Cardiac Remodelling-Extra Reading

Question 1

Porter, Pharmacology and Therapeutics, 2009

Answer 1

• Seminal studies have shown that following birth, the neonatal heart adapts to sudden increases in systolic BP by increasing ventricular wall thickness/tensile strength via massive proliferation of Cardiac Fibroblasts
• Cardiac fibroblasts are arranged in sheets and strands that run in parallel with muscle fibres
• It is known that fibroblast numbers increase with age so is this what causes age-associated remodelling?
• As well as disturbing action potentials through deposition of ECM, fibroblasts can cause arrhythmias because mechanical stretch as a result of heart contraction causes a change in cardiac fibroblast potential known as MECHANICALLY-INDUCED POTENTIAL which modifies myocyte potentials and can produce arrhythmia
• Fibroblasts have been genetically modified to produce excitable cells capable of ELECTRICAL COUPLING
• This supports the notion that gene-based strategies could be developed to repair cardiac conduction deficits
• The majority of myofibroblasts apoptose following healing but a number of them do remain in the myocardium for several years
• The reason behind this is unclear because in other tissues, all myofibroblasts senesce
• It is possible that if these remaining myofibroblasts could be removed, there would be less chance of the development of adverse remodelling
• To prevent fibrosis, we could inhibit the breakdown of ECM. Researchers have tried to pharmacologically boost the action of TIMPs but this has proved ineffective due to their short half life
• Fibroblasts are thought to do the majority of ECM synthesis but Myofibroblasts have been shown to be capable of producing significantly larger quantities of collagen than their fibroblast counterparts
• Cardiac fibroblasts are exposed to cyclic mechanical stretch every heartbeat- 1 Herz
• In pathology the frequency and force of stretch is altered which triggers a change to ECM and fibroblast function
• Rat cardiac fibroblast models showed that cyclic stretch induced expression of Collagen I and III, so if stretch increases in pathology, then more collagen will be produced
• Cyclic stretch has also been shown to induce TNF, TGF and ET-1 expression-so bigger stretch e.g in ventricular dilatation will cause more expression of these proteins
• Exposure of cardiac fibroblasts to hypoxia triggers differentiation to myofibroblasts
• Cardiac fibroblasts co-ordinate mechanical, chemical and electrical signals between the cellular and non-cellular compartments of the myocardium
• We must be very careful with cardiac fibroblast research because much of it is done using rodent and neonatal fibroblasts which differ greatly from adult human fibroblasts
• Plus, most models use a single stimulus whereas in vivo cardiac fibroblasts are exposed to a whole host of complex stimuli

BUT-unique features of cardiac fibroblasts still render them attractive therapeutic targets

• Myoblasts/bone marrow progenitor cells have been injected into damaged hearts and significant efficacy has been noted
• Researchers wish to use gene therapy to inhibit a-SMA however this has halted due to a lack of discovery of a-SMA promotor region
• miR-21 has been identified as over-expressed in the failing myocardium of mice; shown to increase proliferation of fibroblasts and negatively regulate MMPs-so miR-21 could be a novel therapeutic target

Question 2

Liu, Nature, 2012

Answer 2

• Myocytes are terminally differentiated so the adult heart can’t replace them
• 2 studies have shown that cardiac fibroblasts can be reprogrammed into cardiomyocyte-like cells in vivo and this showed a significant improvement in cardiac function following MI
• This is possible because fibroblasts are put into a stem cell-like state and then redirected towards a myocyte-like phenotype rather than fibroblast
• The reprogrammed cells have acquired characteristics such as spontaneous contraction, cardiac electrical potential and sarcomere structure

-These studies are leading us towards a new heart repair opportunity!

Question 3

Sutton, Circulation, 2000

Answer 3

• Changes in circulation dynamics following MI are determined by magnitude of myocyte loss, stimulation of the SNS, RAAs and release of natriuretic peptides
• Myocyte hypertrophy can sometimes show a 70% increase in cell volume
• Hypertrophy is an adaptive response during post-infarction remodelling that offsets increased load, attenuates progressive dilation (can balance it if the wall gets thicker) and stabilises contractile function
• SOME HYPERTROPHY IS NECESSARY-we can’t eliminate it completely
• Patency of the infarct artery or collateral flow may confer survival benefit
• degree of perfusion of the infarct artery has been identified as an important predictor of left ventricular volume- so it is always worth attempting revascularisation as it may reduce remodelling

-There is potential that preventing ECM degradation through inhibition of MMPs would stiffen the infarct zone and prevent ventricular dilation

Question 4

Liehn, JACC, 2011

Answer 4

• The first cells recruited to the infarct zone following MI are NEUTROPHILS (they respond to the DAMPs released by ischaemic cells)
• These neutrophils release proteolytic enzymes, cytokines and ROS to boost the inflammatory response but in the process cause FURTHER DAMAGE TO CELLS
• Animal models have shown that NEUTROPHIL DEPLETION LED TO A MARKED DECREASE IN INFARCT SIZE

-However, neutrophils are needed to recruit macrophages (release of Monocyte Chemotactic Protein) and without macrophages injured/dead myocytes are not phagocytosed-PREDISPOSES TO HEART RUPTURE

SO, even if only for a short period, NEUTROPHILS ARE VITAL as they recruit macrophages
-If we could reduce neutrophil number that would mean that macrophages would still be recruited but there would be less damage done to the already damaged infarct area

• Appropriate blood supply is crucial for heart survival and function, so angiogenesis during healing is vital
• Studies have shown that early transplantation of Endothelial Progenitor Cells has been beneficial

Question 5

Nah, Korean Society of Cardiology, 2009

Answer 5

• Myocardial necrosis releases TNF-a which induces compliment activation, free radical generation and a cytokine cascade
• When an infarcted area is reperfused, an INTENSE INFLAMMATORY REACTION ENSUES
• For this reason, optimal healing of the myocardium needs timely resolution of the inflammatory response-to try and stop any further damage from taking place

-Unfortunately, studies investigating compliment and free radical inhibition showed no clinical improvement

• The three phases of infarct healing are overlapping:
  1. Inflammatory phase
  2. Proliferative phase
  3. Maturation phase

-Many experimental studies have shown a dramatic reduction in infarct size with the use of anti-inflammatory treatment and inhibition of cytokines
-BUT THIS HAS BEEN UNSUCCESSFUL IN CLINICAL PRACTICE:
probably because:
-animal models have fundamental differences to humans
-inflammatory cascade is a complex network of various pathways

Question 6

Krenning, 2010

Answer 6

• Excessive ECM deposition impairs mechano-electric coupling of cardiomyocytes and increases the risk of arrhythmias
• Cardiac fibroblasts are NON-excitable
• In experimental models of cardiac fibrosis, 30% of activated fibroblasts came from enothelial cell mesenchymal transition
• Monocytes has been suggested as a potential source of pathology-associated fibroblasts i.e they are only recruited from monocytes when pathology is present
• Fibroblasts may also come from Pericytes in the perivascular space of cardiac vessels-however there is lack of definite markers to distinguish between pericytes and fibroblasts