Cardiac Fibrosis

Why cardiac chest pain is common in morning than night ? and which type of Cardiac chest pain relievd by physical exertion?

 #1. Circaridan Rhythm and Chest Pain

Mammalian daily rhythms are regulated by a pacemaker within the suprachiasmatic nuclei of the hypothalamus, called the circadian clock. This biological system consists of a combination of genes and proteins that behave in a cyclical way following a 24-hour pattern. It is not only governed by endogenous factors, but also by environmental stimuli, the most important of which is the dark-light cycle. Chronobiological rhythms have been observed for many physiological parameters such as body temperature, blood pressure, hormone levels, etc. In fact, most of the biological ‘drivers’ of human life appear to follow a diurnal pattern A marked circadian variation of disease onset has been reported  with a maximum events occurring between 09.00 and 10.00 in the morning and a minimum events of between 23.00 and 24.00 at night.

Myocardial infarction was approximately four times more likely to occur between 08.00 and 09.00 in the morning than between midnight and 01.00. Hematological factors (e.g., increases in aggregability of platelets), vascular endothelial factors (e.g., increase in vascular tone), autonomic factors (e.g., release of catecholamines), and hemodynamic factors (e.g., morning surge of blood pressure and shear forces) have all been implicated in these adverse cardiovascular events which is activating during morning time.

 The suprachiasmatic nuclei controls the biochemical, metabolic, physiological, and behavioral processes of mammals, including the cardiovascular system. The cardiovascular system follows circadian variations driven by humoral signs. Cortisol and epinephrine levels increase during the morning period and fall during sleep, and both are considered one of the main humoral signs that connect the circadian clock and peripheral system activity. Aldosterone and plasma renin activity also follow circadian patterns, being higher in the morning and modulating the cardiovascular system. The circadian clock also controls melatonin production at the pineal gland. This hormone influences the circadian rhythm by a negative feedback mechanism, regulating circadian physiology. Simultaneously, melatonin influences  cardiovascular pathophysiology by a double mechanism, binding melatonin receptors present throughout the vascular system and heart, and acting directly as an antioxidant  factor. Heart rate and blood pressure oscillate throughout the day in phase with these circulating factors, being higher in the morning and decreasing during the evening.

Endogenous thrombolytic activity and platelet aggregability also follow a circadian pattern. The plasma levels of fibrinogen and plasminogen activator inhibitor-1 activity increase between 6 am and noon, whereas antithrombin levels and the activity of tissue-type plasminogen activators decrease during the morning.This fact suggests a thrombogenic natural status during the first hours of the day that turns into a physiological pro-fibrinolytic status in the evening hours.

There are several clues to the factors responsible for this phenomenon. Platelets aggregation has been reported to be more responsive during morning. Conceivably, early morning hypercoagulability could enhance the intracoronary thrombosis and there by increases the risk of major advance cardiac events (MACE). Another important factor in the pathogenesis of the increased morning incidence of ischemic cardiac events  may be the early morning increase of arterial pressure.The increased arterial blood pressure, increases the myocardial oxygen demand that leads to the increased vulnerability of the myocardium to ischemia, secondly the increase in arterial blood pressure could enhance the risk of plaque fissure that has been shown to occur rapidly before myocardial infarction. Several other factors for e.g. hormonal changes or increase in coronary artery tone may also play a role in the pathogenesis of this phenomenon. It has been proposed that in a number of cases, sudden cardiac death is the result of primary arrhythmic event. Such fatal arrhythmias are more likely to occur in the morning since increased activity of the sympathetic nervous system at that time. which in turn may increase electrical instability and subsequent conduction defects.
 #2.Warm up Angina ( second wind or walk through ) angina 
The traditional view is that angina is the result of an imbalance between the supply and demand of the myocardium for blood. The traditional explanation of warm up angina has therefore been that myocardial blood flow is enhanced on second effort by the opening of collateral channels (ie, collateral recruitment), and vasodilatation of the diseased artery or subtended vascular bed, or both. It is postulated that the collateral coronary channels may dilate slowly, and in the other it may be the larger coronary vessels which maintain a reduced capability of dilatation at their stenotic points.

A large increase in flow would result from only a small increase in diameter, since by Poiseuille's law the flow increases as the fourth power of the radius.

 However, the observation of increased myocardial resistance to ischemia after a brief episode of ischemia, known as ischemic preconditioning, has increased the understanding of warm up or second wind angina. In contrast to the traditional view, ischemic preconditioning does not depend on an increase in myocardial blood flow, but is caused by an increase in the intrinsic resistance of the heart to ischemia.

The term ‘‘ischemic preconditioning’’ and referred to it as myocardial adaptation to ischemic stress induced by repetitive brief periods of ischemia and reperfusion. . Not all time combinations and durations of ischemia and reperfusion will trigger the preconditioning phenomenon and afford myocardial protection. Ischemic preconditioning can be induced by a period of ischemia as short as 3 min, followed by a minimum of 1 min of reperfusion , but a brief 1–2 min period of ischemia followed by subsequent reperfusion has no protective effect.

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Why there is thrombocythopenia in Endocarditis ?

#1- rare causes -one type is Nonbacterial thrombotic endocarditis (Marantic endocarditis) - if this can be seen with thrombocytopenia then called -Para-neoplastic syndrome. Cancer may affect cellular elements of the blood as well as coagulation system , resulting in a wide range of para neoplastic syndrome . In this cases thrombocytopenia is rare but thrombocytosis which results from IL-6 and thrombopoietin release which may play a role in hypercoagulable state and may present as non-bacterial endocarditis in either cases.

#2- is more common : Infective endocarditis (IE) is a life threatening disease caused by a bacterial infection of the endocardial surfaces of the heart. It is typified by the formation of septic thrombi or vegetative growth on the heart valve. Typically, both platelets and fibrin are deposited on exposed extracellular matrix proteins as part of the normal response to damage of the endocardium . However, this sterile platelet-fibrin nidus facilitates colonisation of the endocardium by bacteria in the bloodstream . Following attachment, bacteria can recruit platelets from the circulation inducing platelet activation and platelet aggregation. !! S aureus adheres to platelets, leading to platelet activation and aggregation,platelet consumption, and eventually thrombocytopenia.

#3- Initial studies focused on secreted mediators of platelet activation such as alpha-toxin, which accelerates thrombin generation. Later studies focused on Clf A and fibronectin-binding protein A as the dominant surface proteins mediating platelet activation.Also, Clf A has been shown to be a virulence factor for endocarditis.This platelet activation process requires 2 mechanisms of S aureus binding to platelets: by a fibrinogen or fibronectin bridge to the platelet integrin GPIIb/IIIa and an immunoglobulin bridge to the Fc-γ-RIIa receptor.

 

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Angina with Normal Coronaries

Evidences have been shown that about 30% patient’s who admitted due to chest pain ,  Coronary angiograms show normal coronaries and 60% of post PTCA patients’ show TMT positive for inducible angina .

Normal or nonobstructive coronary disease at angiography is not uncommon and occurs in 10% of women presenting with ST segment elevation myocardial infarction compared with 6% in men.

Randomized placebo-controlled studies have demonstrated that tricyclic antidepressants, beta-blockers, ACE inhibitors, L-arginine, statins and exercise may relieve symptoms, vascular dysfunction, or both, however, long-term studies evaluating cardiac event rates need to be performed.

Features of chest pain may suggest:

- Non-cardiac chest pain

- Atypical angina including vasospastic angina

- Cardiac syndrome X

Normal coronary angiograms do not exclude the presence of myocardial ischemia in women. Coronary disease and chest pain, which may occur despite normal routine angiograms, include variant angina and syndrome X. Differentiation between these 2 entities may not be possible without further specialized provocation tests.

Important to differentiate non-cardiac chest pain from other 2 conditions:

- if angiographic appearance are suggestive of non-obstructing lesions and stress imaging techniques identify an extensive area of ischemia then :

- Intravascular USG of assessment of coronary flow reserve or fractional flow reserve may be considered to exclude missed obstructive lesions.

- Intra coronary ACETYLCHOLINE or ERGONOVIE may be administered during coronary arteriography .

Link between high-fat diet and cardiomyopathy, heart faiulre and early death

Evidences suggest that in healthy individuals SIRT6 suppresses IGF signaling–related genes by binding and silencing expression from AP1-dependent promoters, and this contributes to metabolic homeostasis and the maintenance of a healthy heart. Low expression of SIRT6 possibly caused by a high-fat diet, sedentary lifestyle and/or genetics results in reduced SIRT6 silencing, and overexpression of IGF and possibly also of other AP1-dependent genes, thus promoting cardiomyopathy, heart failure and early death.

Myocardial Dysfunction in Sepsis