As people get older, especially women, they often feel dizzy or even faint when they go from sitting or lying down to standing up. This happens because their blood pressure (BP) drops, which can lead to falls, heart problems, and even death in older adults. When BP changes, it affects how well the heart works and how it talks with blood vessels. However, little research has been done on how the heart and blood vessels talk during times of low BP. The crosstalk between the heart and blood vessels is important, as it allows enough blood and oxygen to reach the brain and other vital organs. Some research shows that as we get older, the crosstalk does not work as well. This can make it harder for blood to flow properly or put extra pressure on the heart and arteries. That's why we want to study how the heart and blood vessels talk during a laboratory-simulated situation of low BP in young and older men and women. In our study, participants will lie down with their lower body in a chamber that creates a vacuum around their legs. This safely mimics what happens when you stand up quickly. We can then measure heart function, the stress on arteries, and BP while your legs are in that vacuum. We'll use an ultrasound to check the heart and a finger cuff to measure BP. We'll also see if gripping something firmly can help protect from sudden drops in blood pressure. This study will help us understand more about a condition called orthostatic hypotension and might even suggest that handgrip exercise could prevent it.

The main questions the current study aims to address are:

• Does the cross-talk between the heart and vessels become more impaired with aging during laboratory-simulated conditions of low BP?
• Do women have worse crosstalk between the heart and blood vessels during laboratory-simulated conditions of BP?
• Does hand gripping protect against drops in BP during conditions of low BP?

All participants will be asked to

• Complete two laboratory conditions on two separate days with a randomized order (like flipping a coin):
• Exposure to a lower body negative pressure (LBNP) chamber to safely simulate low BP (control)
• Exposure to a lower body negative pressure (LBNP) while conducting hand-squeezingexercise (experimental).

The investigators will examine how heart and blood vessel interactions, as well as blood pressure (BP) responses, differ in young and older adults of both sexes when exposed to a laboratory-simulated low BP condition (LBNP), both with and without hand squeezing exercise.

Orthostatic intolerance becomes prevalent with advancing age (≤5% below age 50 but ~20% above age 70), and females are 3 to 5% more susceptible. Orthostatic intolerance is associated with syncope, falls, cardiovascular disease, and mortality in older adulthood. The characteristic excessive fall in blood pressure (BP) underlies a complex dysregulation of heart rate (HR), BP, and flow responses to postural changes. When standing, blood pools in the lower limbs, decreasing venous return, stroke volume (SV), and ultimately BP. The resultant unloading of the heart upregulates the sympathetic arm of the baroreflex to increase HR and peripheral vasoconstriction, but this counter-regulation to restore normal BP appears absent or reduced in people suffering from orthostatic intolerance.

Cardiac unloading, which can be accomplished experimentally via lower body negative pressure (LBNP), produces changes in arterial and ventricular loads while attempting to maintain adequate cardiac output. Heart-vessel interactions are, thus, key to understanding BP regulation during cardiac unloading, but have been ignored by research on orthostatic intolerance. The ventricular-vascular coupling framework based on pressure-volume loops describes how heart contractility (i.e., ventricular elastance (Ees)) and arterial loads (i.e., arterial elastance (Ea)), respond to changing loading conditions. With aging, females show greater increases in Ees to match increased Ea, caused by aortic stiffening and high BP. Hence, the coupling ratio (Ea/Ees) is reduced in females, but is preserved in males. However, whether such changes at rest impact the ventricular-vascular coupling response to acute cardiac unloading is unknown, and may be an important mechanism of orthostatic intolerance in females. Notably, the ventricular-vascular coupling framework disregards the wave reflection phenomenon underlying pulsatile pressure-flow relationships. Early reflection of pressure waves, which is characteristic of aging, increases cardiac afterload and thus has important implications for heart-vessel interactions. Such pulsatile arterial load is expected to rise in response to cardiac unloading due to peripheral vasoconstriction, but this remains untested. Importantly, defining heart-vessel interactions during cardiac unloading will shed light on whether plausible ventricular-vascular mismatch contributes to orthostatic intolerance and may help to develop countermeasures to alleviate the symptoms and consequences of intolerance.

Isometric exercise attenuates the cardiac unloading effects via increases in both cardiac output and BP. The pressor response elicited by isometric handgrip exercise increases both heart and arterial load. While isometric handgrip exercise holds potential to counteract BP reduction during cardiac unloading, the augmented work of the heart may limit tolerance. Thus, defining the effects of isometric handgrip exercise on ventricular-vascular interactions under cardiac unloading and the impact of age and sex on these responses will be key to determining its feasibility as an orthostatic intolerance countermeasure.

Therefore, our specific aims are to determine the impact of age (Aim 1), sex (Aim 2), and isometric handgrip exercise (Aim 3) on ventricular-vascular interactions during LBNP-induced cardiac unloading.

• Aim 1's working hypothesis is that older, compared to young healthy adults will exhibit a more pronounced ventricular-vascular mismatch due to greater increases in Ea and Ew not matched by Ees during presyncope- limited LBNP.
• Aim 2's working hypothesis is that older but not younger healthy females compared to males will exhibit a more pronounced ventricular-vascular mismatch due to smaller increases in Ea and Ew and higher Ees during presyncope-limited LBNP.
• Aim 3's working hypothesis is that isometric handgrip exercise will offset BP reductions, but increase ventricular and arterial load during presyncope- limited LBNP.

Inclusion Criteria

• People aged 18-35 years or aged ≥ 65 years
• Healthy without symptons of orthostatic intolerance (i.e., nausea, sweating, weakness, visual disturbance)
• Seated systolic and/or diastolic BP <140/90 mmHg;
• Body mass index <35 kg/m2
• Recreationally active (≤ 2 days of structured physical activity)
• Regular menstrual cycles in young females

Exclusion Criteria:

• People diagnosed with cardiovascular, diabetes, inflammatory or renal diseases and neurodegenerative-related dementia
• Tobacco users
• People prescribed with beta-blockers
• Pregnant females
• People unable to fit or get into the lower body negative pressure chamber

Data obtained in this study may be provided to qualified researchers with an academic interest in orthostatic intolerance. Data or samples shared will be coded, with no personal health information included. Approval of the request and execution of all applicable agreements (i.e., a material transfer agreement) are prerequisites to the sharing of data with the requesting party.

Time Frame: Data requests can be submitted starting 9 months after article publication and the data will be made accessible for up to 24 months. Extensions will be considered on a case-by-case basis.