Doctor checking heart
September 29 is World Heart Day, a day in which people across the globe take part in the world’s biggest awareness event on cardiovascular disease (CVD). CVD prevention and treatment represent critical fight, as CVD continues to be the leading cause of death and disability in the world. Indeed, in 2015, more than 17.3 million people will die from cardiovascular disease.

CVDs are the #1 cause of death globallyAny disease of the heart, disease of the blood vessel, hypertension but also metabolic disease such as diabetes, may result in a chronic heart disease called heart failure that has a prognosis very often as serious as cancer. Interestingly half of these patients have a heart that still contracts normally, representing what is called “heart failure with preserved ejection fraction (HFpEF)”.

This disease is predominantly a disorder of older adults, especially among women with longstanding hypertension or diabetes. And as the population ages, this condition is expected to become the leading cause of heart failure within a decade.

Initial reports about patients with HFpEF date back about 35 years. Since that time a large body of evidence has accumulated showing that patients may suffer from classical signs and symptoms of heart failure even when the exhibit a ‘normal’ ejection fraction and a non-dilated left ventricle. Yet we still know little about understand the pathophysiology of this sub-category of CVD. HFpEF is currently the smallest common denominator indicating that we do not understand the pathophysiology of the disease.

To date, a number of clinical studies have failed to demonstrate any benefit of the drugs that are otherwise effective in heart failure with systolic dysfunction. As we learn more about this disease, there is however a spurring development of new drugs and drug combinations that could finally give us the leverage we need.

A multi-drug approach
What we do know is that HFpEF is characterized by impaired diastolic function as a multifactorial involving several interconnected physiological systems. In response, we are seeing development of drugs that enhance ventricular-vascular coupling by targeting both ventricular and vascular stiffness, as well as underlying inflammation, oxidative stress and ageing related dysfunction. These are expected to benefit treatment of HFpEF, especially when combined with other drugs that target cardiomyocyte stiffness at the level of the myofilaments or energetics.

Since HFpEF is a disease characterized by comorbidities, many of which impact negatively on cardiovascular-renal function, a multi-drug approach will likely prove essential, but the exact combination still needs to be defined. New targets on endothelial dysfunction, impaired nitric oxide-cyclic guanosine monophosphate (cGMP)-protein kinase G (PKG) signaling, and reactive oxygen species (ROS) production on mitochondrial permeability are promising and under development.

As the industry pushes this research forward, it is important to note that underpowered clinical trials should be avoided and study designs should focus on selecting more homogenous patient populations to control for the impact of comorbidities. Epidemiological data should also be gathered on risk factors for prediction of new onset of HFpEF to add further add benefit for the design of clinical trials on the prevention and treatment of HFpEF. New biomarkers and additional end points will have to be validated, and researchers should consider the timing for effective therapeutic intervention as part of the study design.

HFpEF currently represents one of the largest unmet needs in cardiovascular medicine. There is substantial need for new therapeutic approaches and strategies that target mechanisms specific for HFpEF, and the sooner we can ramp up investment in these efforts, the better.
Topics in this blog post: Biopharma, Cardiovascular Disease, World Heart Day
About The Author

Associate Medical Director, Metabolic and Cardiovascular Medical Strategy & Science Unit, Quintiles