Understanding the performance of the left ventricle requires not only examining the properties of the left ventricle itself, but also investigating the modulating effects of the arterial system on left ventricular (LV) performance. The interaction of the left ventricle with the arterial system, termed arterial-ventricular coupling, is a central determinant of cardiovascular performance and cardiac energetics. Arterial-ventricular coupling (EA/ELV) can be indexed by the ratio of effective arterial elastance (EA;a measure of the net arterial load exerted on the left ventricle) to LV end-systolic elastance (ELV;a load independent measure of LV chamber performance). At rest, in healthy individuals, EA/ELV is maintained within a narrow range, which allows the cardiovascular system to optimize energetic efficiency at the expense of mechanical efficacy. 1. Cardiac Performance at Rest and with Exercise: a longstanding project to measure cardiac volumes via Multi Gated Acquisition Scans (MUGA) at rest and with exercise, has been conducted over many years with multiple measures in individual BLSA participants. The study has now been completed with 341 total subjects and 154 subjects with multiple visits. Analysis is ongoing. 2. Arterial-Ventricular Coupling with Exercise: Resting EA/ELV did not differ between old (70 yr) and young (30 yr) subjects (n=25) because of an increase in EA and ELV in older subjects (Chantler 2009). During exercise, an acute mismatch between the arterial and ventricular systems occurs, due to a disproportionate increase in ELV (from an average of 4.3 to 13.2, and 4.7 to 15.5 mmHg/ml in men and women, respectively) vs. EA (from an average of 2.3 to 3.2, and 2.3 to 2.9 mmHg/ml in men and women, respectively), to ensure that sufficient cardiac performance is achieved to meet the increased energetic requirements of the body. As a result EA/ELV decreases from an average of 0.58 to 0.34, and 0.52 to 0.27 in men and women, respectively. However, with advancing age the reduction in EA/ELV from rest to peak exercise is blunted in older men and women, because of a deficit in the ability to augment ELV during exercise. However, despite limitations in the Frank-Starling mechanism and cardiac function, peak aerobic capacity does not differ by differences in arterial-venous oxygen difference. Therefore, while the change in arterial load during exercise has important effects on the Frank-Starling mechanism and cardiac performance it does not affect exercise capacity (Chantler 2011). 3. Arterial-Ventricular Interaction in the Presence of Nitroprusside: Sodium nitroprusside is a clinically available vasodilating agent that is primarily used in patients with congestive heart failure or with hypertensive crises. Sodium nitroprusside is considered a balanced vasodilator, because, at rest, it lowers LV preload by increasing venous capacitance, and it lowers arterial afterload predominantly by decreasing peripheral vascular resistance. In the heart, sodium nitroprusside enhances LV relaxation through a cGMP-mediated pathway, and it can also increase contractility through a cGMP-independent pathway. We evaluated the effects of sodium nitroprusside on EA/ELV and its components at rest and during graded exercise. Sodium nitroprusside and saline placebo were administered to 15 older (70+/-8years) and 9 younger (31+/-4years) healthy subjects on separate days. EA/ELV was non-invasively characterized as end-systolic volume (ESV)/stroke volume (SV), EA=end-systolic pressure (ESP)/SV, and ELV=ESP/ESV. At rest, in the older and younger groups, sodium nitroprusside respectively lowered EA by 10% (p<0.05) and 4% (p=NS), increased ELV by 47% and 27% (p<0.01), and thus reduced EA/ELV by 31% and 27% (p<0.01) compared to placebo. At peak exercise, sodium nitroprusside did not significantly influence EA in either age group. However, sodium nitroprusside increased ELV by 68% (p<0.01) and 46% (p<0.07) in the older and younger groups respectively, and thus reduced EA/ELV by 36% and 22% (p<0.001) compared to placebo. Importantly, the age-associated deficit in EA/ELV during exercise was attenuated by sodium nitroprusside. Age is the dominant risk factor for cardiovascular diseases. Understanding arterial-ventricular coupling EA/ELV, provides important mechanistic insights into the complex cardiovascular system and its changes with aging in the absence and presence of disease. EA/ELV can be indexed by the ratio of effective arterial elastance EA;a measure of the net arterial load exerted on the LV to left ventricular end-systolic elastance ELV;a load-independent measure of left ventricular chamber performance. Age-associated alterations in arterial structure and function, including diameter, wall thickness, wall stiffness, and endothelial dysfunction, contribute to a gradual increase in resting EA with age. These age-adaptations at rest likely occur, at least, in response to the age-associated increase in EA and ensure that EA/ELV is closely maintained within a narrow range, allowing for optimal energetic efficiency at the expense of mechanical efficacy. During dynamic exercise, EA/ELV decreases, due to an acute mismatch between the arterial and ventricular systems as ELV increases disproportionate compared to EA 200 vs. 40%, to ensure that sufficient cardiac performance is achieved to meet the increased energetic requirements of the body. However, with advancing age the reduction in EA/ELV during acute maximal exercise is blunted, due to a blunted increase ELV. This impaired EA/ELV is further amplified in the presence of disease, and may explain, in part, the reduced cardiovascular functional capacity with age and disease. Thus, although increased stiffness of the arteries itself has important physiological and clinical relevance, such changes also have major implications on the heart, and vice versa, and the manner in the way they interact has important ramifications on cardiovascular function both at rest and during exercise. Examination of the alterations in arterial-ventricular coupling with aging and disease can yield mechanistic insights into the pathophysiology of these conditions and increase the effectiveness of current therapeutic interventions.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Investigator-Initiated Intramural Research Projects (ZIA)
Project #
1ZIAAG000802-21
Application #
8552481
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
21
Fiscal Year
2012
Total Cost
$79,760
Indirect Cost
Name
National Institute on Aging
Department
Type
DUNS #
City
State
Country
Zip Code
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