Cardiovascular Flashcards
What are some key characteristics of IUGR (Intrauterine Growth Restriction)?
Low birth weight <2500g
Placenta insufficiency leads to this
<2SD below population mean
Why are babies born small?
Uteroplacental insufficiency
Maternal undernutrition (Majority 3rd world)
Maternal disease
Genetic
babies born small have an increased risk of developing……
Adult diseases such as Obesity and Diabetes Osteoporosis Cardiovascular Disease Renal Disease
Describe what happens in accelerates postnatal growth
90% of small babies have accelerated growth in first 6 months
Early growth=protective, Late growth=adverse problems
Critical periods for this are during lactation/after wearing/after puberty
What are the differences between males and females with uteroplacental insufficiency?
Males have an increase in BP and glucose intolerance compared to women
What is an intervention that aids in delaying the onset of these adult diseases?
Exercise and Nutrition
How is exercise relevant and what occurs when exercise is used to reduce disease?
Early exercise leads to partial restoration of cell masses with full restoration by 24 weeks
Late exercise leads to full restoration from childhood deficits
What is the timeline of events that occur with uteroplacental insufficiency and overall adult disease susceptibility
Decrease in nutrient supply Leads to decrease in mammary development Leads to fatal growth restriction, decrease in lactation Leads to postnatal growth restriction \+possible late accelerated growth =increase in adult disease possibilities
What is the transgenerational programming idea?
That effects of adults born small are not limited to affect the first generation but could be transmitted to subsequent generations
F1 females born small when pregnant have…
Glomerular hypertrophic
Vascular adaptations
Impaired glucose tolerance
Future diabetes risk
F1 females born small have higher changes of passing certain traits to their offspring. Name 2 of these traits
Smaller F2 foetus
F2 pancreatic and nephron deficits- nephron deficits have been found to be restored after time leading to a possible delayed nephrogenesis
Maternal stress during pregnancy is associated with…
F2 fatal growth restriction
Decreases placental weight
Describe problems associated with an F2 generation of F1 small babies
Decreased nephron number
Increased BP (males)- females not affected
Decrease beta cell mass in males and increased in females
Decrease in insulin secretion
What do obese women have an increased susceptibility in pregnancy with?
Diabetes, Preeclampsia and Gestational hypertension
Define obesity
Inflammatory condition
BMI>30
Increased risk of co-morbidities (cardio disease, diabetes, metabolic disease etc.)
Describe Adipose tissue and the cells within it
Adipocytes secrete many proteins (Cytokines, Chemokines and Hormone-like factors)
What are Adipokines?
Secreted by Adipose tissue
Anti-inflammatory
Increased calorie intake results in adipocyte hyperptrophy
Due to being exposed to an increased inflammatory response when the mother is obese during pregnancy, what is at greater risk for the child?
Greater risk of developing obesity due to this exposure
What is the question that has been circulating in regards to the microbiome and obese women?
Is there a difference in obese maternal microbiomes that can impact maternal/fetal health?
How does maternal gut microbiota differ between women with normal weight and obesity?
Increase in Staphylococcus and E.Coli in the latter half of pregnancy
Fathers disease susceptibility can be transmitted to …..
His children down the paternal line
Even though there has been minimal studies, how do obese fathers effect their offspring
Increased Adipose to
Decrease in glucose tolerance and increase in insulin sensitivity- leading to Diabetes
Male infertility
Can be transmitted up to 2 subsequent generations
What happens to males who are born small and consume high fat diet?
Increased renal dysfunction
What happens to the size of growth restricted females varying on their diet?
Nothing, they remain small
What intolerance do growth restricted females offspring have with an high fat diet?
Glucose intolerance
What is Leptin and what is its function?
Small protein secreted by adipocytes
For the maintenance of hunger
Reflects Adiposity
Maintains hunger
Reduces hypertension except in Chronic leptin where there is an increase in BP
Modulates renal sodium handling, increase however in Chronic leptin
Decreases Na/K-ATPase activity
Describe the Leptin signalling pathway
Leptin sends signals to 2 sets of neurons in the Arcuate nucleus
POMC neurons- decrease food intake
NPY neurons- increase food intake
Describe leptin signalling and what receptors are involved
Leptin receptor- ObR
6 different ISO forms (a-f)
Larger extracellularly and small intracellularly
ObRb activates signalling pathways
Describe the signalling pathways of Leptin signalling
ObRb activates…
JAK/STAT- cell growth and proliferation
MAPK- cell growth and differentiation
PI3K- cell growth, proliferation and differentiation
What altered signalling pathways produces a reduction in hypertension?
Leptin signalling, through experiments it can be seen that leptin directly or something leptin regulates is controlling BP
What are the functions of the kidney?
Reabsorb nutrients, excrete wastes, regulate blood pressure and volume, secrete hormones
What is the function of the Glomerulus?
To filter proteins
What is Albumin?
Protein that maintains oncotic pressure, driving force of movement from lympathatics to circulation
What happens with an exposure of acute leptin?
Increase in Na excretion
What is Megalin?
Scavenger receptor in the proximal tubule
Binds ligands such as Albumin, Leptin and Vitamin D
Acts as a signal transducer
Also can contribute to gene regulation
What happens to the Glomerulus when there is an increase in plasma leptin?
It decreases the ability to filter the good stuff through to maintain normal concentrations
What is AMPK?
AMP activated protein kinase
Regulator of cellular energy homeostasis
What are the three components that make up blood pressure?
Individual environment, shared environment and genes
Describe some common non-coding variants
Transcription factors
Enhancers
Silencers
Insulators
How much more/less leptin is there in obese people?
5x more
Name the two interventions for ischaemic heart disease
Surgical and pharmacological
What are some surgical interventions used for ischaemic heart disease
Angioplasty
Coronary artery bypass grafting
Name some pharmacological interventions for ischaemic heart disease
Anti-thrombotic, nitrates (angina), ACE inhibitors or Statins (cholesterol lowering)
What are pluripotent stem cells and their 2 classes?
Two classes of stem cells that can be moulded to form any cell in the body.
Embryonic stem cells- Derived from inner cell mass of blastocyst, allogeneic transplanation
Induced pluripotent stem cells- From somatic cells that are reprogrammed, Autologous transplantation
What are the pros and cons of pluripotent stem cells?
Pros- Unlimited proliferation potential, can differentiate into all cel types, high cardiogeneic potential
Cons- risk of tumour formation through contamination of pluripotent cells
Risk of arrhythmia due to immature phenotype when implanting from another person
How do pluripotent stem cells differentiate into cardiomyocytes?
Through growth factors and signalling pathways such as TGF-beta pathway, Nodal signalling pathway
What can Adult stem cells be differentiated into?
Skeletal muscle, bone marrow, peripheral blood, fat, umbilical cord, brain
What are the pros and cons of Adult stem cells?
Pros- Multipotent, low risk of Timor formation, autologous, low risk of rejection, readily available
Cons- Low cardiogenic potential, risk of arrhythmia, limited proliferation potential- when you push them too far unlike pluripotent they become aged and stop growing
What are skeletal myoblasts?
Undifferentiated cells in muscle
Showed improved cardiac function when differentiated into myocytes, however ventricular arrhythmia was reported due to lack of gap junctions and specific structures needed for electrical coupling with host cardiomyocytes
What are bone marrow derived cells?
Cells containing mesenchymal stem cells
Modest improvement in cardiac function and safe
What are adipose derived mesencephalon stem cells?
Multipotent stem cells from fat tissue, easily obtained, modest improvement in cardiac function with no major complications
What are cardiac resident stem cells?
Isolated form heart tissue, showed promising outcome with a reduction in infarct size and improved cardiac function
What are all the classes for stem cells?
Pluripotent Stem Cells
-Embryonic stem cells
-Induce pluripotent stem cells
Adult Stem Cells
What are the 3 stages of infract healing following an ischaemic insult
Inflammation- myocyte death, immune cells enter (high risk of wall rupture with large amounts of breakdown)
Proliferation- Angiogenesis (factors released to promote new growth)
Remodelling- hypertrophy due to demand of only being able to grow back a small amount of cells
What are stem cell secretomers?
They release growth factors and promote cell survival
What are some challenges for stem cell based therapy before transplantation?
Selection of patient source (Autologous/Allogenic)
Ideal cell type (Pluripotent vs. Adult Stem cell)
Isolation method (Mechanical or enzymatic)
Cell expansion (How far can they be stretched)
Purification
What are some challenges of stem cell based therapy during transplantation?
Dosing (How many cells? One shot or repetitive?)
Route of admin (Intravenous, Intramyocardial)
Time of administration (Right after infarct, after recovery)
What are some challenges to stem cell based therapy after transplantation?
Cell survival
Differentiation into functional units of the heart
Electrical integration
What contributes to the blood pressure phenotype and by how much percent?
Genes- 30%
Environment- 70%
How many genes roughly contribute to hypertension?
107-200 genes
What is the aim of genomics?
To explain the understanding of molecular causes through genes and mechanisms behind it all
To predict potential biomarkers
What are SNPS?
Single Nucleotide polymorphisms which are changes to DNA that are powerful for association studies within the human genome
Most common DNA variant
Mostly transitions between G-A and C-T
15 million per genome
What are GWASs?
Genome Wide Association Study- they look for thousands of SNPs that are associated with a disease phenotype
What are microarrays?
Slides with SNP mutations dotted through them that represent genetic markers
What are some other genetic variations that could lead to hypertension?
Genetic variation, gene expression epigenetic processes (microRNA, methylation)
What is copy number variation?
Variations in the number of copies of larger segments of the genome
125 of the human genome
Variations can be inverted, duplicated, repeated etc.
What are the Coding and Non-coding pathways of RNA
Coding
DNA-Transcription to RNA-Translation-Protein
Non-Coding
DNA-Transcription-Non-coding RNA-either Longer non-coding RNA or shorter Micro RNA
What are micro RNAs?
Short 22 base pairs
Transcribed from DNA
Control expression, block translation, degrade mRNA
What are the cons of microRNAs in blood pressure?
They are easily available but low amount of RNA and difficult to interpret
How does RNA sequencing work?
Get samples of interest, isolate RNAs, generate cDNA/fragment the pieces, sequence the sample through a machine
What does genetic intervention offer for disease?
risk prediction, better prevention, possible treatment and personalized treatment
What are the contemporary tools used for genetic clues into disease?
Linkage mapping LD mapping Transcriptomics Proteomics Bioinformatics Systems Biology
Describe the human genome
3 billion base pairs
20-25,000 genes which is only 2% of the genome
98% are non coding genes
What happens with genome variation?
There are changes in protein function, RNA expression, epigenetic marks (enviro changes)
What is LD?
Linkage Disequilibrium- correlation between nearby alleles on the same chromosome that have to do with the disease we are interested in
What is Linkage analysis?
Analysis of the genome between family members
What is Association analysis?
Where you compare genomes through
case v control or high v low
higher resolution then linkage analysis
What is missing heritability in GWAS?
GWAS only codes for less than 5% of the heritability of a disease, the other 95% is unknown
What are the unknown factors that could lead to the missing heritability in GWAS?
Inflated heritability- maybe have overestimated the importance of genes)
Rare coding variants
Gene-gene interaction
Gene-environment interaction
Maybe one GWAS test is not enough, maybe need combination of genes/tests to get a full picture
What are association studies for genes?
Association between markers- but these are just markers not actual variants
Prone to bias of the whole population when maybe doesn’t fit
What is Transcriptomics?
Looking into gene and non-coding RNA expression
What is Bioinformatics?
Recognizing patterns in sequence and expression data and trying to put sense to it
Showing the association
What is Systems biology of genes?
Trying to put the computational biology into a physiological context- functional associations
