Health Consequences of Circadian Disruption in Humans and Animal Models - Progress in Molecular Biology and Translational Science - page 294

tissue. 214 One factor that may contribute to the manifestation of these phe-
notypes is that clock mutant and bmal1 mice display skeletal muscle and

mitochondrial dysfunction. 215 Abnormal metabolic function, including
altered lipid metabolism, impaired glucose tolerance, and/or insulin resis-
tance can also be observed in mice with a null mutation in the

/

per

gene, 216-222 double cry knockout mice, 223,224 cry1 transgenic mice, 225,226

and rev - erb knockout mice. 227,228 One question left unresolved in these
models is whether the metabolic disruptions develop due to a disrupted
clock per se or atypical synchronization under 24 h LD cycles. Recent
genetic association studies have also provided evidence linking altered clock
function with metabolic syndrome ( bmal1 , 229

clock , 230-234 cry2 , 235,236

per2 , 237 and rev - erb

238

).

4.4. Cardiovascular disorders
Hemodynamic, hemostatic, endothelial, and autonomic variables fluctuate
over the course of the day, with consequences for the peak incidence of car-
diac ischemic events such as angina, acute myocardial infarction, and sudden
cardiac arrest (reviewed in Refs. 239,240 ) . Shift workers display symptoms
of cardiovascular disease, 68,241-244 including atherosclerosis, 245 coronary and
ischemic heart disease, 158,169,171,246-248 infarction, 171,245 myocardial

stroke, 68,249,250 atherosclerosis, 251 left ventricular hypertrophy, 167

and

hypertension. 160,167,252-255

4.4.1 Environmental models
In humans, light at night can acutely increase heart rate and cortisol
levels. 256-263 Simulated conditions of circadian misalignment with and
without sleep deprivation alters cardiovascular function in humans. 190,191
Following inversions of the LD cycle in rats, daily rhythms in systolic blood
pressure, diastolic blood pressure, and heart rate rhythms resynchronize at a
similar rate to the rhythm in locomotor activity. 264 In hypertensive,
cardiomyopathic, and obese rodent models, chronic shifting of the LD cycle
decreases survival, increases blood pressure, and increases expression of car-
diovascular risk factors. 75,265,266

4.4.2 Genetic models
When heterozygote taumutant hamsters are housed under 24 h LDcycles that
conflictwith their inherent period length (22 h), theydisplaymultiplemeasures
of cardiomyopathy, including hypotension, myocyte hypertrophy, interstitial
fibrosis, and collagen deposition. 267

Interestingly, these pathologies are not