Abstract 5937: Cardiovascular Phenotypic Characterization of a Missense Adenylyl Cyclase 6 Genetic Variant in Humans
Adenylyl cyclase (ADCY) is a critical regulator of metabolic and cardiovascular function. The phenotypic effect of a recently discovered hyper-functional ADCY6 S674 variant is unclear. The hypothesis that this variant is associated with a hyper-dynamic cardiovascular system was tested in 12 healthy, normotensive subjects, six known to express the ADCY6 S674 variant and six similarly-aged controls. Forearm blood flow (FBF; ultrasound), blood pressure (Finometer and sphygmomanometry), heart rate, cardiac output, and total peripheral resistance were assessed at quiet rest and in response to hand-gripping exercise (vasodilator response) and orthostatic stress (vasoconstrictor response). At rest, those expressing ADCY6 S674 had higher heart rates (69±7 vs. 62±5 beats·min−1), blood pressures (systolic: 126±8 vs. 113±11 mm Hg; diastolic: 69±7 vs. 61±6 mm Hg; mean: 91±11 vs. 82±5 mm Hg), and cardiac output (3.61±0.62 vs. 3.07±0.53 L · min−1·m2) (all P<0.05). In the ADCY S674 group plasma renin activity was 0.42±0.07 ng·L−1·s−1 compared to 0.25·ng·L−1·s−1 in the controls (P<0.05). There were no differences in plasma norepinephrine and epinephrine (P>0.05). FBF and total peripheral resistance were not different. In response to acute hand-gripping exercise FBF was greater in those expressing ADCY6 S674 compared to the control group (15.9±5.41 vs. 8.9±1.32 ml·min−1·100 ml tissue−1; P<0.01). During orthostatic stress, the decrease in cardiac output was similar between groups (P<0.05). However, the rise in heart rate was greater in the ADCY6 S674 group (~20%) than the control group (~10%) (P<0.05). In contrast, the increase in total peripheral resistance was ~20% (~5 mm Hg · L· min−1· m2) in the controls with little change in the ADCY6 S674 group (P<0.05). During orthostatic stress, those expressing the ADCY6 S674 variant appear to rely on cardiac, rather than peripheral mechanisms for the control of blood pressure. The expression of this ADCY6 variant produces an elevated hemodynamic phenotype both at rest and in response to cardiovascular stressors typical of daily life.