Gender Differences in Physiology: Cardiovascular

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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)
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Surprize!M?F
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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.
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Physiology Cardiovascular

• Heart Rate Women gt 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

HRSV CO ?P/TPR
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With Respect to Coronary Function

• QT interval longer in Women than Men
• Atrial Fibrillation gt in Men who are heavy
  drinkers
• Contractility Women gt 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 gt Men
• After menopause lipid profile more atherogenic
• Decreased HDL
• Increased triglycerides

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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 lt
  Men
• African-American lt 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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Pathophysiology Cardiovascular II

• Cardiac arrest 3x gt 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 gt Men after
  75 reverses
• Women with CHF more likely to have co-morbid
  diabetes and hypertension than Men.

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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 estrogens 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.

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How could it be that we did not recognize the
differences until now?
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?
What is the physiological basis for these
cardiovascular "Sex" differences?
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More than the Sex HormonesXX 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

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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

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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

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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

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Remember the others.

• Thus far we have left out
• Progesterone,
• Testosterone,
• their receptors
• 2 PR
• 1 AR,
• the aromatases, and
• dC/dt vs. C

Figure from Mendelsohn and Karas (Science)
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Progesterone

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

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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

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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

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Basic Physiology Starling's Law of Filtration in
Males Females
Tissue
Blood
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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
Tissue
Gradient
Blood
Pcap
Pint
?P Pcap - Pint
?p
?int
?? ?p - ?int
Men Women are in volume balance, except..
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Plasma Protein
adults
Geigy Scientific Tables Vol. 3, 1984 p. 140-141
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Oncotic Pressure, ? Onsagers Law p FnC
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BP lower in women than men
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Males Females?

• Pcap FemalesltMales

• ?p FemalesltMales

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Pathophysiology Hypertension

• Pcap FemalesltltMales

• Oncotic pressure FemalesltMales

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Pathophysiology Hypertension
Assume Lp and S are the same in M F in health
and disease
In fact Capillary density (S) Hypertensive
Maleslt Females
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Males Females?
From the perspective of Basal Coronary Exchange
Properties, Sure, the statistics say males
females.
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With respect to response, NO!
APS 2006 Refresher Course
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Response to Exercise Influenced by Sex

2.5
2.5

2.0
2.0
ADO

P
S
Control
P

S
1.5
1.5

N7
N35
N35
N9
1.0
1.0
N25
N36
N7
N6



SED
EX
SED
EX
SED
EX
SED
EX
Venules
Arterioles
0.5
0.5
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How can sex influence one parameter,
permeability response to a stimulus, and not
another, basal permeability?
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2 Investigators traveling from A to B
Temp, C
40
20
0
2000
6000
10000
14000 miles
-20
Rainfall, mm
2000
0
2000
6000
10000
14000 miles
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(No Transcript)
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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.
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Why should Teachers of Physiology care?
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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.
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But,

• Women often dont 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.
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Future Challenge Reality
Frequency
Time
Measured variable
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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.