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Gender Differences in Physiology: Cardiovascular Virginia H. Huxley, Ph.D. Director, National Center for Gender Physiology University of Missouri School of Medicine Columbia, MO USA Research Support from the National Institutes of Health (NIH), Heart, Lung & Blood Institute, American Heart Association, and the National Areonautics Space Agency (NASA) APS 2006 Refresher Course Surprize! M≠F APS 2006 Refresher Course Definitions: Sex vs. Gender Biology: “Sex” = XX or XY, genomic determination; correct Scientific term. “Gender” = psychological term describing the self-designation of male or female vs. Societal: “Sex” is reproduction and has negative connotation “Gender” is softer and less likely to be misinterpreted. APS 2006 Refresher Course Physiology: Cardiovascular Heart Rate: Women > Men; sleep, rest, exercise Women less tolerant to upright posture or gravitational stress than men - primarily due to reduced ability to maintain venous return and cardiac output. Mechanisms behind sex difference in BP control unknown. In response to cardiovascular stress: Men increase vascular resistance HR*SV = CO = ∆P/TPR Women increase heart rate APS 2006 Refresher Course With Respect to Coronary Function: QT interval longer in Women than Men Atrial Fibrillation > in Men who are heavy drinkers Contractility Women > Men Cardiac myocyte expression of glycolytic & mitochondrial enzymes differs With Respect to Coagulation: Platelet aggregation & secretion change w/ sexual maturity differently in Males & Females With Respect to Blood Lipids: HDL Women > Men After menopause lipid profile more atherogenic Decreased HDL Increased triglycerides APS 2006 Refresher Course Pathophysiology: Cardiovascular CVD kills 2X American Women than from all cancers combined. ~ 500,000 women die from CVD vs. ~ 41,500 by breast cancer. CVD declining but rate of decline for Women < Men; African-American < Caucasian Women Women develop CHD ~10 yr later than Men Men have a greater risk of MI & at earlier ages Ave 1st MI 65.8 yr Men 70.4 yr Women Strokes more common in Women than Men & associated with atrial fibrillation APS 2006 Refresher Course Pathophysiology: Cardiovascular II Cardiac arrest ~ 3x > in Men than Women, but lower recovery and survival rates in Women Cardiac arrhythmias, drug-induced torsades de pointes, and long QT syndrome more prevalent in Women At younger ages, prevalence of CHF > Men; after 75 reverses Women with CHF more likely to have co-morbid diabetes and hypertension than Men. APS 2006 Refresher Course Pathophysiology: Type II Diabetes & CVD Type II Diabetic Women 3-4X more likely to develop CHD 2X risk of a 2nd heart attack have lower E2 & loose “estrogen’s protective effect” experience reproductive problems 2-4X more likely to be African American, Hispanic, American Indian, or Asian Pacific Islander than Caucasian Diabetes associated with low total testosterone in Men high levels of bioavailable testosterone in Women Lower estrogen levels may account for the same rate of kidney and CV disease-related conditions. APS 2006 Refresher Course How could it be that we did not recognize the differences until now? Frequency 70 kg Male Measured variable Caucasian: 18-22 yr, military/athlete or European Medical Student APS 2006 Refresher Course ? What is the physiological basis for these cardiovascular "Sex" differences? APS 2006 Refresher Course More than the Sex Hormones: XX vs. XY Obvious: why only males develop prostate cancer and only females get ovarian cancer Not Obvious: why Females are more likely than Males to recover language ability after suffering a left-hemisphere stroke, or why Females have a far greater risk than Males of developing life-threatening ventricular arrhythmias in response to a variety of K+ channel-blocking drugs APS 2006 Refresher Course Basic truths Every Cell Has a Sex Sex Begins in the Womb Pre-natal environment Testosterone produced first Prepubertal sex hormone differences E2 higher in girls than boys Sex Affects Health Susceptibility/prevalence Natural history Mobility/mortality APS 2006 Refresher Course Estrogen: The (?) Mediator of Sex Differences Estrogen, E2 & Estrogen Receptors ER & ERb Nongenomic, cytoplasmic actions Genomic actions Male/Female differences in receptor distribution E2 Required by Males and Females APS 2006 Refresher Course Estrogen: The (?) Mediator of Sex Differences ERactivation "protective" Re-endothelialization post injury Smooth muscle proliferation & matrix deposition inhibited Lipid profile via prostacyclin production & hepatic actions Reduced function in Males results in impaired vascular tone & coronary arterial calcification Associated with eNOS activation in endothelial cells Polymorphisms in ER identified with advanced cardiovascular disease in both men and women ERb BP regulation Vasodilitation via NO production & NOS gene induction APS 2006 Refresher Course Remember the others…. Thus far we have left out: Progesterone, Testosterone, their receptors 2 PR 1 AR, the aromatases, and d[C]/dt vs. [C] APS 2006 Refresher Course Figure from Mendelsohn and Karas (Science) Progesterone Declines in Women at menopause May partake in variability of vascular tone with menstrual cycle Lowers BP whereas synthetic progesterone elevates BP ? APS 2006 Refresher Course Testosterone Declines with age in Men & Women but more slowly than E2 Increases in E2-deficient Males Androgen replacement therapy (ART) Controversial Improves cardiac ischemic indices in Men W/o effect on peripheral vascular ischemia Lower HDL-C & Lipoprotein (a) Activates AR & ER (via aromatase conversion to E2) Aromatase AR inhibition disrupts regulation of VSM tone in Males Vasodilitation APS 2006 Refresher Course Solution Teach Physiology of what is known Desire to learn the basis for the differences Encourage use of differences to learn mechanisms Hallmarks of disease as means for sussing out pathways Question assumptions Think APS 2006 Refresher Course Basic Physiology: Starling's Law of Filtration in Males & Females Tissue APS 2006 Refresher Course water Blood Starling's Law of Filtration Volume flow is determined by the balance of hydrostatic and osmotic pressures across a semipermeable membrane. Text Book for Water: Pcap Blood p J v L p S P Tissue Gradient Pint ∆P = Pcap - Pint int ∆ = p - int Men & Women are in volume balance, except….. APS 2006 Refresher Course Plasma Protein Total Protein & Albumin by Sex 7.5 “adults” 7 g/100 ml 6.5 6 Males 5.5 Females Males 5 Females 4.5 4 3.5 3 8-19 20-39 40-59 Ag e ranges Geigy Scientific Tables Vol. 3, 1984 p. 140-141 APS 2006 Refresher Course 60-95 “Oncotic Pressure, ” Onsager’s Law: π = FnC Oncotic Pressure 30 25 M ale s Fe males M ale s Fe males 20 15 10 8-19 20-39 40-59 60-95 A ge ranges Text Book for Water: J v L p S P ∆π male > ∆π female APS 2006 Refresher Course Left Heart (Left Ventricle) BP lower in women than men Pcap Right Heart (Right Atrium) Shore AC, Sandeman DD, Tooke JE. Capillary pressure, pulse pressure amplitude, and pressure waveform in healthy volunteers. Am J Physiol 1995;268:H147-H154 APS 2006 Refresher Course Males = Females? J v L p S P Pcap: Females<Males ∆π: Females<Males ∆P APS 2006 Refresher Course ∆ ∆P ∆ Pathophysiology: Hypertension J v L p S P Pcap: Females<<Males Oncotic pressure: Females<Males ∆P APS 2006 Refresher Course ∆ Pathophysiology: Hypertension J v L p S P Assume: Lp and S are the same in M & F in health and disease In fact: Capillary density (S) Hypertensive Males< Females ∆P APS 2006 Refresher Course ∆ ∆P ∆ Males = Females? Female n=55 -lactalbumin Male n=21 * Female n=36 Albumin Male n=25 0 5 10 15 20 Ps x 10-7 cm s-1 From the perspective of Basal Coronary Exchange Properties, Sure, the statistics say males = females…. Huxley, V.H., J-J Wang, and S.P. Whitt. 2005. Sexual dimorphism in the permeability response of coronary microvessels to adenosine. Am J P hysiol Heart Circ Physiol, 288: 2006 - 2013. APS 2006 Refresher Course With respect to response, NO! PADO/Pc 2.0 *** 1.5 1.0 * 0.5 APS 2006 Refresher Course * ** *** ** * * * arteriole venule PADO/P c ° 1, p< 0.5 ° arteriole ° venule Huxley, V.H.,APS J-J Wang, S.P. Whitt. 2005. Sexual dimorphism in the permeability response of 2006 and Refresher Course coronary microvessels to adenosine. Am J P hysiol Heart Circ Physiol, 288: 2006 - 2013. Response to Exercise Influenced by Sex 2.5 * 2.0 2.0 PSADO PSControl * 1.5 1.5 N=35 1.0 N=36 N=35 N=25 * SED EX 0.5 * 2.5 N=9 * N=7 1.0 N=6 * SED EX Arterioles APS 2006 Refresher Course * SED EX 0.5 * N=7 SED EX Venules How can “sex” influence one parameter, permeability response to a stimulus, and not another, basal permeability? APS 2006 Refresher Course 2 Investigators traveling from A to B Temp, °C 40 ND 20 0 2000 6000 10000 14000 miles 2000 6000 10000 14000 miles -20 Rainfall, mm 2000 0 APS 2006 Refresher Course * Temp, °C Rainfall, mm 2000 1000 2000 6000 10000 0 14000 London, UK Moscow, Russia Ottawa, Canada Memphis, USA Monterrey, Mexico Bangkok Brisbane, Australia Tahiti, French Polynesia Christchurch, NZ Christchurch, NZ Temp, °C Rainfall, mm 2000 1000 2000 APS 2006 Refresher Course 6000 10000 0 14000 Just as the direction of travel between London and Christchurch can matter, so too can males and females of the same species be in balance with respect to volume and solute exchange, but not by the same means. Consequences….. APS 2006 Refresher Course Why should Teachers of Physiology care? APS 2006 Refresher Course Signs of Heart Attack: 1. Chest discomfort or uncomfortable pressure, fullness, squeezing or pain in the center of the chest that lasts longer than a few minutes, or comes and goes. 2. Spreading pain to one or both arms, back, jaw, or stomach. 3. Cold sweats and nausea. APS 2006 Refresher Course But, Women often don’t experience the “hallmarks” (only 30%), instead: shortness of breath, nausea, vomiting sleeplessness back pain or jaw pain, and a feeling of generalized weakness, fatigue in weeks prior to Acute MI! Consequently treatment delayed, inappropriate, or wrong leading to preventable deaths. APS 2006 Refresher Course Frequency Future Challenge ~ Reality Measured variable APS 2006 Refresher Course The last 10 years: Differences between Men and Women noted in normal organ functions in health as well as in disease, including diabetes and cancer. The Physiological basis for these differences is unknown. Slow response as the focus has been on differences and similarities between females and males at the societal level by researchers evaluating how individual behaviors, lifestyles, and surroundings affect one's biological development and health. Critical gaps in our basic understanding of sex differences create serious medical and societal shortcomings. APS 2006 Refresher Course