Predictions in Cardiovascular Disease in 2040

ForewordDennis V. Cokkinos, Professor Emeritus (cardiology), University of Athens

Arterial Hypertension – Giuseppe Mancia, Emeritus Professor of Medicine, University Mifano-Bicocca

Heart Failure – What Lies Ahead Dimitris A. SiderisProfessor Emeritus (Cardiology) University of loannina

The Future of the Management of Arrhythmias John CammProfessor of Clinical Cardiology (Emeritus) St. George’s University of London

Interventional Cardiology: Predictions for the Next 20 Years Ulrich SigwartProfessor Emeritus, University of Geneva


Predictions in Cardiovascular Disease in 2040: Foreword

Dennis V. Cokkinos
Professor Emeritus (cardiology), University of Athens
Honorary President of the Association of Professors Emeriti of the University of Athens / Past President of EAPE

By 2020 the first quintile of the 21st century had elapsed. It is customary at such milestones to venture predictions for the future. I can quote four predictions and statements concerning perspectives for the next 20 years.

The Patriarch of contemporary cardiology Eugene Braunwald expressed enthusiastic predictions for the next 10 years as regards coronary artery disease during the European Society of Cardiology annual Congress in 2018. He mainly focused on non-invasive coronary artery imaging and the detection of vulnerable plaques, the use of genomics to define risk with greater precision and target medical treatment. New drugs especially PCSK9 inhibitors for further lowering cholesterol with a 3 or 6 month injection, even starting at 30 years of age have been introduced.

Ortendahl1 et al. offer a less favorable approach; they predict that advancing age and increasing obesity and type 2 diabetes prevalence will raise cardiovascular mortality by 2040, unless acute interventions and pharmaceutical therapies are upgraded. Two more approaches from a social viewpoint must be given: Dame Ann Johnson2 in 2016 stressed that health needs to be valued as a common good, necessitating the participation of individuals in the maintenance of their own health. The clinician scientists of tomorrow are admonished to appreciate the interplay between social, economic, genetic and biological drivers of individual and Public Health.

Many authors continuously, and in 2020 in the Lancet Non-Communicable Diseases and Injuries (NCDI) Poverty Commission argue that for Universal Health to improve a gap must be bridged in the health coverage of the poorest billion of our world’s population. We have asked four expert colleagues, Emeriti Professors to make their predictions for the next 20 years in an equal number of very important aspects of cardiovascular diseases which occupy a large space in today’s efforts.

  • Giuseppe Mancia, (University of Milan-Bicocca), President of the Hypertension Foundation of the European Society of Hypertension will address the continuing population load of hypertension.
  • Dimitris Sideris (University of Ioannina) with great clinical and experimental experience, will discuss the prospects in heart failure.
  • John Camm, (St. George’s University of London) will give his predictions on the future treatment of arrhythmias, which he has been studying over the last many years.
  • Ulrich Sigwart, (University of Geneva), will assess the future of invasive cardiology and the evolution of stents, in which he was pioneer.

They have produced an outstanding and far-reaching statement which will be valuable to all scientists besides physicians. I hope that more predictions as regards the future of medicine will follow.

These considerations are profoundly affected by the Covid-19 pandemic in many ways. Funds for research are preferentially funnelled towards combating the deadly virus. The costs for the vaccines’ production and propagation must be staggering. Joseph Hill3, Editor-in-Chief of Circulation early in 2020 pointed out that our own ways of conducting cardiological research are necessarily being affected.3 The virus also affects the myocardium. Troponin elevation is associated with higher mortality. Moreover, decrease of  acute coronary units in favor of acute Covid-19 units will very probably affect acute coronary syndrome care.

However, it must not be forgotten that cardiovascular diseases still are and will remain the main cause of mortality and morbidity even after the Coronavirus pandemic has been defeated. Our efforts should not abate.

1. Ortendahl JD, Diamant AL, Totb PP, et al. Protecting the gains. Clinical Cardiology. 2019;42:47-55.
2. Johnson Ann. Health of the public in 2040. Lancet. 2016. PIIS014- 6736. (16) 002-64-6.
3. Hill JA, McGuire DK, De Lemos JA. Science in a time of crisis. Circulation. 2020;141:1277-78


Predictions in Cardiovascular Disease in 2040: Arterial Hypertension

Giuseppe Mancia
Emeritus Professor of Medicine, University Mifano-Bicocca
President ESH Foundation/Chairman ESH Educational Board
Chairman, Council of the Italian Scientific Societies for Cardiovascular Prevention

Hypertension has a staggering prevalence around the world and a unanimous prediction is that unfortunately in the next 20 years the number of individuals with a blood pressure (BP) elevation will increase by 20-25%, keeping this condition as the number one cause of death worldwide. This can be opposed by fighting against the increase in the prevalence of factors and comorbidities that accompany and favour a BP increase. It can also be opposed by extending effective antihypertensive treatment to a larger fraction of the world population because of the evidence that lowering an elevated BP protects against virtually all hypertension-related cardiovascular and renal outcomes.

BP can be reduced, albeit to a limited degree, by appropriate lifestyle changes, which are difficult to be extensively implemented, however, because adherence to their prescription is extremely poor, as exemplified by the failure to achieve long-term reduction of an excessive body weight by low caloric diets or physical exercise, and thus to benefit of the documented BP-lowering effect of this measure1. Fifty years of clinical research, however, have resulted into a large number of effective antihypertensive drugs and drug combinations which, in principle, can adequately reduce BP in more than 90% of hypertensive patients, achieving the BP value at which cardiovascular protection is maximized in most of them. Regretfully, however, this is far from what happens in real life, in which BP control does not exceed 15-20% of the global hypertensive population, with uncertain evidence of any substantial time-related improvement in western countries and evidence of a progressive worsening in the much larger low income hypertensive population.

It is now clear that low adherence to antihypertensive drug prescriptions is the most important factor behind this disappointing situation, which keeps hypertension as the first cause of death worldwide. This makes improvement in adherence to BP-lowering treatment a key goal to pursue in the next decades. After being overlooked for years, adherence has become a major topic for research not only in hypertension but also in the other areas of cardiovascular preventive medicine. This has shown that adherence to antihypertensive treatment (as well as to antidiabetic and lipid-lowering treatment) is extremely low and that this leads to a marked increase in hospitalization for cardiovascular events and mortality. Evidence from real life studies has also shown that adherence depends on psychological, socioeconomical and educational factors, that the patient-doctor relationship is primarily involved, but also that the choice of proper treatment strategies plays a key role2. Recent studies, for example, have shown that starting antihypertensive treatment with a two-drug combination markedly improves long-term adherence to treatment compared to starting treatment with monotherapy, with a concomitant substantial longterm reduction of treatment discontinuation, a more frequent BP control and a parallel increase of cardiovascular protection3. An important goal for the next twenty years will thus be to try to make initial drug combinations the most common treatment type for hypertension, at variance from its current use in only a small number of patients. In conjunction with an increased awareness of the protective effect of antihypertensive treatment, an improvement of the doctor-patient relationship and the use of technologies that may 1) remind patients to assume drugs and 2) allow doctors to more timely know BP values and intervene, this might result into a marked improvement of the adherence to and the extent of BP control and cardiovascular prevention.

Future research might further help by providing a more in-depth knowledge of the factors involved in low adherence to treatment at individual level, a better ability to measure adherence in medical practice and perhaps also by discovering other means to effectively reduce an elevated BP. After years of discrepant results it seems clear that device treatment of hypertension, such as renal denervation, can be a helpful adjunctive antihypertensive measure, presumably via reduction of sympathetic cardiovascular control which is high in many patients. There is also the hope that future research will provide agents capable of reducing BP with rarefied (e.g. monthly oral or even parenteral) administrations, a treatment schedule that might substantially minimize the problem of low adherence to preventive treatments and its assessment.

1. Ezzati M, Riboli E. Behavioral and dietary risk factors for noncommunicable diseases. N Engl J Med 2013 Sep 5;369(10):954-64. doi: 10.1056/ NEJMra1203528
2. Chow CK, Teo KK, Rangarajan S, et al. PURE (Prospective Urban Rural Epidemiology) Study investigators. Prevalence, awareness, treatment, and control of hypertension in rural and urban communities in high-, middle-, and low-income countries. JAMA 2013 Sep 4;310(9):959-68. doi: 10.1001/jama.2013.184182.
3. Mancia G, Rea F, Corrao G, Grassi G. Two-Drug Combinations as FirstStepAntihypertensive Treatment. Circ Res 2019 Mar 29;124(7):1113- 1123. doi: A0.116A/CIRCREAAHP.118.313294.


Heart Failure – What Lies Ahead

Dimitris A. Sideris
Professor Emeritus (Cardiology) University of loannina, Greece

In heart failure (HF) the heart is unable to pump sufficiently to maintain blood flow to meet the body’s needs. Its causes vary. Once established, however, the elimination of the cause does not usually result in restoration of normal function, with few exceptions. The mechanism of HF is poorly understood, so that it is not possible to apply a targeted personalized treatment to patients. Up to now favorable results have been observed mainly in cases with reduced ejection fraction but not with preserved ejection fraction. Possible therapeutic approaches will be presented and from the existing trends an extrapolation of the possibilities will be attempted.

Treatment, apart from causative, includes medicines, electrical interventions, transplantation and mechanical assistance and replacement. Digitalis is the oldest drug still used. Because of its narrow therapeutic window and its failure to reduce mortality it is now considered a second-line medication. Several neuro-endocrine interventions have proved promising. Beta-blockers, inhibitors of angiotensin-converting enzyme or angiotensin-receptor blockers are the contemporary standard treatment of choice, neprilysin inhibitors retard degradation of natriuretic peptides; omecamptiv mecarbil activates a cardiac myosin; levosimendan is a calcium sensitizer that may have positive inotropic action; neuregulin-l proteins are important for the development and function of cardiac myocin. Allnheve Saeeivs have yielded positive results in improving survival, symptoms or reducing hospitalizations. Relieving congestion is another important target. Torasemide and bumetanide are considered to be superior to furosemide, a loop diuretic. Acetazolamide, a carbonic-anhydrase inhibitor, and similar diuretics may enhance the distal effects of loop diuretics. Aldosterone antagonists can improve symptoms and reduce mortality. Vasopressin-receptor antagonists (e.g. conivaptan) may treat euvolemic hyponatremia. Reducing afterload may also alleviate the work of the heart. The essential factor for vasoconstriction is nitric oxide (NO), that activates soluble guanylate cyclase (sGC) causing an elevation of intracellular cyclic guanosine monophosphate (cGMP). It is reduced and its degradation is increased in HF. Nitroxyl is a second-generation donor of NO. Vesiciguat is an oral soluble sGC stimulator which increases cGMP production. Both have shown favorable effects in HF. Augmentation of natriuretic peptides (e.g. sacubitril/valsartan) may also alleviate congestion. Sodium glucose cotransporter 2 inhibitors (empagliflozin, canagliflozin) may have beneficial effects in HF even without diabetes. The electrical approaches, pacemakers, defibrillators, ablation, are primarily targeted to treat cardiac arrest rather than HF. Resynchronization treatment is useful in cases with LBBB, while, with normal QRS duration, cardiac contractility modulation using non-excitatory electrical signals has been tried.

The results of using stem cell therapy are inconsistent. They have failed to create new myocardium and their action is considered to be obtained through paracrine mechanisms. In this context mitochondrial transplantation is being tied1.

All the above therapeutic approaches are expected to alleviate HF, but not halt the course of the myocardial and elastic fibers being replaced by connective tissue. Cure is expected with cardiac transplantation. However, even if the problems with rejection are met, the insufficient number of donors is prohibitory. Mechanical assistance and artificial heart, progressing from the intra-aortic balloon pump2 to left ventricular assist devices which are currently used for destination therapy; they offer an exciting field of study of the recovering myocardium with views into possible regeneration pathways.

The total artificial heart3 has had a slow but steady progression. The inexorable course of HF is finally expected to be met only by a similarly steady course of technology, as artificial kidney “cured” renal failure, alone or in combination with gene therapy which in a halting but steadfast way is treading forward.

1. Naim C, Yerevanian A, Hajjar RJ. Gene therapy for heart failure: where do we stand? Curr Cardiol Rep.2013;15:333.
2. Moulopoulos S.D, Topaz S, Kolff W.J. Diastolic balloon pumping (with carbon dioxide) in the aorta – a mechanical assistance to the failing circulation. Am Heart J 1962; 63: 669.
3. Cook JA, Shah KB, Quader MA, et al. The total artificial heart. J Thorac Dis. 2015 Dec; 7(12): 2172-2180.


The Future of the Management of Arrhythmias

John Camm
British Heart Foundation, Professor of Clinical Cardiology (Emeritus) St. George’s University of London, United Kingdom

Today we are usually surprised when an arrhythmia suddenly crops up, seemingly “out of nowhere”, but then we begin to scratch our heads about the investigation, diagnosis and management. We are generally too late to do anything but offer rescue therapy, generally to alleviate symptoms and occasionally to extend life. An arrhythmia is an expression of an underlying disease or condition. Often multiple circumstances can provoke the same arrhythmia and the underlying diseases or disorders usually present long before the arrhythmia emerges. Progressively we will be able to predict the occurrence of an arrhythmia and intervene to prevent its development and the disaster it might provide. Great strides are being made in the epidemiology surrounding arrhythmias, the accurate prediction of arrhythmia occurrence using techniques such as computer modelling and artificial intelligence, the mechanisms supporting them and the identification of the substrates that support the rhythm disorders. Of course, proving that an intervention might deter the appearance of an important arrhythmia in the long-term is fraught with difficulty. Clinical trials of long duration are expensive and difficult to sustain, but registries and trials within registries are beginning to happen and will make it possible to evaluate early therapeutic gambits. Arrhythmia mechanisms are exposed by detailed mapping of the electrical hot spots and circuits within the heart, which will soon be a noninvasive, readily available and appropriate for any and many rhythm disturbances. The substrate for an arrhythmia will be revealed using electrical, biochemical, radiographic and other imaging techniques that are approaching resolutions that will identify irritable and compliant tissues even before an arrhythmia presents.

If we miss the chance to anticipate an arrhythmia, even a clinically silent arrhythmia, it will not lie dormant for long. Modern society is infested with electronic gadgets that can sense disturbances of the heart rhythm. Pulse monitors, plethysmography devices and ECG recorders have been squeezed into vests, phones, watches, rings and other everyday gadgets and garments1. A large proportion of the population will be watched over by these electronic angels, eager to sound the alarm and expose the danger. If arrhythmias are not detected by these inquisitive gizmos, opportunistic and systematic screening will expose them. Dynamic digital, facial, or retinal scans encountered during daily life or purposeful ECG screening of the population-atlarge will reveal rhythm abnormalities or their precursors. The physician/cardiologist will initiate therapy at an early stage and prevent the arrhythmia from becoming a disease in its own right and causing death or disaster in its wake2. What a change this will be – in the “driving seat”, at last.

Not every electrophysiological aberration will support a serious or symptomatic arrhythmia. Risk assessment becomes increasingly important to target the medical resource. Which patient with ventricular premature beats and poor left ventricular function will die suddenly from ventricular fibrillation, which patient with atrial fibrillation will harbour a life-threatening thrombus? Biosensors of every kind are being interrogated to discover those which hold the answers to these secrets. Huge population studies and the big data that these populations furnish will disgorge these truths someday not too far away. The patients that we target for increasingly sophisticated therapies will change out of all recognition- it will be a new world, not brave but better.

For years we have juggled with drugs that are half therapeutic and half poisonous, trying to use them at the right dose and in the right circumstances to tip the balance in favour of success. The search for agents that are more arrhythmia specific with few, if any, off-target effects has been a mantra for antiarrhythmic drug development. Arrhythmias are caused by processes which must be amenable to medical therapy – we have not made the right discoveries yet but the Livingstone spirit to explore and discover will grow strongly in this almost forgotten arena. Many novel ideas and new progress is certain3.

Surgeons demonstrated that it was possible to restore a heart prone to arrhythmia to a normal heart by severing an accessory AV pathway. Almost every arrhythmia can now be tackled using these sophisticated techniques, which are highly dependent on accurate imaging of the heart to identify structural and functional abnormalities, detailed electrophysiological mapping of the heart and easily controllable energy sources. A new form of energy, known as electroporation, has emerged from the field of cancer surgery and offers a method of very careful dosing of energy which may differentiate between tissue types sufficiently to destroy only pathologically disrobed tissue. This success story will continue to expand to levels far in excess of what is happening today.

The watchwords for the future of arrhythmia management are early discovery of arrhythmia and early intervention, highly focussed therapy with few off-target effects and holistic and patient-centred care.

1. Chandrasekaran R, Katthula V, Moustakas E. Patterns of Use and Key Predictors for the Use of Wearable Health Care Devices by US Adults: Insights from a National Survey. J Med Internet Res. 2020 Oct 16;22(10):e22443. doi: 10.2196/22443. PMID: 33064083; PMCID: PMC7600024.
2. Kirchhof P, Camm AJ, Goette A, et al. EAST-AFNET 4 Trial Investigators. Early Rhythm-Control Therapy in Patients with Atrial Fibrillation. N Engl J Med. 2020 Oct 1;383(14):1305-1316. doi: 10.1056/NEJMoa2019422. Epub 2020 Aug 29. PMID: 32865375
3. Heijman J, Hohnloser SH and Camm AJ. Antiarrhythmic drugs for atrial fibrillation: lessons learned from the past and opportunities for the future. Europace (2021) doi: 10.1093/europace/euaa426


Interventional Cardiology: Predictions for the Next 20 Years

Ulrich Sigwart
Professor Emeritus, University of Geneva, Switzerland

Interventional cardiology is a rather young discipline; it was launched not even half a century ago1. Since then it has replaced open heart surgery in the majority of cases. The advantages are lesser morbidity, shorter hospital stay and, in general, lesser expenses. The discipline of interventional cardiology, although employing methods previously reserved for surgeons, is still considered a daughter of internal medicine and cardiologists specializing in interventions are officially still called ‘internists’.

The reasons for this separation reside in historic classifications that are no longer valid. The term ‘internal medicine’ is outdated and ought to be replaced by ‘general medicine’. The coming 20 years will hopefully take into account that the battle between cardiovascular surgeons and interventional cardiologists is coming to an end: both disciplines employ mechanical methods to improve cardiovascular function and the patient’s well-being; their approach may differ, but not to the point of creating separate disciplines. The targets of either discipline are identical; the methods are in the process of merging – I am convinced that in the coming 20 years ‘Interventional Cardiology’ will have separated itself from ‘Internal Medicine’ and merge with ‘Cardiovascular Surgery’ to an entity under the same roof! Such entities do exist already and may simply be called ‘Cardiovascular Centre’. Hybrid units are already established.

What are the targets for improvement?

Ongoing attempts to improve imaging for interventional procedures are likely to be successful in the coming years. This should include higher spacial resolution, reduction of irradiation to patients and operators alike and cheaper production. With more and more transluminal techniques for diagnosis and treatment of all kinds of human pathology such endeavours are of the highest priority.

It appears to me that catheter procedures will develop further in the years to come and require highly sophisticated installations exploited jointly by interventionists with a background in either surgery or cardiology. Targets are new vascular support systems -commonly called stents-, which were introduced to cardio-vascular medicine in 19862. Such endovascular support systems ought to be genuinely anti-thrombotic; they should be elastic with extremely thin walls and improved cover. Ideally such devices should disappear once the artery is stabilized.

For the time being bio-resorbable metals, like special magnesium alloys, are high on the agenda, but the search for even stronger products is ongoing. In the early 90’s of the last century I have tried everything to persuade the industry to focus on thinner stent struts in order to improve hemodynamics and reduce turbulence. With the existing metal alloys limits were obvious, however. In my mind this area will be addressed in the coming years. Removal of atherosclerotic material without the risk of creating embolization will certainly come up with new approaches and drugs inhibiting intimal hyperplasia may hopefully find their place for local delivery as well.

In short, there is reason to believe that transluminal techniques will remain at the forefront of all kinds of therapeutic interventions for years to come.

1. Gruntzig,A Transluminal dilatation of coronary-artery stenosis, 1978 Lancet. vol. 1, no 8058, p. 263.
2. Sigwart U, Puel J, Mirkovitch V, Joffre F, Kappenberger L: Intravascular stents to prevent occlusion and restenosis after transluminal angioplasty. N Engl J Med. 1987;316:701-706