Huxley

Slide1: 

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)

Surprize!M≠F: 

Surprize! M≠F

Definitions: Sex vs. Gender: 

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.

Physiology: Cardiovascular: 

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 unknown. Heart Rate: Women > Men; sleep, rest, exercise In response to cardiovascular stress: HR*SV = CO = ∆P/TPR

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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 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: Cardiovascular: 

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

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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 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.

Pathophysiology: Type II Diabetes & CVD: 

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.

How could it be that we did not recognize the differences until now?: 

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: 

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

Basic truths: 

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 (?) Mediator of Sex Differences: 

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

Estrogen: The (?) Mediator of Sex Differences: 

Estrogen: The (?) Mediator of Sex Differences ERactivation "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 ER BP regulation Vasodilitation via NO production & NOS gene induction

Remember the others…. : 

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] Figure from Mendelsohn and Karas (Science)

Progesterone: 

Progesterone Declines in Women at menopause May partake in variability of vascular tone with menstrual cycle Lowers BP whereas synthetic progesterone elevates BP ?

Testosterone: 

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

Solution: 

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

Basic Physiology: Starling's Law of Filtration in Males & Females: 

Tissue Blood Basic Physiology: Starling's Law of Filtration in Males & Females

Starling's Law of Filtration: 

Volume flow is determined by the balance of hydrostatic and osmotic pressures across a semipermeable membrane. Starling's 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…..

Plasma Protein: 

Geigy Scientific Tables Vol. 3, 1984 p. 140-141 “adults”” Plasma Protein

“Oncotic Pressure, ” Onsager’s Law: π = FnC: 

“Oncotic Pressure, ” Onsager’s Law: π = FnC

BP lower in women than men: 

BP lower in women than men

Males = Females?: 

Males = Females? Pcap: Females<Males ∆π: Females<Males

Pathophysiology: Hypertension: 

Pcap: Females<<Males Oncotic pressure: Females<Males Pathophysiology: Hypertension

Pathophysiology: Hypertension : 

Assume: Lp and S are the same in M & F in health and disease In fact: Capillary density (S) Hypertensive Males< Females Pathophysiology: Hypertension

Males = Females?: 

Males = Females? From the perspective of Basal Coronary Exchange Properties, Sure, the statistics say males = females….

With respect to response, NO!: 

With respect to response, NO! APS 2006 Refresher Course

Response to Exercise Influenced by Sex: 

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=36 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

Slide30: 

How can “sex” influence one parameter, permeability response to a stimulus, and not another, basal permeability?

2 Investigators traveling from A to B: 

-20 2000 6000 10000 14000 miles 2000 0 Rainfall, mm 2000 6000 10000 14000 miles Temp, °C 0 20 40 2 Investigators traveling from A to B

Consequences…..: 

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 of Physiology care?: 

Why should Teachers of Physiology care?

Signs of Heart Attack:: 

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, : 

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.

Future Challenge ~ Reality: 

Future Challenge ~ Reality Frequency Measured variable Time

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. Critical gaps in our basic understanding of sex differences create serious medical and societal shortcomings. The Physiological 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 one's biological development and health.