1、,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 Associat
2、ion, and the National Areonautics Space Agency (NASA),Surprize! MF,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 negati
3、ve connotation “Gender” is softer and less likely to be misinterpreted.,Physiology: Cardiovascular,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 u
4、nknown.,Heart Rate: Women Men; sleep, rest, exercise,In response to cardiovascular stress:,HR*SV = CO = P/TPR,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 R
5、espect to Coronary Function:,HDL Women Men After menopause lipid profile more atherogenic Decreased HDL Increased triglycerides,With Respect to Blood Lipids:,With Respect to Coagulation:,Platelet aggregation & secretion change w/ sexual maturity differently in Males & Females,Pathophysiology: Cardio
6、vascular,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 1s
7、t MI 65.8 yr Men 70.4 yr Women Strokes more common in Women than Men & associated with atrial fibrillation,Cardiac arrest 3x in Men than Women, but lower recovery and survival rates in Women,Pathophysiology: Cardiovascular II,Cardiac arrhythmias, drug-induced torsades de pointes, and long QT syndrom
8、e 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.,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
9、 E2 & loose “estrogens protective effect” experience reproductive problems 2-4X more likely to be African American, Hispanic, American Indian, or Asian Pacific Islander than CaucasianDiabetes associated with low total testosterone in Men high levels of bioavailable testosterone in WomenLower estroge
10、n levels may account for the same rate of kidney and CV disease-related conditions.,How could it be that we did not recognize the differences until now?,?,What is the physiological basis for these cardiovascular“Sex“ differences?,More than the Sex Hormones: XX vs. XY,Obvious: why only males develop
11、prostate cancer and only females get ovarian cancerNot 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 varie
12、ty of K+ channel-blocking drugs,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,Estrogen: The (?
13、) 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,Estrogen: The (?) Mediator of Sex Differences,ERactivation “protective“ Re-endothelialization pos
14、t 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 calcificationAssociated with eNOS activation in endothelial cells Polymorphisms in ER identif
15、ied with advanced cardiovascular disease in both men and women ER BP regulation Vasodilitation via NO production & NOS gene induction,Remember the others.,Thus far we have left out:Progesterone,Testosterone,their receptors 2 PR 1 AR,the aromatases, anddC/dt vs. C,Figure from Mendelsohn and Karas (Sc
16、ience),Progesterone,Declines in Women at menopauseMay partake in variability of vascular tone with menstrual cycleLowers BP whereas synthetic progesterone elevates BP ?,Testosterone,Declines with age in Men & Women but more slowly than E2Increases in E2-deficient MalesAndrogen replacement therapy (A
17、RT)ControversialImproves cardiac ischemic indices in MenW/o effect on peripheral vascular ischemia Lower HDL-C & Lipoprotein (a)Activates AR & ER (via aromatase conversion to E2)AromataseAR inhibition disrupts regulation of VSM tone in Males Vasodilitation,Solution,Teach Physiology of what is knownD
18、esire to learn the basis for the differencesEncourage use of differences to learn mechanismsHallmarks of disease as means for sussing out pathwaysQuestion assumptionsThink,Tissue,Blood,Basic Physiology: Starlings Law of Filtration in Males & Females,Volume flow is determined by the balance of hydros
19、tatic and osmotic pressures across a semipermeable membrane.,Starlings Law of Filtration,Text Book for Water:,Tissue,Blood,Pcap,p,Pint,int,P = Pcap - Pint, = p - int,Gradient,Men & Women are in volume balance, except,Geigy Scientific Tables Vol. 3, 1984 p. 140-141,“adults”,Plasma Protein,“Oncotic Pr
20、essure, ” Onsagers Law: = FnC,BP lower in women than men,Males = Females?,Pcap: FemalesMales,: FemalesMales,Pcap: FemalesMales,Oncotic pressure: FemalesMales,Pathophysiology: Hypertension,Assume: Lp and S are the same in M & F in health and disease,In fact: Capillary density (S) Hypertensive Males F
21、emales,Pathophysiology: Hypertension,Males = Females?,From the perspective of Basal Coronary Exchange Properties, Sure, the statistics say males = females.,With respect to response, NO!,APS 2006 Refresher Course,Venules,SED,EX,*,*,N=35,N=25,1.0,2.5,1.5,0.5,2.0,P,S,Control,P,S,ADO,SED,EX,*,*,N=35,N=3
22、6,SED,EX,*,N=7,N=6,SED,EX,1.0,2.5,1.5,0.5,2.0,*,*,N=7,N=9,Arterioles,*,Response to Exercise Influenced by Sex,How can “sex” influence one parameter, permeability response to a stimulus, and not another, basal permeability?,-20,2000,6000,10000,14000 miles,2000,0,Rainfall, mm,2000,6000,10000,14000 mil
23、es,Temp, C,0,20,40,2 Investigators traveling from A to B,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,Why should Teachers
24、of Physiology care?,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.,But,Women o
25、ften dont experience the “hallmarks” (only 30%), instead:shortness of breath, nausea,vomitingsleeplessness back pain or jaw pain, anda feeling of generalized weakness, fatigue in weeks prior to Acute MI!,Consequently treatment delayed, inappropriate, or wrong leading to preventable deaths.,Future Ch
26、allenge Reality,Frequency,Measured variable,Time,Differences between Men and Women noted in normal organ functions in health as well as in disease, including diabetes and cancer.,Critical gaps in our basic understanding of sex differences create serious medical and societal shortcomings.,The Physiol
27、ogical basis for these differences is unknown.,The last 10 years:,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 ones biological development and health.,
