Heart Failure and the Ryanodine Receptor
Define the syndrome heart failure and discuss the cellular and molecular basis of poorly
contracting hypertrophic myocardium. Secondly discuss the potential role of the ryanodine
receptor in the pro-arrhythmic status of failing heart.
Heart failure (HF) has several aetiologies however it most commonly occurs due Artherosclerotic cardiovascular ischaemia, in an acute case following a myocardial infarction (MI) or more chronically due to coronary artery disease. It can be broadly described by the haemodynamic model as to be when the metabolic requirement of the body is not met due to decreased cardiac contractility and output (Braunwald, 2013).
It may arise at any age but statistically it is more prevalent in the elderly. Epidemiologically it is of great concern, as even though overall there is a decrease in cardiovascular disease-related mortality HF is a noticeable exception in this encouraging trend.
In HF due to the loss of healthy myocardium there is a compensatory cardiorenal and neurohormonal changes including an increase of Angiotensin II and aldosterone in order to produce vasoconstriction and a decreased blood volume, which though beneficial at the onset of the disease (compensated HF) develops into a maladaptive feature. There is resultant thinning of the left ventricular myocardial layer due to increased fibroblast proliferation, focal fibrosis, stiffening of the myocardium and cardiac hypertrophy; subsequently causing a significant decrease in the force of contractility (negative inotropy).
Paroxysmal nocturnal dyspnoea, exertional dyspnoea, chest pain and over all fatigue can be sympotmatic of HF. In the clinic HF is diagnosed following a serious of tests including the standard blood test in order to see classic biomarkers of HF such as atrial natriuretic peptide, brain natriuretic peptide and inflammatory cytokine such as Interleukin-6; electrocardiography, in order to see the altered electrical activity in HF; echocardiograms in order to visualise the 3D structure of the failing heart and chest X-ray in order to visualise the whole cardiopulmonary system to observe is there is fluid in the lungs and abdomen. Physician physical exams can also illicit classic signs of HF such as the rales, rhonchi and S3 gallop heard via the stethoscope.
The physiological cardiac hypertrophy seen in professional athletes and in pregnancy is a result of proportional growth of the cardiac tissue. However, in contrast, the pathophysiological hypertrophy seen in HF result in non-proportional, concentric (greater width) and eccentric (greater length) remodeling of myocytes, resulting in disorganization of sarcomere, whole heart dilation and hypertoprhy. This maladaptation is a initiator of the 'foetal program' gene within the hypertrophied myocytes, furthering the hypertrophy and worsening the HF progression. Cardiogenic shock can occur as the failing heart ability to contract even at rest worsens.
HF around half of patients will die as a result of pump failure while the other 50% will suffer from sudden cardiac death (SCD). With SCD being most common in New York Heart Association (NYHA) Class II of HF with an 80% probability. Ventricular arrhythmia is the main the cause of SCD, in particular Ventricular tachycardia (VT) deteriorating into ventricular fibrillation (VFib).
In normal sinus rhythm the cardiac rhythm originates from sinus node in the right atria and travels to the ventricles via the His-Purkinje fibers, which are essential for this, as the atria is electrically isolated from the ventricles due to the fibrous annulus.
Calcium transient and the length of action potential is longer in the failing heart, in particular in the sub-epicardial and M layer. While in the sub-endocardial layer there is shortening of AP and calcium flux; this increase in heterogeneity is a pro-arrhythmic property.
Sodium channels are normally uniformly expressed throughout the myocardium, however have shown to be decreased in infarct border areas, increasing spatial heterogeneity (Pu and Boyden, 1997).
The L-type Calcium Channel (LTCC) is the mild/moderate failing heart is increased in expression however in severely hearts have shown to be slightly decreased.
There is also an overall reduction in Potassium ion channel density in the failing heart with a subsequent effect of prolonging AP length and membrane potential instability.
The suboptimal contractility of concentric and eccentric hypertrophic myocytes can also be attributed to the significant negative impact of Ca2+ homeostasis dysregulation, which includes the process of detubulation and the incomplete t-tubules system, which ensures E-C coupling occurs throughout the diameter of the muscle cell. Due to the non-proportional morphological enlargement of the cell, experimentally, detubulated regions of hypertrophied cardiac myocytes are commonly visualised (Lyon et al., 2009). The invagination of the plasma membranes at the Z- line of each cardiomyocyte sarcomere allows for the electrical depolarisation of the cell to be instantaneous during systole, along with efficient extrusion of Ca2+ in diastole for relaxation to occur. Also known as the transverse axial tubular system (TATS), essential receptors and channels involved in myocardial E-C coupling, such as the L-type Calcium Channel (LTCC) and the sodium-calcium exchanger (NCX), are located in this domain. Thus, the loss of this key area, leads to incomplete activation of contractile proteins. A key issue is the inefficient recruitments of the calcium releasing units, due to the loss of the dyadic interface between LTCC and ryanodine (RyR) channels, leading to the phenomenon of ‘orphaned’ RyRs, which are prone to a higher probability of arrhythmogenic spontaneous Ca2+ release.
Re-entrant arrhythmia are also commonly seen in the failing heart due to the presence unidirectional conduction block (infarct scar/fibrotic area), triggering activity (premature beats occuring due to prolonged AP and altered Calcium transient resulting in early- or delayed- after depolarization (EADs/DADs)) while the heterogeneity of AP seen throughout the failing myocardium provides the substrate for the progression of the re-entrant waveform to be propagated.
Wavelength (λ) = Action Potential Duration x Conduction Velocity
In an animal study by Akar et al., 2004 non-ischemic dilated cardiomyopathy with eccentric hypertrophy showed a prolongation of both the QRS and QT complexes of ECG in HF and overall slowed conduction. There was also reduced expression of connexin which in turn increases intercellular resistance and reduces conduction velocity.
contracting hypertrophic myocardium. Secondly discuss the potential role of the ryanodine
receptor in the pro-arrhythmic status of failing heart.
Heart failure (HF) has several aetiologies however it most commonly occurs due Artherosclerotic cardiovascular ischaemia, in an acute case following a myocardial infarction (MI) or more chronically due to coronary artery disease. It can be broadly described by the haemodynamic model as to be when the metabolic requirement of the body is not met due to decreased cardiac contractility and output (Braunwald, 2013).
It may arise at any age but statistically it is more prevalent in the elderly. Epidemiologically it is of great concern, as even though overall there is a decrease in cardiovascular disease-related mortality HF is a noticeable exception in this encouraging trend.
In HF due to the loss of healthy myocardium there is a compensatory cardiorenal and neurohormonal changes including an increase of Angiotensin II and aldosterone in order to produce vasoconstriction and a decreased blood volume, which though beneficial at the onset of the disease (compensated HF) develops into a maladaptive feature. There is resultant thinning of the left ventricular myocardial layer due to increased fibroblast proliferation, focal fibrosis, stiffening of the myocardium and cardiac hypertrophy; subsequently causing a significant decrease in the force of contractility (negative inotropy).
Paroxysmal nocturnal dyspnoea, exertional dyspnoea, chest pain and over all fatigue can be sympotmatic of HF. In the clinic HF is diagnosed following a serious of tests including the standard blood test in order to see classic biomarkers of HF such as atrial natriuretic peptide, brain natriuretic peptide and inflammatory cytokine such as Interleukin-6; electrocardiography, in order to see the altered electrical activity in HF; echocardiograms in order to visualise the 3D structure of the failing heart and chest X-ray in order to visualise the whole cardiopulmonary system to observe is there is fluid in the lungs and abdomen. Physician physical exams can also illicit classic signs of HF such as the rales, rhonchi and S3 gallop heard via the stethoscope.
The physiological cardiac hypertrophy seen in professional athletes and in pregnancy is a result of proportional growth of the cardiac tissue. However, in contrast, the pathophysiological hypertrophy seen in HF result in non-proportional, concentric (greater width) and eccentric (greater length) remodeling of myocytes, resulting in disorganization of sarcomere, whole heart dilation and hypertoprhy. This maladaptation is a initiator of the 'foetal program' gene within the hypertrophied myocytes, furthering the hypertrophy and worsening the HF progression. Cardiogenic shock can occur as the failing heart ability to contract even at rest worsens.
HF around half of patients will die as a result of pump failure while the other 50% will suffer from sudden cardiac death (SCD). With SCD being most common in New York Heart Association (NYHA) Class II of HF with an 80% probability. Ventricular arrhythmia is the main the cause of SCD, in particular Ventricular tachycardia (VT) deteriorating into ventricular fibrillation (VFib).
Calcium transient and the length of action potential is longer in the failing heart, in particular in the sub-epicardial and M layer. While in the sub-endocardial layer there is shortening of AP and calcium flux; this increase in heterogeneity is a pro-arrhythmic property.
Sodium channels are normally uniformly expressed throughout the myocardium, however have shown to be decreased in infarct border areas, increasing spatial heterogeneity (Pu and Boyden, 1997).
The L-type Calcium Channel (LTCC) is the mild/moderate failing heart is increased in expression however in severely hearts have shown to be slightly decreased.
There is also an overall reduction in Potassium ion channel density in the failing heart with a subsequent effect of prolonging AP length and membrane potential instability.
The suboptimal contractility of concentric and eccentric hypertrophic myocytes can also be attributed to the significant negative impact of Ca2+ homeostasis dysregulation, which includes the process of detubulation and the incomplete t-tubules system, which ensures E-C coupling occurs throughout the diameter of the muscle cell. Due to the non-proportional morphological enlargement of the cell, experimentally, detubulated regions of hypertrophied cardiac myocytes are commonly visualised (Lyon et al., 2009). The invagination of the plasma membranes at the Z- line of each cardiomyocyte sarcomere allows for the electrical depolarisation of the cell to be instantaneous during systole, along with efficient extrusion of Ca2+ in diastole for relaxation to occur. Also known as the transverse axial tubular system (TATS), essential receptors and channels involved in myocardial E-C coupling, such as the L-type Calcium Channel (LTCC) and the sodium-calcium exchanger (NCX), are located in this domain. Thus, the loss of this key area, leads to incomplete activation of contractile proteins. A key issue is the inefficient recruitments of the calcium releasing units, due to the loss of the dyadic interface between LTCC and ryanodine (RyR) channels, leading to the phenomenon of ‘orphaned’ RyRs, which are prone to a higher probability of arrhythmogenic spontaneous Ca2+ release.
Re-entrant arrhythmia are also commonly seen in the failing heart due to the presence unidirectional conduction block (infarct scar/fibrotic area), triggering activity (premature beats occuring due to prolonged AP and altered Calcium transient resulting in early- or delayed- after depolarization (EADs/DADs)) while the heterogeneity of AP seen throughout the failing myocardium provides the substrate for the progression of the re-entrant waveform to be propagated.
Wavelength (λ) = Action Potential Duration x Conduction Velocity
In an animal study by Akar et al., 2004 non-ischemic dilated cardiomyopathy with eccentric hypertrophy showed a prolongation of both the QRS and QT complexes of ECG in HF and overall slowed conduction. There was also reduced expression of connexin which in turn increases intercellular resistance and reduces conduction velocity.
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