Download Systemic and Pulmonary Artery Compliance: Lessons

Systemic and Pulmonary Artery Compliance: Lessons learned and
Implications for the Treatment of HFpEF
David A. Kass, M.D.
Abraham and Virginia Weiss Professor of Cardiology
Professor of Medicine, Biomedical Engineering, and Pharmacology and Molecular Sciences
Johns Hopkins University School of Medicine
Baltimore, MD, USA
The heart provides a given stroke volume with each beat, and to dampen its
pulsatile impact on circulatory pressure and flow, arteries are compliant. More than a half
a century ago, researchers realized that declines in systemic vascular compliance with
aging was common, particularly in Westernized societies. This augments pulsatile
perfusion to organs and imposes high late-systolic loads on the heart. The mechanical and
energetic consequences of vascular stiffening were then identified, and with respect to the
heart, recognition came that ejecting into a stiff arterial system reduces cardiac efficiency
and requires countering ventricular systolic stiffening to preserve ventricular-vascular
coupling. This combination, observed with aging and more in women, leads to acute load
and heart function instability. Other studies assessed the effects of pulsatile pressure/flow
on vascular tone and endothelial regulation. A critical role of both nitric-oxide dependent
and independent signaling on resistance artery tone from cyclic arterial stretch was
revealed and shown to be separate from established shear stress mediated effects.
However, pulsatile perfusion in vessels unable to stretch – e.g. aged, stiff – led to defects in
these vasoactive signals, suppressing endothelial protection against oxidative stress.
The pulmonary circulation also imposes pulsatile load, and more recent studies
have examined this load, how it differs from the systemic circulation, and the impact of
pulmonary hypertension. Unlike the systemic circulation, where the arteries that stiffen
are not the same ones responsible for resistance, both properties reside principally in the
same peripheral vessels in the lung. While aging stiffens systemic arteries, its impact on
lung vessels is much less. This results in tight coupling of resistance and compliance and
has implications for the treatment of PAH. Also unlike the systemic circulation, the
downstream pressure for the pulmonary circulation, left atrial pressure (or PCWP), is
much higher relative to mean artery pressure, and so itself impacts the net pulsatile load.
All of this pathobiology is particularly relevant to the syndrome of heart failure with
a preserved ejection fraction (HFpEF), impacting over 15 million patients worldwide. This
syndrome is really a compendium of co-morbidities, some of the heart, but also of other
organs, including the lung as PAH is common. No targeted treatments have yet been
successful, but new insights into signaling pathways, and understanding the interaction of
vascular stiffening, ventricular remodeling, and inflammatory and metabolic defects
common in affected patients, is leading to new therapy efforts. Alas, directly de-stiffening
systemic vessels has proven very difficult, and it may be too late once this has settled in,
while the lung presents different challenges. However, approaches to molecularly reverse
the negative impacts from vascular stiffening may work, and exciting times lie ahead.