, relevant not only for scientists, but also for clinicians. The Symposium has become highly regarded as the international community has increasingly engaged in vascular biology and those interested in endothelium-dependent responses have sought symposia for exchange and discussion. The John T. Shepherd Lecture is in memory of an eminent integrative physiologist contributing to our understanding on neurogenic cardiovascular control who was at the Mayo Clinic. The David Bohr Lecture remembers the work of the late David Bohr, who was an eminent vascular physiologist contributing to our understanding of vascular smooth muscle tone at the University of Ann Arbor MI. The Bjo¨rn Folkow Lecture is in memory of the late Bjo¨rn Folkow for his work in the field of vascular adaptation to hypertension. The Paul M. Vanhoutte Lecture is in recognition for his contributions to the regulation of the cerebrovascular circulation.

Ruth Amstein, PhD, Director Zu¨rich Heart House Thomas F. Lu¨scher, MD, Cardiology Director, Zu¨rich University Hospital Paul M. Vanhoutte, MD, PhD, University of Hong Kong

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Vascular adaptation in hypertension

failure, both the EARTH-Trial as well as the ENABLE-Trial found no difference on remodelling and clinical outcome, respectively. Therefore, endothelin receptorantagonists have not been further considered for the treatment of heart failure, another example of a molecule lost in translation in this condition. It appears that endothelin receptor antagonists are particularly efficacious in pulmonary hypertension of different causes with lower morbidity and mortality as demonstrated in large outcome trials. Finally, endothelin may play a role in Takotsubo syndrome where plasma levels of endothelin are increased due to a down-regulation of the regulating mRNA. However, effects of endothelin antagonists in this condition have not yet been evaluated.



Controversies in imaging ischaemic heart disease Arguments for and against the statement ‘Evaluation of intermediate coronary lesions: coronary flow reserve can only be measured accurately invasively’ from the EuroEcho Imaging Conference, December 2013

Protagonist view: Justin E.R. Davies (UK)

Figure 1 Close resemblance of coronary flow in left anterior descending measured non-invasively and invasively. Non-invasive transthoracic coronary flow was performed using the Esoate MyLab (upper panel) and invasive coronary flow using the Volcano Combowire (lower panel). Pictures from Chris Broyd, Imperial College London.

Contra view: Eugenio Picano (Italy) Assessment of CFR integrates and complements classic stress echocardiography founded on regional wall motion analysis. With the addition of CFR to wall motion, stress echocardiography response can be better stratified in patients with diabetes, hypertension, dilated cardiomyopathy, hypertrophic cardiomyopathy, heart transplant, or intermediate stenosis of single-vessel disease. As a general rule, a reduced CFR makes the prognosis more malignant in patients with, and less benign in those without, inducible wall motion abnormalities. However, there are conceptual and technical limitations with CFR assessment by ultrasound. Stress echocardiography with the evaluation of CFR needs a longer learning curve than traditional regional wall motion analysis, and is highly feasible (. 90%) on the left anterior descending artery, less in posterior descending and in the left circumflex. The CFR depends on a coronary as well as a myocardial

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Frequently, we debate about which technique gives the most ‘accurate’ measurements, or perhaps which has the ‘most evidence’. However, such debates seem to miss the wider picture, which is, if there is such good evidence to use physiology in guiding assessment—why are we not using it more frequently? Large clinical studies such as FAME have shown the prognostic benefits of using physiological measures of stenosis severity to guide coronary revascularization. This technique uses fractional flow reserve (FFR), an invasive measure of intracoronary pressure obtained at the time of coronary angiography. While nowadays most pressure-based assessments are made using FFR, it is important to recognize that these indices are designed to act as surrogates of coronary flow. The need for pressure-based measurements arose as flow was thought to be technically too difficult to measure rapidly and reliably in clinical practice. Flow is still measured in many catheter laboratories around the world using both invasive and non-invasive techniques. Invasive techniques offer the possibility of assessing flow at any location with each of the left or right coronary arteries or even bypass grafts. Non-invasive techniques are most robust and excel when made in the left anterior descending artery. While measurements of flow in the right and circumflex arteries are important for arterial evaluation, it is now widely acknowledged that from a prognostic perspective the left anterior descending artery’s circulation is paramount. Many studies have demonstrated that identification of such lesions and their potential significance using coronary flow reserve (CFR) can be made using either non-invasive or invasive approaches. This suggests that the ‘best’ technique depends on whom it is being performed in and the laboratory in which they are being evaluated. In the catheter laboratory, where patients are already undergoing an invasive procedure, it is appropriate to use intra-arterial wires to measure coronary physiological indices such as FFR or CFR. In the noninvasive laboratories, the use of echocardiography or PET imaging may be useful to identify ischaemia and those at a greatest risk of cardiac events. Having multiple methodologies at their disposal provides investigators with a range of tools to evaluate patients. Choice gives our patients the best possible opportunities of having a physiological assessment made in the widest range of settings (Figure 1).



impact on the management of patients with coronary artery disease for three reasons: first, it can be performed upstream of the cardiac cath lab; second, it can be used as a running mate of the main information represented by wall motion abnormalities; and third, and most importantly, it is non-invasive, low-cost, radiation-free, and thus in the current age of sustainability can better spare patients useless coronary angiographies, prognostically futile coronary interventions, and the inherent costs, radiation exposure and long-term cancer risks of an invasive procedure.2 Jennifer Taylor MPhil

References 1. Picano E, Pellikka PA. Stress echo applications beyond coronary artery disease. Eur Heart J 2014; doi:10.1093/eurheartj/eht394. First published online 14 October 2013. 2. Picano E, Van˜o´ E, Rehani MM, Cuocolo A, Mont L, Bodi V, Bar O, Maccia C, Pierard L, Sicari R, Plein S, Mahrholdt H, Lancellotti P, Knuuti J, Heidbuchel H, Di Mario C, Badano LP. The appropriate and justified use of medical radiation in cardiovascular imaging. A position document of the ESC associations of Cardiovascular Imaging, Percutaneous Cardiovascular Interventions and Electrophysiology. Eur Heart J 2013, doi:10.1093/eurheartj/eht394. First published online 8 January 2014.

Heart failure accelerates male ‘menopause’ Four-fold increase of andropausal syndrome in men with heart failure Heart failure accelerates the ageing process and brings on early andropausal syndrome (AS), according to research presented at the Heart Failure Congress 2013 in Lisbon, Portugal. AS, also referred to as male ‘menopause’, was four times more common in men with heart failure. As men get older they are more likely to suffer from andropausal syndrome (AS), also called ‘menopause’, androgen deficiency in the ageing male (ADAM), or late-onset hypogonadism. Men with AS have decreased levels of anabolic hormones, including testosterone, and it has been suggested that these hormone deficiencies are what cause the clinical symptoms. The symptoms of AS according to the Aging Male Symptom Rating Scale can be divided into three categories: (1) Sexual: erectile dysfunction, problems with libido, reduced beard growth, feelings of ‘having passed the zenith of life’. (2) Psychological: feeling discouraged, depressed, irritable, anxious, nervous. (3) Somato-vegetative: joint and muscle complaints, sweating, need for more sleep, sleep disturbances, weakness, exhaustion. Heart failure increases with age. Deficiencies of anabolic hormones are common in men with systolic heart failure, leading to reduced exercise capacity, depression, and poor prognosis. But until now the impact of heart failure on the prevalence of AS and the severity of andropausal symptoms has not been studied.

Prof. Ewa A. Jankowska (Wroclaw, Poland) said: ‘AS leads to poor quality of life. We wanted to discover whether heart failure increases AS and whether additional androgen therapies could improve quality of life in heart failure patients’. For the study,1 the researchers compared the prevalence of AS and the severity of andropausal symptoms between 232 men with systolic heart failure aged 40 –80 years and 362 age-matched healthy peers. The magnitude of andropausal symptoms (psychological, sexual, and somato-vegetative) was assessed using the Aging Males’ Symptoms (AMS) Rating Scale and AS was diagnosed if the total AMS score was 50 points or more. They found that AS affected almost one-third of men with heart failure, regardless of their age group. In men aged 40–59 years, heart failure led to a four-fold increase in the prevalence of AS (28 vs. 7%, P , 0.001) and an increase in the severity of sexual and somato-vegetative andropausal symptoms (P , 0.001). Men aged 60 –80 years with and without heart failure had a similar prevalence of AS and severity of andropausal symptoms. Among men with systolic heart failure, the prevalence of AS was similar in both age groups (40–59 and 60– 80 years). The authors concluded that heart failure accelerates the natural process of ageing and favours early onset of AS. Prof. Jankowska said: ‘Heart failure leads to anabolic hormone deficiencies at a relatively young age and thereby accelerates male aging

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component, and can be reduced in the presence of left ventricular hypertrophy and/or scarred myocardial tissue and/or small vessel disease (with normal epicardial arteries). The assessment of absolute blood velocity can be limited in some patients by the large incident angle between the Doppler beam and blood flow. However, calculation of flow reserve allows the assessment of flow patterns without the need for absolute values. More importantly, the velocity ratio is used as a surrogate of flow reserve; flow within the coronary artery is not calculated because cross-sectional visualization of the vessel does not accurately measure the diameter of the vessel. The estimated flow reserve can be accurate if the coronary artery functions only as a conduit, with no change in its diameter during drug infusion. In reality, the diameter of epicardial coronary arteries increases by an average of 30% in healthy subjects following adenosine.1 With these limitations in mind, the assessment of CFR has shown—in single-centre and multi-centre trials—excellent feasibility, close correlation with the invasive gold standard, proved added diagnostic value and incremental prognostic yield when used on the top of regional wall motion during stress. It can have a significant

408 and the development of AS. These patients have poor quality of life and need endocrinology and sexual counselling’. It has been suggested that the anabolic hormone deficiencies in heart failure could be caused by heart failure treatments, which could affect the metabolism of hormones, or comorbidities, which might impair endocrine function. But in a second abstract (61 271) the research group found few and weak associations between the presence of anabolic deficiencies, comorbidities and therapies in men with systolic heart failure. Prof. Jankowska said: ‘This shows that it is the heart failure itself which impacts on the functioning of


the endocrine glands’. She concluded: ‘Further research is needed to determine whether androgen supplementation can reduce the severity of andropausal symptoms’. Andros Tofield

Reference 1. Thaczyszyn M, Nega K, Lopuszanska M, Szklarska A, Me˛dras´ M, Ponikowska B, von Haehling S, Doehner W, Banasiak W, Anker SD, Ponikowski P, Jankowska EA. Andropausal syndrome in men with systolic chronic heart failure. Presented at Heart Failure Congress 2013 Final Programme Number P640.

Stress echocardiography in valve disease

Valve disease is usually considered static and management relies mainly upon resting evaluation. However, most valve diseases have a dynamic component. Exercise testing can induce symptoms and reveal the dynamic of the valve and the ventricle.

of systolic pulmonary arterial pressure .60 mmHg. A significant increase in mitral regurgitation during the test can also be observed.

Primary mitral regurgitation Aortic stenosis Exercise testing is contra-indicated in symptomatic patients. In contrast, it should be performed in asymptomatic patients. Limiting symptoms during an exercise test have been observed in more than one-third of patients who claimed to be asymptomatic. In the elderly population, it is often difficult to ascertain that the symptoms are related to valve disease. The addition of exercise Doppler echocardiography provides incremental prognostic value over resting echocardiographic and exercise electrocardiographic parameters. In particular, a .20 mmHg increase in the mean pressure gradient is associated with a lower event-free survival. In addition, exercise ECHO can identify impaired contractile reserve, diastolic dysfunction, and increase in left ventricular filling pressure. In particular, exercise pulmonary hypertension predicts the occurrence of events.

Aortic regurgitation The role of stress testing in patients with asymptomatic severe aortic regurgitation remains limited. Abnormal haemodynamic responses to exercise and in particular the absence of contractile reserve may be considered.

Mitral stenosis Valve repair or replacement if repair is not feasible is indicated in patients who deny symptoms but exhibit severe exercise limitations. Haemodynamic changes can be identified during exercise echocardiography by an increase of the mean pressure gradient and/or rapid development

Approximately one-third of patients presenting primary mitral regurgitation (MR) show a significant increase in regurgitation severity which is not related to the severity at rest. A ≥15 mL increase in regurgitant volume has been shown to be associated with low symptom-free survival. Exercise pulmonary hypertension may develop in patients with primary MR, even if resting systolic pulmonary arterial pressure is normal. Frequency of pulmonary hypertension is low in asymptomatic patients. Approximately one-half of the population develop pulmonary hypertension at exercise (systolic pulmonary arterial pressure .60 mmHg). Exercise pulmonary hypertension has been shown to predict the onset of symptoms and has been included as a class IIb indication of surgery in the 2012 ESC/EACTS Guidelines.

Secondary ischaemic mitral regurgitation This is not a valve disease, but the valvular consequences of left ventricular dysfunction and remodelling. It results from increased tethering forces and reduced closing forces. Ischaemic MR is dynamic with possible increased or decreased severity during exercise. Exercise-induced changes in an effective regurgitant orifice area and regurgitant volume can be accurately quantified. There is no relation between MR severity at rest and exercise-induced changes. Exercise-induced changes are related to exercise changes in tethering forces. The patients who stop their exercise test because of dyspnoea, when compared with those who stop for fatigue, have a significant increase in an effective regurgitant orifice area accompanied by an increase in systolic pulmonary arterial

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Exercise echocardiography enables a comprehensive functional evaluation of the dynamic component and the haemodynamic repercussions of valve disease says Luc A. Pierard at the EuroEcho Imaging Conference, December 2013



pressure. Dynamic ischaemic MR can also be responsible for the development of acute pulmonary oedema. A .13 mm2 increase in an effective regurgitant orifice area has been shown to be associated with a four-fold increase in mortality and a high incidence of acute heart failure. Although the management of this condition remains difficult, exercise echocardiography could be helpful in patients with systolic left ventricular dysfunction and unexplained dyspnoea or acute pulmonary

oedema, for risk stratification or before bypass grafting in the presence of moderate MR. In summary, beyond symptoms inducible by exercise, exercise echocardiography allows a comprehensive functional evaluation of the dynamic component and the haemodynamic repercussions of valve disease. Jennifer Taylor MPhil

CardioPulse contact: Andros Tofield, Managing Editor. Email: [email protected]

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Controversies in imaging ischaemic heart disease.

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