Identifying needs and opportunities for advancing translational research in cardiovascular disease

In Western Europe, as in the USA, mortality of cardiovascular disease (CVD) has declined significantly in the last 30 years. Life expectancy for patients with coronary heart disease in the USA increased on average by 3 years between 1970 and 2000.1 Several epidemiological analyses support this positive evolution. An analysis of the underlying causes identifies improvements in quality of care and treatment as a major cause, accounting from 50 up to 75% of the success depending on the study samples, the remainder being accounted for by changes in lifestyle and prevention.2 Research and development in several areas of CVD have contributed to this success. In acute coronary events, the identification and development of efficient and safe thrombolytic agents followed by percutaneous coronary intervention with stent implantation were milestones in the reduction of acute mortality and salvage of myocardium.3–5 Statins have brought a major advance in preventing the progression of atherosclerotic disease and have been recognized for their wide mode of action.6 In heart failure (HF), beta-blockers and ACE-inhibitors have increased life expectancy by a leap.7 Some of these improvements have been the result of a classic bench-to-bedside development of a targeted treatment, such as the statins, others have known a more serendipitous development, such as beta-blockers. In other areas, progress in terms of treatment has been less spectacular and fraught with difficulties. Development of antiarrhythmic agents received a large boost from basic insights into cardiac ion channel structure and function, but translation into pharmacology unveiled unexpected pro-arrhythmia risks of some of the highly specific ion channel blockers in class III.8 Automatic defibrillators have taken an important role in the treatment of life-threatening arrhythmias and save lives, but are not without burden and come at a high cost.9 This latter example is but one highlight of the more sobering and darker side of this medical success story: the improved survival and quality of life of patients with CVD comes at a high economic cost. In the US hospitalizations for CVD have tripled and the cost of care is estimated at 386 billion USD per annum (AMA, Kaiser Family Foundation). Within the EU, the annual cost for healthcare systems for CVD was just under €110 billion in 2006 (British Heart Foundation statistics at www.heartstats.org). Interventions, device therapy, and imaging take up a large share of the cost. Ageing of the population, without further improvement in care and prevention, will lead to a high increase in prevalence of CVD. This is already noticeable in the statistics of the last 10 years, showing a decrease in mortality but an increase in prevalence.10 In addition, in countries with less access to medical care, the incidence of CVD is rising and is expected to continue to increase dramatically.11,12 The WHO has estimated that rising life expectancy coupled with adverse trends in major cardiovascular risk factors including obesity and type II diabetes could lead to a doubling in the absolute incidence of CVD by 2050. There is thus a clear need for continued investment into improving our approach to CVD and thus into cardiovascular research. In addition to the remaining need, the major progress that has been made constitutes a strong incentive for priority funding of cardiovascular research in order to build on this success. Addressing the economic need to contain cost, as well as the necessity to provide better care for a growing patient population, a new paradigm is put forward focusing on promoting health and intervening at the early onset of CVD.13,14 This requires that we (i) improve our physiological and molecular understanding of mechanisms of health and disease so we can implement earlier preventive interventions and better-targeted diagnosis and therapy, (ii) that we develop personalized preventive and therapeutic regimens, and (iii) that we streamline the processes involved in translating knowledge into practice to accelerate implementation of new knowledge. The concept of translational research can be interpreted and defined in many ways by scientists. A consensus view is that the end-target of translational research is the patient, with the goal to improve care. The classic or traditional one-dimensional track of translational research is a sequence of events: discovery of a new mechanism and potential therapeutic target in an experimental or basic research setting, with a drug or device being developed, the approach being validated in the clinical setting and eventually being introduced into clinical practice. This concept is still valid, but in recent years it has come under increasing pressure. The drug development and validation in clinical trials come at a huge cost, largely carried by industry, and in a number of cases, the expected clinical benefits have been disappointing. For example, the development of the CETP inhibitor, torcetrapib, was halted in 2006 when phase III studies showed excessive mortality in the treatment group receiving a combination of atorvastatin and the study drug.15 Therefore, the willingness of industry to take risks has decreased. In this ‘traditional’ approach, the principal actors partake in sequence: basic, industry, and clinical researchers. More recent models of translational research give up on this traditional sequence and can start, for example, from clinical data, feeding into experimental or basic research for further mechanistic insight, or from clinical observations on unexpected drug effects, feeding into new applications (‘reverse’ translational research), with many variations in iterative interactions between the different stages, as illustrated in Figure 1. In the traditional process of translation, basic research is the first step to identify new mechanisms of disease and potential targets for therapy that are elaborated in a proof-of-concept and eventually validated in a clinical trial. In reverse translation, this process starts with a clinical observation that is tested in basic experimental research and a proof-of-concept, with re-iterative steps validating new concepts. Such approaches have been quite successful, as can be illustrated by the example of post-conditioning as a mechanism of cardiac protection. 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