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ESC Rene Laennec Lecture on Clinical Cardiology: Prof. Milton Packer

Foetal recapitulation and cellular stress in the evolution and progression of heart failure

25 Aug 2023

The presenter of this year’s ESC Rene Laennec Lecture in Clinical Cardiology is Professor Milton Packer (Baylor University Medical Center - Dallas, USA), whose many contributions to the field of heart failure (HF) include enhancing our understanding of its mechanisms and defining its rational management.

What first made you interested in cardiology?

I have always loved physiology and finding out how the body works, both when it is healthy, and, particularly, when it is not. In patients with heart disease, it is important to see not only the disease process, but also the body’s response to it. If the body compensates well, it can curb the disease but if it compensates poorly, it can exacerbate the disease mechanisms.

My early work in HF focused on mechanisms and pathophysiology. HF is particularly interesting, since it is a system of biological chaos that typically unravels slowly, allowing us to decipher the pieces of the puzzle. If you want to understand the heart, it is critical to study it when it is under severe stress.

When I first started my career in cardiology, pathophysiology was the dominant theme. However, in recent decades, the focus in cardiology has fractured into two domains: one focused on molecular mechanisms and the other on clinical trials. A study of pathophysiological mechanisms lies in the middle – few cardiologists are interested in these mechanisms in the current era, but I think this is an important area to focus on.

What are the key themes of your lecture?

I have spent most of my career leading large-scale randomised controlled clinical trials that have developed the key foundational drugs for the treatment of HF. I have resisted the temptation to discuss these milestones since it would just yield a talk that everyone has already heard many times. Thirty years ago, in 1992, I proposed the neurohormonal hypothesis of HF and that framework has served us very well. But now we need a new and more comprehensive framework – my lecture will discuss a novel ‘cellular stress hypothesis of HF.’

So what is the ‘cellular stress hypothesis of HF’? When the heart is injured, it recapitulates its foetal programming and although this is useful during in utero development, it is highly deleterious when expressed in the adult heart, which lives in a high-oxygen high-workload environment. It has long been assumed that this foetal reprogramming is adaptive, but recent work indicates that it is the primary cause of cellular stress in the failing heart. The accumulation of cellular stress and the inability to deal with this stress is responsible for many of the abnormalities that we see in HF. A greater understanding of the foetal recapitulation process and its implications for cellular stress may enable us to find novel and highly important targets for the management of HF.

I realise that the Rene Laennec Lecture is typically focused on clinical cardiology but I think that it is timely for clinical cardiologists to talk about and understand mechanisms. My goal is to inspire my colleagues to think about HF differently.

What are the challenges in the current and future management of HF?

Although we have been remarkably successful in developing new drugs for HF, the unfortunate reality is that most patients do not receive optimal treatment. Lack of access and cost of drugs are key contributors, but the most important issue is the lack of an effective workforce. We do not have enough physicians who can devote the necessary time to implement the relatively complex algorithms required for the optimal care of patients with HF. The problem will get worse as the population ages and as cost constraints on health systems become even more limiting.

The solution lies in the development of a new workforce of highly trained, non-physician specialists. This requires our urgent attention, since it is the only way that we can deliver adequate care to millions of people with HF.