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Resistant hypertension affects 8.9% to 33% of all persons with hypertension, and is associated with higher risks of death, major cardiovascular events, left ventricular hypertrophy, progressive kidney disease, and cognitive impairment. Guidelines recommend diagnostic work-up for resistant hypertension including assessment of the renal vasculature but rates of diagnostic studies in real-world practice are not well known. From a cohort of patients with resistant hypertension (n = 4660) from 2008-2016 prior to the founding of the Stanford Hypertension Center, we quantified assessment of renovascular disease. We observed that 2.5% (n = 118) of the patients had an abdominal magnetic resonance imaging (MR abdomen) performed, and were of ages 45-92, 61% male and 39% female. Although all 118 of these patients had an MR abdomen after their index date of resistant hypertension (their most recent MR abdomen was taken an average of 7.4 years after their index date), only 36% (n = 43) of these 118 patients had imaging reports that described the renal arteries in the body or the conclusion of the report. Of these 43 patients, 7% (n=3) had MR records describing renal artery stenosis. In comparison, 100% (n = 263) of kidney donors who had had an MR abdomen performed during the same interval (2017-2021) had imaging reports that described their renal arteries. Full clinical descriptions of cohorts will be provided. Since abnormalities in renal vasculature can cause hypertension, this lack of renal artery description in imaging reports of patients with resistant hypertension may reveal missed opportunities in multidisciplinary communication and/or in the use of imaging to assess for causes of resistant hypertension. This missed opportunity for diagnosis of renovascular disease is similar to the low screening rates for primary aldosteronism as a cause of resistant hypertension, previously found at Stanford and across the US.

Clamp loaders are AAA+ ATPases that load sliding clamps onto DNA. We mapped the mutational sensitivity of the T4 bacteriophage sliding clamp and clamp loader by deep mutagenesis, and found that residues not involved in catalysis or binding display remarkable tolerance to mutation. An exception is a glutamine residue in the AAA+ module (Gln 118) that is not located at a catalytic or interfacial site. Gln 118 forms a hydrogen-bonded junction in a helical unit that we term the central coupler, because it connects the catalytic centers to DNA and the sliding clamp. A suppressor mutation indicates that hydrogen bonding in the junction is important, and molecular dynamics simulations reveal that it maintains rigidity in the central coupler. The glutamine-mediated junction is preserved in diverse AAA+ ATPases, suggesting that a connected network of hydrogen bonds that links ATP molecules is an essential aspect of allosteric communication in these proteins.

Clamp loaders are AAA+ ATPases that load sliding clamps onto DNA. We mapped the mutational sensitivity of the T4 bacteriophage sliding clamp and clamp loader by deep mutagenesis, and found that residues not involved in catalysis or binding display remarkable tolerance to mutation. An exception is a glutamine residue in the AAA+ module (Gln 118) that is not located at a catalytic or interfacial site. Gln 118 forms a hydrogen-bonded junction in a helical unit that we term the central coupler, because it connects the catalytic centers to DNA and the sliding clamp. A suppressor mutation indicates that hydrogen bonding in the junction is important, and molecular dynamics simulations reveal that it maintains rigidity in the central coupler. The glutamine-mediated junction is preserved in diverse AAA+ ATPases, suggesting that a connected network of hydrogen bonds that links ATP molecules is an essential aspect of allosteric communication in these proteins.