Endocrine cvs present copy

Prof. Mahmoud
Youssof
Professor of Cardiology,
Mansoura University
You can contact me at:
myousif200@gmail.com

Agenda
-Introduction
-Endocrine Signals and the Cardiovascular System
-Nuclear Receptors
-Second Messenger Signaling Systems
-Clinical Endocrinology:-
A. Hypertension
B. Metabolic syndrome
C. Obesity
D. Dyslipidemia
E. Thyroid disease
F. Cushing’s syndrome
G. Diabetes and cardiovascular disease
VI. Hormone Replacement Therapy

Normal endocrine function is essential for
cardiovascular health.
Disorders of endocrine system,consisting
of hormone hyperfunction & hypofunction,
have multiple effects on the cardiovascular
system.

• Endocrinologists made great
contributions to understanding the
function of the c.v.s,in heath and
disease.
• Cardiovascular tissues are endocrine
organs, and stimuli that affect the c.v.s.
work through hormone receptors.

Endocrine Signals and
Cardiovascular System

• Endocrine signals that influence the cardiovascular system
can be divided largely into two types:-
(A)mediated by nuclear receptors
(including cholesterol and fatty acid metabolites, steroids,
and thyroid hormones)
(B) cell surface receptors that work by initiating
second messenger signaling cascades (including peptide
hormones, cytokines, and neurotransmitters).

Nuclear Receptors
• They transduce signals of fatty acid and cholesterol
metabolites, vitamins, and bile acid breakdown
products plus actions of the classic steroid and
thyroid hormones.
• They have extensive and overlapping effects on
C.V.S., including:-
- roles in atherosclerotic plaque formation.
-cholesterol and lipid metabolism.
-heart rate, heart function, contractility, and vascular
response.
-also regulate inflammatory responses, which are a
key contributors in the incidence of C.V. disease

Nuclear receptors in c.v. disease
•
Reverse cholesterol transport
PPAR, LXR
Lipoprotein levels
PPARs, LXRs, FXRs, SHP, TRs, ER, AR, VDR
Atherogenic response
PPARs, LXR, ROR, RXR, VDR, ER, AR
Cardiac fibrosis
MR
Blood pressure
MR, GR, ER
Obesity/metabolic syndrome
PPARs, TR, GR, RARs, RXR
Vascular tone
ER, AR, MR
Arrhythmia
TR
Cardiac myopathy
PPARs, TR
SHP, Short heterodimer partner; AR, androgen receptor; ROR,
retinoid orphan receptor; RXR, retinoid X receptor; RAR, retinoic acid
receptor.
.

effects on lipid andlipoprotein metabolism and glucose homeostasis and influences
proliferation, differentiation, and apoptosis.
• PPAR alpha is expressed in liver, muscle, kidney, heart and is involved in
- oxidative degradation of fatty acids.
- mediates actions of hypolipidemic fibrate drugs on plasma lipoprotein metabolism.
-Down-regulation of PPAR alpha is implicated in development of pathological cardiac
hypertrophy .
• PPAR gamma is expressed in intestine and adipose tissue and regulates adipocyte
differentiation and lipid storage.
It mediates actions of ligands of the glitazone class that are used to treat diabetes
and hypertension.
Unfortunately, the glitazones can also lead to obesity.
PPARgamma enhances expression of CD36,which promotes uptake of oxidized LDL
cholesterol into macrophages,
• PPARBeta/Delta is expressed in many tissues, may play a role in adipogenesis.
• In addition, PPARs work in reverse cholesterol transport and inhibit inflammatory
response genes in the immune system and vascular wall with possible uses in treatments
of inflammatory diseases such as atherosclerosis.

• The classic steroid receptors also influence C.V. disease.
• Aldosterone is a well known cardiovascular risk hormone .
(1) aldosterone has deleterious effects on the heart (and on the
kidneys and vasculature) to cause cardiac fibrosis that are
independent of its blood-pressure-elevating activities.
(2) primary aldosteronism is a much more common cause of
hypertension, accounting for as much as 5–10% of cases of essential
hypertension .
Glucocorticoid receptors (GRs) have extensive effects in the metabolic
syndrome but are also classic antiinflammatory hormones
The increasing realization of the importance of inflammatory
response in cardiovascular disease points toward possible roles for
glucocorticoids in medical therapy

• Receptors for androgens (ARs) mediate actions of testosterone
and dihydrotestosterone and have extensive effects on the
cardiovascular system and have a relation to vascular biology,
coronary artery disease, hypertension, cardiac hypertrophy,
cerebrovascular disease, peripheral arterial disease, and other
aspects of cardiovascular biology.
• Estrogen receptors (ERs) mediate diverse actions on the
cardiovascular system .
• These actions involve influences on vasculature, lipoprotein
metabolism, and other systems.

• Interestingly, some of these estrogen effects on
the vasculature may not involve classic effects on
ERs on gene transcription, but may instead involve
nonclassical effect of estrogens at the cell
membrane.
• it was thought that estrogen replacement in
postmenopausal women would prevent
cardiovascular complications, but recent
prospective trials have not supported this.

• Thyroid hormone receptors (TRs) have profound and
direct effects on the heart.
• They can increase the force of cardiac contractility and
are being tested for their ability to treat heart failure.
• TR activation increases the rate of contraction of the
heart and, in excess, can result in atrial arrhythmias.
• TRs have profound effects on lipid , lipoprotein
metabolism.
• TR activation stimulates cholesterol synthesis, promotes
cholesterol breakdown, and elevates (LDL) receptors.
• Despite the increased synthesis of cholesterol, the net
effect is to decrease plasma levels of LDL

Second Messenger Signaling
Systems

. Hormone binding to surface receptors triggers
complex chains of integrated intracellular second
messenger pathways e.g. catecholamines(
ALPHA & BETA receptors) .
• Beta-Adrenergic blockers uses?
• beta-adrenergic agonists uses?
• alpha-adrenergic blockers usrs?

• The renin-angiotensin system
• Angiotensin II has multiple actions,.
• circulating renin-angiotensin system, and local
tissues system
• widespread use of blockers of the system to
treat hypertension,
prevent the progression of renal disease
diabetic
treatment of heart failure.
proteinuria
atrial fibrillation
atherosclerosis and CHD

-Insulin receptors have extensive effects on the
cardiovascular system, including regulation of
vascular resistance.
-Resistance to insulin is a central component of
the metabolic syndrome .

• Atrial peptides are produced in the heart and, to a lesser
extent, in other tissues.
• . These include atrial natriuretic peptide and brain natriuretic
peptide.
• Receptors for these peptides are present in the heart
and peripheral vessels, and they have
vasodilatory actions,
block the renin-angiotensin system,
increase the glomerular filtration rate
enhance sodium excretion.
• they are elevated in heart failure,( measurements for D)

• GH has extensive effects on the cardiovascular system.
• in acromegaly (hypertension, type2 diabetes mellitus, dyslipidemia,
abdominal adiposity, insulin resistance, endothelial dysfunction|)
• Calcium ion levels in the circulation are regulated by PTH that acts on
the cell surface and by vitamin D, whose metabolite acts through
nuclear receptors .
• Calcium ions are involved in regulating blood pressure and numerous
aspects of vascular biology.
• They are also deposited in atherosclerotic plaques.
• the cell membrane also plays key roles in regulation of import and
export of cholesterol into different cells and tissues.
• The dual role of PPARgamma and LXR alpha in regulation of reverse
cholesterol transport via regulation of CD36 and ABCA1 in
macrophages/foam cells is evident.
•

Endocrine causes of hypertension
•
Adrenal-dependent
Pheochromocytoma-,Primary aldosteronism-,Hyperdeoxycorticosteronism
Congenital adrenal hyperplasia
11-Hydroxylase deficiency 17-Hydroxylase deficiency
Deoxycorticosterone-producing tumor
Primary cortisol resistance
Cushing’s syndrome
Apparent mineralocorticoid excess (AME)/11-hydroxysteroid
dehydrogenase deficiency
GeneticType I AME-Type II AME
Acquired
Licorice or carbenoxolone ingestion (type I AME)
Cushing’s syndrome (type II AME)
Thyroid-dependent: Hypothyroidism-Hyperthyroidism
• Parathroid-dependent Hyperparathyroidism
• Pituitary-dependent Acromegaly-Cushing’s DS.
• Insulin-related Insulin resistance
• Renin-related Renovascular disease-
• Renin-secreting tumor-
• Coarctation of the aorta
Perirenal hematoma (Page kidney

• abdominal obesity, insulin resistance,
hypertension,dyslipidemia, and glucose
intolerance (or type 2 diabetes
mellitus).
• Current treatments involve attacking the
individual components, although newer
pharmaceuticals such as the
thiazolidinediones affect more than one
component simultaneously.

• Mechanisms.
• Therapies
• Some endocrinal causes:
cushing syndrome
hypothyroidism

• the endocrinologist can play a specific role with
patients that are difficult to control with standard
regimens and that have unusual phenotypes.
• As with obesity, it is also remembered that
hypothyroidism itself can result in elevations in LDL .
• Cushing’s syndrome can also be associated with lipid
abnormalities, and clinicians need to look for these
conditions when appropriate
• PPAR ,LXR---reverse cholesterol transport?

• Both and hyperthyroidism have deleterious effects on
CVS.
• In hypothyroidism:-
elevations of LDL, hypertension,cholesreol
pericardial effusion , cardiomyopathy and heart failure.
Hyperthyroidism can lead to hypertension, atrial
arrhythmias, including A.F., precipitate or exacerbate angina
pectoris and myocardial infarction, and heart failure.
In addition, up to 15% of women over age of 60 have
subclinical hypothyroidism(elevations of LDL?) .
Furthermore, subclinical hyperthyroidism, may be
associated with an increased incidence of atrial fibrillation.
management with or without H F……????

•Hypertension
•Obesity
•Glucose intolerance

• Relation with C.V. diseases: 2-4 FOLDS
M.I.
CVA
HF
CHD
PVD
MORTALIRT AND MORBIDITY

• both estrogens and androgens have
major effects on the cardiovascular
system.
• there is controversy whether
deficiencies of both of these classes of
hormones, as occurs after menopause
and andropause, result in an increased
risk for developing cardiovascular
complications.
•

• Most clinicians agree that replacement of
androgens is indicated in men with testosterone
deficiency.
But estrogen replacement therapy is controversial.
• recent studies using estrogen and progestin
replacement therapy failed to demonstrate
improvement in cardiovascular risk in
postmenopausal women.
• Because estrogens have complex actions on other
tissues, including bone, uterus, breast, and the
central nervous system, the decision to initiate
estrogen replacement therapy has become more
complex.

Agenda
-Introduction
-Endocrine Signals and the Cardiovascular System
-Nuclear Receptors
-Second Messenger Signaling Systems
-Clinical Endocrinology:-
A. Hypertension
B. Metabolic syndrome
C. Obesity
D. Dyslipidemia
E. Thyroid disease
F. Cushing’s syndrome
G. Diabetes and cardiovascular disease
VI. Hormone Replacement Therapy
VII.PITUIRY GLAND

PITUITARY GLAND AND THE
CARDIOVASCULAR SYSTEM

-pts with prolactinoma may be treated for
decades thus increasing risks of valvulopathy,
including T.R., M.R,, and A.R..
-SO,clinicians are advised to use the lowest
possible doses of dopamine agonists(including
cabergoline, bromocriptime, and quinagolide) ,
with Echocardiographic monitoring.
-Peripartum cardiomyopathy is a rare clinical
entity. It has been suggested that a 16 kDa
prolactin fragment may play a role in its
pathophysiology.
-Case reports have described the use of
bromocriptine in addition to standard heart failure
therapy in peripartum cardiomyopathy.

Growth Hormone
• It acts directly on tissues via interaction with
the GH receptor, and indirectly via stimulation
of insulin-like growth factor type 1 (IGF-1)
synthesis.
• In virtually all cell types, IGF-1 promotes
glucose uptake and cellular protein synthesis.
GH and IGF-1 regulate somatic growth,
including cardiac development and function

• GH Defiency is associated with
increased body fat and central adiposity,
dyslipidemia ,low HDLc,high total cholesterol, and
high LDLc, endothelial dysfunction, and insulin
resistance and Increased carotid arterial intima-media
thickness (IMT).
GH replacement therapy can result in increased
lean body mass and decreased visceral adipose
tissue,and may decrease total and LDLc levels,
Several studies have shown that GH replacement
therapy improves cardiac performance and increases
LV mass, LVEDV, and stroke volume

Acromegaly :-
Hypertension occurs in 20%-50%
increased prevalence of diabetes mellitus.
Cardiac histological abnormalities in acromegaly include myocyte
hypertrophy, interstitial fibrosis, inflammatory cell infiltration, reduced capillary
density, myofibril derangement, and extracellular collagen deposition.
early stage of acromegaly, there is enhanced myocardial contractility
overall increased cardiac performance.
intermediate stage, after about 5 years of active disease, there is
biventricular hypertrophy, diastolic dysfunction, and impaired exertional cardiac
performance.
Late-stage acromegalic cardiomyopathy is characterized by systolic and
diastolic dysfunction, increased myocardial mass, increased systemic vascular
resistance.
• Acromegalic cardiomyopathy is frequently present at diagnosis in two thirds
of patients including about half of all normotensive acromegalics.
• Patients with severe cardiomyopathy may progress to heart failure, with
heart failure seen in 3%-10% of patients.

• Cardiac valve disease (aortic and mitral regurgitation)
is frequent in acromegaly(myxomatous valvulopathy. )
and often persist despite treatment.
• cardiac rhythm abnormalities in acromegaly.
severity of vent. arrhythmias correlates with LV mass.
• Resting ECG changes include left axis deviation,
increased QT intervals, septal Q-waves, and ST-T wave
depression.
• Somatostatin analogs have been shown to reduce QT
intervals, and to improve the arrhythmic profile in
acromegalic patients.

Cushing’s Syndrome and Cardiovascular
Disease
Hypercortisolism is associated with
- HTN,
-central obesity,
-insulin resistance, diabetes
-dyslipidemia(increased lipoprotein (a), HDL
increased triglycerides)
-acne,
-menstrual disorders,hirsutism
-alterations in clotting and platelet function

• Cushing’s syndrome has been associated with
LVH, concentric remodeling, diastolic
dysfunction, and subclinical LV systolic
dysfunction.
• patients may continue to exhibit exercise
intolerance due to steroid-induced myopathy .

THYROID AND THE CARDIOVASCULAR
SYSTEM

cardiovascular hemodynamic changes in overt hyperthyroidism
• decreased systemic vascular resistance (SVR),
• increased H.R.,
• increased cardiac preload, and increased cardiac
output.
(The decrease in SVR activates RAAS, leading to
increased plasma volume and increased cardiac
preload.
Thyroid hormone also promotes an increase in blood
volume via upregulation of erythropoietin secretion,
further enhancing cardiac preload.)
• the increase in cardiac output, which may be 50%-
300% higher than normal .
• Treatment of hyperthyroidism reverses these
hemodynamic changes.

• Hyperthyroid patients often present with
palpitations, sinus tachycardia, atrial fibrillation,
systoli hypertension, widened pulse pressure,
exercise intolerance, and exertional dyspnea.
• Systolic hypertension may be seen in up to 30%
of hyperthyroid patients.
• Sinus tachycardia occurs in approximately 40% of
cases of overt hyperthyroidism.
• Atrial fibrillation is the second most common
arrhythmia in overt hyperthyroidism, and occurs
in 10%-15% of patients, its prevalence increasing
with age

• Hypothyroid patients may present with
mild increased SVR, diastolic hypertension
(20%), narrowed pulse pressure, and
bradycardia.
• Cardiac output may be reduced by up to
30%-40% as a result of decreased stroke
volume and heart rate.

• In hypothyroidism there is resting LV
diastolic dysfunction, and both systolic and
diastolic dysfunction with exertion.
• Pericardial effusions occur in up to 25% of
patients with overt hypothyroidism
• hese pericardial effusions accumulate slowly
---SO,rare cases of cardiac tamponade
• resolve after 2-3 months of thyroid
hormone replacement
therapy.

• Overt hypothyroidism is associated with
accelerated atherosclerosis and CAD .
hypercholesterolemia,
increased LDLc (90% ).
increased Apo B and lipoprotein(a)
VLDL(TG) normal to increased,
HDL are variable
Overt hypothyroidism has also been
associated with hyperhomocysteinemia,
increased C-reactive protein levels, and altered

• ECG changes in hypothyroidism include
sinus bradycardia,
low voltage(small P or QRS complexes),
prolonged PR and QT intervals, and
flattened or inverted T waves,
ventricular conduction abn.

• Amiodarone, causes thyroid
dysfunction in 15%–20% of
treated patients, either causing
hypothyroidism or thyrotoxicosis

• Amiodarone-induced thyrotoxicosis (AIT) is present in
two forms:
type 1 AIT, or iodine-induced hyperthyroidism,
type 2 AIT, or destructive thyroiditis.
Type 1 AIT ---synthesis and release of excess thyroid
hormone,
Type 2 AIT ---- release of preformed thyroid hormone from
the inflamed thyroid gland.
Differentiating between the two forms can be difficult,
Type 1 AIT is managed with antithyroid drugs and possibly
potassium perchlorate.
Type 2 AIT is managed with glucocorticoids, beta-blockade,
and rarely thyroidectomy.

• Baseline thyroid function tests and
thyroid peroxidase antibodies should be
performed prior to initiating
amiodarone, and monitored every 6
months for the duration of
amiodarone therapy.

Congestive Heart Failure and Thyroid
Hormone
• A low serum T3 is the most common thyroid function
abnormality in patients with heart failure(10%–30% ).
• It remains unclear whether this reduction in T3 is an
adaptive or maladaptive process.
• role of thyroid hormone therapy remains unclear in
patients with heart failure and low serum T3 level
• Current areas of research include thyroid hormone
replacement with T3 and/or T4, use of thyroid hormone
analogs (e.g. diiodothyropropionic acid), and gene therapy
to modify thyroid hormone receptor or deiodinase
expression and activity.
•

Hyperparathyroidism and Cardiovascular
Disease
•
--hypertension,obesity,
--glucose intolerance, and insulin resistance.
increased calcium deposition leading to arterial
stiffness(Carotid IMT ).
direct PTH-mediated stimulation of RAAS, PTH-
mediated endothelial dysfunction .
increased sympathetic activity.

• LVH
Calcifications of the aortic valve, mitral valve, and
myocardium
Hypercalcemia, particularly serum calcium >12 mg/dL,
ECG findings include shortened QT and QTc intervals,
increased QRS amplitude, early peaking and gradual
down slope of the descending limb of the T wave,
biphasic T waves, and shortened ST segment intervals.

Hypoparathyroidism and
cardiovascular disease
decreased myocardial performance,
dilated cardiomyopathy,
congestive heart failure
QT prolongation is ECG hallmark of
hypocalcemia,
ST segment elevation, possibly due to
coronary artery spasm.

THE ADRENAL GLAND AND THE
CARDIOVASCULAR SYSTEM
• Hypertension is the clinical hallmark of PA,
Hypokalemia is characteristic .
altered glucose metabolism.
volume expansion from sodium and fluid retention, and
vasoconstriction.
Aldosterone-mediated periv.fibrosis reduces vascular compliance
• measuring plasma aldosterone and plasma renin activity, and
calculating an aldosterone to renin ratio (ARR positive >20 with
aldosterone >15ng/dL), -----confirmatory testing (oral sodium loading,
saline
infusion, fludrocortisone suppression, or captopril challenge).

• maladaptive cardiac remodeling associated with LVH,
cardiac fibrosis, and diastolic dysfunction
• Aldosterone has been shown to directly stimulate cell
growth and cardiomyocyte hypertrophy, promote collagen
deposition, and stimulation of fibroblast proliferation
• Aldosterone blockade reduces LV remodeling and collagen
deposition, improves endothelial function,, and increases
myocardial perfusion
• two landmark randomized controlled trials, the Randomized
Aldactone Evaluation Study (RALES) and the Eplerenone
Postacute Myocardial
Infarction Heart Failure Efficacy and Survival Study
(EPHESUS),
aldosterone blockade was added to clinical guidelines for
TTT of Ch.HF heart failure

Pheochromocytoma and Cardiovascular
Disease
• Hypertension is present in over 50% of patients(sustained
or paroxysmal).
• Higher variability of blood pressure
• a higher incidence of target organ damage.
• increased carotid IMT attributed to the effects of excess
catecholamines on vascular wall growth
• 5 Ps---
• paroxysmal hypertension,
• palpitation,
• perspiration,
• paleness and
• pulsating headache

• Excess catecholamine causer
cardiomyopathy (DCM,HCM,26%),, ischemic
heart disease(VC, increased cardiac oxygen
demand. ),
myocardial stunning,
and, rarely, cardiogenic shock.
• arrhythmias may be seen in 20% of patients
• case reports of tako-tsubo-like apical
dyskinesia

CONCLUSIONS
• Endocrine dysfunction may have a significant
impact on the cardiovascular system.
• Restoration of normal endocrine function
often results in reversal of cardiovascular
changes.
• Hormone-mediated cardiac changes should
be considered when evaluating endocrine
and cardiac patients

Endocrine cvs present copy

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