BMS 200 Cardiology E-learning PDF

BMS 200 – Week 6 Cardiology E-learning Cardiomyopathies and Atherosclerosis Pathogenesis Instructor: Nishanth Lakshman, PhD Outcomes Describe the basic epidemiology, pathogenesis, clinical features, and prognosis of the following cardiomyopathies: Hypertrophic cardiomyopathy, Dilated cardiomy...

BMS 200 – Week 6 Cardiology E-learning Cardiomyopathies and Atherosclerosis Pathogenesis Instructor: Nishanth Lakshman, PhD Outcomes Describe the basic epidemiology, pathogenesis, clinical features, and prognosis of the following cardiomyopathies: Hypertrophic cardiomyopathy, Dilated cardiomyopathy (hereditary) Restrictive cardiomyopathy Describe the pathogenesis of atherosclerosis and generation of unstable plaques, focusing on: Lipoprotein A (Lp(a)) biology Metabolic syndrome Factors that contribute to plaque instability The Cardiomyopathies Disorders that target cardiac myocytes or the extracellular tissue in the myocardium Major cardiomyopathies: ▪ Dilated cardiomyopathies Genetic deficits in sarcomere proteins Acquired – usually infectious, inflammatory, or toxic in etiology ▪ Hypertrophic cardiomyopathy Genetic deficits in sarcomere proteins ▪ Restrictive cardiomyopathy Numerous causes that are related to abnormal deposition of extracellular material  The Cardiomyopathies FYI – a vast array of sarcomere- and non-sarcomere- associated proteins have been implicated in dilated and hypertrophic cardiomyopathies  Hypertrophic Cardiomyopathy Often abbreviated as HOCM – the “O” stands for “obstructive” ▪ The septum is usually massively overgrown, resulting in outflow obstruction for the left ventricle i.e. the entry to the aorta is blocked by the septum One of the more common autosomal disorders (usually dominant) – prevalence is 1 in 500, though severity varies greatly across patients  Hypertrophic Cardiomyopathy General Pathogenesis: If sarcomere proteins (i.e. myosin) are implicated, then tends to be gain-of-function mutation ▪ How exactly this leads to impressive hypertrophy is not well understood The myocytes are disorganized in orientation ▪ Can see this in diagram B (septal overgrowth in A)  Hypertrophic Cardiomyopathy Clinical Features: Many are asymptomatic – which is what makes the disease dangerous ▪ One of the major causes of “athlete’s heart” – sudden cardiac death or arrest that occurs due to dangerous dysrhythmias ▪ As the patient ages, angina, dyspnea, and syncope become more predominant Syncope = sudden loss of consciousness due to globally impaired cerebral hypoperfusion With time, HFpEF can occur Some develop HFrEF later Dilated Cardiomyopathy Most common cardiomyopathy… but not really a fair competition, because there are so many causes ▪ Toxicities – alcohol use disorder, excessive catecholamines (i.e. pheochromocytoma, aggressive resuscitation, even grief), cancer therapies ▪ Peripartum cardiomyopathy ▪ Genetic causes In general, most mutations are autosomal but some (such as dystrophin) can be X-linked Can be mutations in proteins that “support” the sarcomere (dystrophin, titin, actinin) or in proteins closely associated with contraction (tropomyosin, troponins, myosin) ▪ Inflammatory causes Infection – we will address in a future class (Cardiology 9) Sarcoidosis (addressed more thoroughly in BMS 250)  Dilated Cardiomyopathy Although the heart wall looks thin, the heart is massive ▪ Often weighs 2-3 X the weight of a healthy heart ▪ Ventricles are usually more affected (dilated) than the atria Heart wall appears flabby Dilation can lead to regurgitation of AV valves Usual finding on echocardiography is HFrEF Microscopy can alternate between hypertrophy and atrophic/fibrotic sections of myocardial cells Dilated Cardiomyopathy Clinical Features Can be asymptomatic until symptoms of heart failure appear ▪ Typical heart failure symptoms include fatigue, exercise intolerance, dyspnea, dependent edema ▪ The degree of ventricular enlargement can be great enough that it causes mitral regurgitation Can also manifest as palpitations/syncopal episodes due to the development of dysrhythmias ▪ More on dysrhythmia development in Cardiology 7 Many acquired causes of DCM reverse if damage is not long-term and the initial insult is eliminated ▪ However, if the inciting cause cannot be remedied then the prognosis is more serious – DCM is one of the most common indications for heart transplant Restrictive Cardiomyopathy Characterized by restricted ventricular filling, reduced diastolic volume in one or both ventricles, and normal or near-normal ventricular systolic function and wall thickness ▪ least common cardiomyopathy of the 3 cardiomyopathies we’re discussing ▪ carries a high mortality rate with death and disability due mainly to heart failure – it does not usually resolve on its own ▪ Usually presents with an isolated diastolic dysfunction, HFpEF picture – stroke volume is normal in most cases Restrictive Cardiomyopathy Pathogenesis: ▪ Some are autosomal dominant mutations, and how they contribute to the pathogenesis is not well understood ▪ Most are secondary, caused by conditions “outside the heart”: Amyloidosis – accumulation of abnormal proteins in various tissues ▪ Typical tissues at risk – kidneys, heart (more discussion in future classes) ▪ Proteins tend to form beta-pleated sheets – can be derived from the liver (abnormal transthyretin) or antibody fragments (multiple myeloma) ▪ Proteins deposit extracellularly and reduce ventricular compliance Hemochromatosis – accumulation of iron in cardiomyocytes and a number of other tissues (more in hematology) Sarcoidosis – chronic, granulomatous disease that infiltrates the wall of the ventricle (more in respiratory) Atherosclerosis – Pathogenetic Mechanisms Atherosclerosis is a complex disorder that is multifactorial and is somewhat unique across individuals depending on environmental and genetic factors: ▪ Systemic and local inflammation ▪ Dyslipidemia ▪ Higher levels of lipoprotein A – Lp(a) ▪ Metabolic syndrome and diabetes ▪ Hypertension  Review - atherosclerosis Progression from fatty streak ! deposition of oxidized LDL ! migration and activation of macrophages ! ▪ Calcification, accumulation of cholesterol, foam cell development ▪ Increased deposition of extracellular matrix under the intima ▪ A variably-stable fibrous cap with underlying necrotic tissue and immune cells ▪ Stenosis of the lumen and impaired blood flow Review – risk factors and the development of atherosclerosis Smoking, high blood pressure, oxidative stress increase endothelial damage Lp(a) – likely increases endothelial damage through increasing immune cell recruitment at a developing plaque ▪ May also inhibit breakdown of clots Diabetes and dyslipidemia (including metabolic syndrome): ▪ Diabetes – LDL is more likely to be incorporated into the intima in the setting of AGEs in the endothelium – likely site of oxidation of LDL ▪ AGEs can also increase general inflammation, leading to increased oxidative stress ▪ Increased LDL ! increased oxidized LDL ! deposition in fatty streaks ! activation of macrophages (via the scavenger receptor) More on Lp(a) Everyone has a little Lp(a) ▪ Produced by the liver – release can be increased by acute phase response (precipitated by elevated IL-6, other pro-inflammatory cytokines) We usually make about 10X less Lp(a) than the amount of circulating LDL ▪ Women make a little bit more than men ▪ Those that make higher levels (2-3 X normal) have an increased risk of IHD, stroke, and calcific aortic stenosis Tendency to produce higher Lp(a) is genetic, and antihyperlipidemics, exercise, do not seem to decrease it much Thyroid hormone may decrease production Looks a lot like LDL (see next slide) ▪ Apo(B) containing protein ▪ surface has a group of proteins that look like plasminogen, composed of units known as “kringle” units (KIV) ▪ Transports oxidized phospholipids (OxPL) – these are thought to be the major drivers of Lp(a) pathogenicity Volgman et al., Genetics and Pathophysiological Mechanisms of Lp(a)-associated Cardiovascular Risk, J. AHA, Vol 13., Iss. 12 (2024): https://doi.org/10.1161/JAHA.123.033654  Lp(a) vs. LDL Note: KIV repeats (part that looks like plasminogen) presence of oxidized phospholipids (OxPL) on Lp(a) Volgman et al., Genetics and Pathophysiological Mechanisms of Lp(a)-associated Cardiovascular Risk, J. AHA, Vol 13., Iss. 12 (2024): https://doi.org/10.1161/JAHA.123.033654 More on Lp(a) Lp(a) may increase atherogenesis by: ▪ Initiating coagulation ▪ Contributing to the development of unstable plaques ▪ Activation of monocytes in the arterial wall ▪ Eliciting secretion of pro-inflammatory cytokines and expression of adhesion molecules in the arterial wall Lp(a) secretion is increased when IL-6 levels increase, and seems to do more harm when systemic inflammation is also present Thought that many of the effects are due to the OxPL that is carried by the Lp(a) particle, though not yet confirmed Volgman et al., Genetics and Pathophysiological Mechanisms of Lp(a)-associated Cardiovascular Risk, J. AHA, Vol 13., Iss. 12 (2024): https://doi.org/10.1161/JAHA.123.033654 More on plaque types: Unstable plaque: a plaque with an unstable fibrous cap that is prone to rupture ▪ Rupture ! release of pro-coagulant molecules into the bloodstream Factors that increase stability – amount of collagen in the fibrous cap ▪ Activated platelets can release growth factors that stimulate collagen production and deposition However, often the reason why the platelet was activated in the first place was that it bound to a small rupture in the cap or bound to an activated endothelial cell ▪ Activated macrophages produce metalloproteinases that degrade collage ! weaker fibrous cap ▪ Therefore, inflammation tends to decrease stability of atherosclerotic plaques  Unstable Plaques and ACS Harrison’s video here: https://accessmedicine- mhmedical- com.ccnm.idm.oclc.org/ MultimediaPlayer.aspx? MultimediaID=19398993 ▪ In Atlas of Atherosclerosis chapter  More on plaque types - FYI There is also another pathophysiological alteration of the plaque - the erosion of a plaque Different from a ruptured plaque – eroded plaques have a more stable fibrous cap, an overlying thrombus, and lots of NETS ▪ NET = neutrophil extracellular trap ! release of neutrophil DNA upon activation Although plaque erosion is thought to be responsible for up to 50% of ACS, not as well understood as rupture of an unstable plaque Diabetes and the metabolic syndrome Remember the metabolic syndrome: ▪ Elevated VLDL ! increased circulating LDL ▪ Hypertension ! increased atherogenesis ▪ Visceral obesity ! insulin resistance, increased FFAs, and increased release of pro-inflammatory cytokines ▪ Insulin resistance ! production of advanced glycation end- products (AGEs) As previously mentioned AGEs can be found in the basement membrane of the tunica intima ! increased likelihood of LDL oxidation and recruitment of pro-inflammatory cells ▪ As well, LDL can also be glycated ! activation of macrophages ! development of foam cells