Materiały źródłowe

• #1 Mitral valve disease—morphology and mechanisms | Nature Reviews Cardiology

  https://www.nature.com/articles/nrcardio.2015.161

  Mitral valve disease is a major cause of heart failure and mortality. […] Genetic analysis has revealed that regulation of growth signalling and cell migration pathways could potentially be modified to limit progression from developmental defects to clinically evident valve degeneration, such as mitral valve prolapse. […] Mitral valve enlargement is an important determinant of left ventricular outflow tract obstruction in hypertrophic cardiomyopathy and might be stimulated by valvular-ventricular interactions. […] Mitral valve plasticity allows adaptation to ventricular remodelling, but adverse processes create relative leaflet deficiency in the ischaemic setting, leading to mitral regurgitation with worse prognosis. […] Understanding these concepts can create new opportunities to reduce the clinical progression of mitral valve disease through early detection and biological modification.

• #2 Mitral valve disease−morphology and mechanisms – Archive ouverte HAL

  https://hal.science/hal-01830969

  Mitral valve disease is a frequent cause of heart failure and death. Emerging evidence indicates that the mitral valve is not a passive structure, but even in adult life remains dynamic and accessible for treatment. […] This concept motivates efforts to reduce the clinical progression of mitral valve disease through early detection and modification of underlying mechanisms. Discoveries of genetic mutations causing mitral valve elongation and prolapse have revealed that growth factor signalling and cell migration pathways are regulated by structural molecules in ways that can be modified to limit progression from developmental defects to valve degeneration with clinical complications. […] Mitral valve enlargement can determine left ventricular outflow tract obstruction in hypertrophic cardiomyopathy, and might be stimulated by potentially modifiable biological valvular-ventricular interactions. Mitral valve plasticity also allows adaptive growth in response to ventricular remodelling. However, adverse cellular and mechanobiological processes create relative leaflet deficiency in the ischaemic setting, leading to mitral regurgitation with increased heart failure and mortality. […] Our approach, which bridges clinicians and basic scientists, enables the correlation of observed disease with cellular and molecular mechanisms, leading to the discovery of new opportunities for improving the natural history of mitral valve disease.

• #3 Mitral valve disease–morphology and mechanisms – PubMed

  https://pubmed.ncbi.nlm.nih.gov/26483167/

  Mitral valve disease is a frequent cause of heart failure and death. Emerging evidence indicates that the mitral valve is not a passive structure, but–even in adult life–remains dynamic and accessible for treatment. […] This concept motivates efforts to reduce the clinical progression of mitral valve disease through early detection and modification of underlying mechanisms. Discoveries of genetic mutations causing mitral valve elongation and prolapse have revealed that growth factor signalling and cell migration pathways are regulated by structural molecules in ways that can be modified to limit progression from developmental defects to valve degeneration with clinical complications. […] Mitral valve enlargement can determine left ventricular outflow tract obstruction in hypertrophic cardiomyopathy, and might be stimulated by potentially modifiable biological valvular-ventricular interactions. Mitral valve plasticity also allows adaptive growth in response to ventricular remodelling. However, adverse cellular and mechanobiological processes create relative leaflet deficiency in the ischaemic setting, leading to mitral regurgitation with increased heart failure and mortality. […] Our approach, which bridges clinicians and basic scientists, enables the correlation of observed disease with cellular and molecular mechanisms, leading to the discovery of new opportunities for improving the natural history of mitral valve disease.

• #4

  https://journals.lww.com/mamc/fulltext/2015/01030/mechanisms_and_pathophysiology_of_mitral_valve.6.aspx

  The mitral valve (MV) is a sophisticated natural engineering marvel. The MV requires coordinated action of all its interrelated anatomical components: The MV leaflets, the annulus, the left atrium, the tendinous chords and the papillary muscles with its surrounding left ventricular wall for an effective closure of its orifice. […] Mitral valve regurgitation (MR) is frequently found in patients undergoing cardiac surgery with cardiopulmonary bypass. MR can be secondary to a structural or a functional defect of one or several components of the MV. The mechanism(s) of functional MR is the most complex. A precise understanding of the pathophysiology of MR helps resolving the cardiac status of a patient and choice of therapy for a particular patient. […] The mechanism of the functional MR is most intriguing and interesting, and its sound understanding helps understanding mechanisms of MR in other clinical situations.

• #5 Mitral Valve Disease (Regurgitation) | Inova

  https://www.inova.org/our-services/inova-schar-heart-and-vascular/conditions-treatments/mitral-valve-disease

  The mitral valve is located between the left atrium and the left ventricle and controls the flow of blood as it returns from the lungs before being pumped out to the body. It is a one-way valve that opens and closes with each heartbeat. When open, the valve allows blood to pass from the atrium into the ventricle. When closed, it prevents blood from returning to the atrium. […] A healthy mitral valve maintains blood flow in one direction, from the atrium to the ventricle, and from the ventricle to the rest of the body. If the valve becomes damaged, surgery may be necessary to ensure proper blood flow through the heart. […] Mitral valve disease is often asymptomatic in its early stages. Over time, patients will notice common symptoms such as shortness of breath, lightheadedness, fatigue, racing or irregular heartbeat (arrhythmia), and a dry cough.

• #6

  https://journals.lww.com/mamc/fulltext/2015/01030/mechanisms_and_pathophysiology_of_mitral_valve.6.aspx

  The MV closes as soon as LV pressure exceeds the LA pressure, and the closure occurs within moments of the initiation of LV systole. […] It is intuitive that MR is likely, if the annulus is dilated or its sphincter mechanism is interfered, or there is insufficient increase in transmitral gradient or there is defect in the coaptation between AML and PML or there is impaired function of the tendinous chords due to their rupture, elongation or tethering, or the mitral leaflets are damaged. […] Both ischemic (coronary artery disease) and nonischemic heart diseases (e.g., idiopathic dilated cardiomyopathy) cause „functional” MR via multiple different mechanisms including impaired LV wall motion, LV dilatation, and papillary muscle displacement and dysfunction. […] The precise mechanism of functional mitral regurgitation remains unclear; the factors described above can be grouped as those causing: (1) Abnormally increased tension on the leaflets caused by displacement of the papillary muscles or annular dilatation, restricting leaflet motion, and those causing (2) decreased global LV systolic function, decreasing the transmitral pressure force acting to close the mitral leaflets.

• #7 Mitral valve disease – Symptoms and causes – Mayo Clinic

  https://www.mayoclinic.org/diseases-conditions/mitral-valve-disease/symptoms-causes/syc-20355107

  Mitral valve disease is a problem with the valve located between the left heart chambers. The upper left heart chamber is called the left atrium. The bottom left heart chamber is called the left ventricle. […] In mitral valve regurgitation, the flaps don’t close tightly. Blood flows backward when the valve is closed, making it harder for the heart to work properly. […] In mitral valve stenosis, the valve opening narrows. The heart now must work harder to force blood through the smaller valve opening. If the opening in the valve becomes small enough, it can reduce blood flow between the left heart chambers. […] Mitral valve disease has many causes. Some forms of mitral valve disease can be present at birth. A heart problem that you’re born with is called a congenital heart defect. […] Mitral valve disease also may develop later in life. This means it is acquired. For example, mitral valve stenosis is often caused by rheumatic fever. This fever is a complication of a strep infection that can affect the heart. When this happens, it’s called rheumatic mitral valve disease.

• #8 Mitral Valve Disease: Types, Symptoms and Treatment

  https://my.clevelandclinic.org/health/diseases/23235-mitral-valve-disease

  Mitral valve disease can slow down your blood flow or cause it to leak in the wrong direction, depending on the form. […] The three forms of mitral valve disease include: Mitral valve stenosis. Your valve’s flaps become thick and stiff. This narrows the valve opening and makes it harder for blood to get through. Mitral valve prolapse. Your valve’s flaps become too stretchy and bulge into your left atrium. This prevents your valve from closing as well as it should. It sometimes leads to regurgitation (leaky valve). Mitral valve regurgitation. This is commonly known as a leaky valve. It’s also sometimes called mitral insufficiency. Your valve’s flaps become pulled apart and can’t close all the way. So, some blood leaks backward into your left atrium. […] There are many possible causes for mitral valve disease. These include: Congenital heart defect. Some people are born with mitral valve disease. It may be mild or severe. Babies with life-threatening defects need surgery right away. Connective tissue disorders. These include Marfan syndrome and Ehlers-Danlos syndrome. Endocarditis. This is an infection in your heart. Enlargement of your left ventricle, usually due to a heart attack or cardiomyopathy. Getting older. As we age, calcium can slowly build up on our heart valves. For many people, this buildup only causes mild or moderate mitral valve stenosis. Radiation therapy. People who had radiation to their chest have a higher risk of heart valve damage. These issues usually don’t show up until 10 to 20 years later. Rheumatic fever. This infection, when untreated, can lead to heart valve damage. The damage can show up years or decades after the infection. Rheumatic fever is the most common cause of mitral valve stenosis, especially among people born before 1943. Modern use of antibiotics to treat bacterial infections has greatly reduced this problem in the U.S. and many other countries.

• #9 Mitral Valve Disease: Types, Symptoms and Treatment

  https://my.clevelandclinic.org/health/diseases/23235-mitral-valve-disease

  Mitral valve disease can slow down your blood flow or cause it to leak in the wrong direction, depending on the form. […] The three forms of mitral valve disease include: Mitral valve stenosis. Your valve’s flaps become thick and stiff. This narrows the valve opening and makes it harder for blood to get through. Mitral valve prolapse. Your valve’s flaps become too stretchy and bulge into your left atrium. This prevents your valve from closing as well as it should. It sometimes leads to regurgitation (leaky valve). Mitral valve regurgitation. This is commonly known as a leaky valve. It’s also sometimes called mitral insufficiency. Your valve’s flaps become pulled apart and can’t close all the way. So, some blood leaks backward into your left atrium. […] There are many possible causes for mitral valve disease. These include: Congenital heart defect. Some people are born with mitral valve disease. It may be mild or severe. Babies with life-threatening defects need surgery right away. Connective tissue disorders. These include Marfan syndrome and Ehlers-Danlos syndrome. Endocarditis. This is an infection in your heart. Enlargement of your left ventricle, usually due to a heart attack or cardiomyopathy. Getting older. As we age, calcium can slowly build up on our heart valves. For many people, this buildup only causes mild or moderate mitral valve stenosis. Radiation therapy. People who had radiation to their chest have a higher risk of heart valve damage. These issues usually don’t show up until 10 to 20 years later. Rheumatic fever. This infection, when untreated, can lead to heart valve damage. The damage can show up years or decades after the infection. Rheumatic fever is the most common cause of mitral valve stenosis, especially among people born before 1943. Modern use of antibiotics to treat bacterial infections has greatly reduced this problem in the U.S. and many other countries.

• #10 Mitral valve incompetence: epidemiology and causes

  https://www.escardio.org/Journals/E-Journal-of-Cardiology-Practice/Volume-16/Mitral-valve-incompetence-epidemiology-and-causes

  Mitral regurgitation may occur for organic or functional causes. The common causes of organic (primary) MR include prolapse syndrome, flail leaflet, rheumatic heart disease, CAD, infective endocarditis, certain drugs, and collagen vascular disease. […] MR may also occur secondary (functional) to a dilated annulus from dilatation of the left ventricle (from an imbalance between closing and tethering forces) or left atrial enlargement in patients with atrial fibrillation.

• #11 Mitral valve incompetence: epidemiology and causes

  https://www.escardio.org/Journals/E-Journal-of-Cardiology-Practice/Volume-16/Mitral-valve-incompetence-epidemiology-and-causes

  Mitral regurgitation (MR) is the second most frequent indication for valve surgery. The common causes of organic (primary) MR include prolapse syndrome, flail leaflet, rheumatic heart disease, coronary artery disease (CAD), infective endocarditis, certain drugs (some anorectic drugs), and collagen vascular disease. […] In primary MR, one or several components of the mitral valve apparatus are directly affected. […] The most frequent aetiology of mitral incompetence is degenerative (prolapse, flail leaflet). […] Myxomatous degeneration is the main aetiology of prolapsing valvar leaflets, explaining the fact that MVP is uncommon before adolescence. […] Primary MVP occurs with increased frequency in patients with Marfan syndrome and other connective tissue diseases (Ehlers-Danlos syndrome, osteogenesis imperfecta, dominant cutis laxa or pseudoxanthoma elasticum).

• #12 Mitral valve incompetence: epidemiology and causes

  https://www.escardio.org/Journals/E-Journal-of-Cardiology-Practice/Volume-16/Mitral-valve-incompetence-epidemiology-and-causes

  Mitral regurgitation (MR) is the second most frequent indication for valve surgery. The common causes of organic (primary) MR include prolapse syndrome, flail leaflet, rheumatic heart disease, coronary artery disease (CAD), infective endocarditis, certain drugs (some anorectic drugs), and collagen vascular disease. […] In primary MR, one or several components of the mitral valve apparatus are directly affected. […] The most frequent aetiology of mitral incompetence is degenerative (prolapse, flail leaflet). […] Myxomatous degeneration is the main aetiology of prolapsing valvar leaflets, explaining the fact that MVP is uncommon before adolescence. […] Primary MVP occurs with increased frequency in patients with Marfan syndrome and other connective tissue diseases (Ehlers-Danlos syndrome, osteogenesis imperfecta, dominant cutis laxa or pseudoxanthoma elasticum).

• #13 Heart: mitral valve degenerative disease in Dogs (Canis) | Vetlexicon

  https://www.vetlexicon.com/canis/cardiology/articles/heart-mitral-valve-degenerative-disease/

  MMVD has been studied for a long time and while the underlying cause of it remains unknown, the pathology of the disease has been well described. Histologic changes in this disease show accumulation of the mucopolysaccharides hyaluronic acid and chondroitin sulfate. […] Fibroblastic proliferation results in swirls and nodules in the expanded mucopolysaccharide matrix. The fibrosa layer degenerates with swelling, hyalinizination, and disintegration of the collagen bundles. […] Gross lesions become more severe with time. The lesions begin as small discrete nodules at the margins of the valve leaflets. At this stage, the valve is typically competent. When the nodules enlarge they also start to coalesce, forming irregular opacities at the tips of the leaflets. These lesions enlarge further and tend to bulge up on the atrial surface. Calcification and hemorrhage can be seen in the body of the valve.

• #14 Mitral valve incompetence: epidemiology and causes

  https://www.escardio.org/Journals/E-Journal-of-Cardiology-Practice/Volume-16/Mitral-valve-incompetence-epidemiology-and-causes

  Rheumatic heart disease is the most serious sequela of rheumatic fever, developing to a varying degree in up to 50% of patients with rheumatic fever, leading to mitral valve regurgitation early or later in life. […] Rheumatic heart disease affects the mitral valve in up to 50% of cases and results in mitral insufficiency, mitral stenosis, or both. […] Papillary muscle rupture is another cause of acute mitral regurgitation. […] Mitral incompetence may occur as congenital malformations of the mitral valve. […] Mitral valve regurgitation may occur as a result of mitral chordal rupture, leaflet rupture (flail leaflet), leaflet perforation or interference of the vegetation mass with leaflet closure. […] Prolonged use of certain medications can cause mitral valve regurgitation, such as those containing ergotamine.

• #15 Mitral Stenosis: Background, Pathophysiology, Epidemiology

  https://emedicine.medscape.com/article/155724-overview

  Mitral stenosis (MS) is characterized by obstruction to left ventricular inflow at the level of mitral valve due to structural abnormality of the mitral valve apparatus. The most common cause of mitral stenosis is rheumatic fever. […] Acute insult leads to formation of multiple inflammatory foci (Aschoff bodies, perivascular mononuclear infiltrate) in the endocardium and myocardium. […] Whether the progression of valve damage is due to hemodynamic injury of the already affected valve apparatus or to the chronic inflammatory nature of the rheumatic process is unclear. […] Severe mitral stenosis occurs with a valve area of less than 1 cm2. As the valve progressively narrows, the resting diastolic mitral valve gradient, and hence left atrial pressure, increases. This leads to transudation of fluid into the lung interstitium and dyspnea at rest or with minimal exertion.

• #16 Mitral valve incompetence: epidemiology and causes

  https://www.escardio.org/Journals/E-Journal-of-Cardiology-Practice/Volume-16/Mitral-valve-incompetence-epidemiology-and-causes

  Rheumatic heart disease is the most serious sequela of rheumatic fever, developing to a varying degree in up to 50% of patients with rheumatic fever, leading to mitral valve regurgitation early or later in life. […] Rheumatic heart disease affects the mitral valve in up to 50% of cases and results in mitral insufficiency, mitral stenosis, or both. […] Papillary muscle rupture is another cause of acute mitral regurgitation. […] Mitral incompetence may occur as congenital malformations of the mitral valve. […] Mitral valve regurgitation may occur as a result of mitral chordal rupture, leaflet rupture (flail leaflet), leaflet perforation or interference of the vegetation mass with leaflet closure. […] Prolonged use of certain medications can cause mitral valve regurgitation, such as those containing ergotamine.

• #17 Mitral valve incompetence: epidemiology and causes

  https://www.escardio.org/Journals/E-Journal-of-Cardiology-Practice/Volume-16/Mitral-valve-incompetence-epidemiology-and-causes

  Rheumatic heart disease is the most serious sequela of rheumatic fever, developing to a varying degree in up to 50% of patients with rheumatic fever, leading to mitral valve regurgitation early or later in life. […] Rheumatic heart disease affects the mitral valve in up to 50% of cases and results in mitral insufficiency, mitral stenosis, or both. […] Papillary muscle rupture is another cause of acute mitral regurgitation. […] Mitral incompetence may occur as congenital malformations of the mitral valve. […] Mitral valve regurgitation may occur as a result of mitral chordal rupture, leaflet rupture (flail leaflet), leaflet perforation or interference of the vegetation mass with leaflet closure. […] Prolonged use of certain medications can cause mitral valve regurgitation, such as those containing ergotamine.

• #18 Mitral valve incompetence: epidemiology and causes

  https://www.escardio.org/Journals/E-Journal-of-Cardiology-Practice/Volume-16/Mitral-valve-incompetence-epidemiology-and-causes

  Rheumatic heart disease is the most serious sequela of rheumatic fever, developing to a varying degree in up to 50% of patients with rheumatic fever, leading to mitral valve regurgitation early or later in life. […] Rheumatic heart disease affects the mitral valve in up to 50% of cases and results in mitral insufficiency, mitral stenosis, or both. […] Papillary muscle rupture is another cause of acute mitral regurgitation. […] Mitral incompetence may occur as congenital malformations of the mitral valve. […] Mitral valve regurgitation may occur as a result of mitral chordal rupture, leaflet rupture (flail leaflet), leaflet perforation or interference of the vegetation mass with leaflet closure. […] Prolonged use of certain medications can cause mitral valve regurgitation, such as those containing ergotamine.

• #19 Mitral valve incompetence: epidemiology and causes

  https://www.escardio.org/Journals/E-Journal-of-Cardiology-Practice/Volume-16/Mitral-valve-incompetence-epidemiology-and-causes

  Mitral regurgitation may occur for organic or functional causes. The common causes of organic (primary) MR include prolapse syndrome, flail leaflet, rheumatic heart disease, CAD, infective endocarditis, certain drugs, and collagen vascular disease. […] MR may also occur secondary (functional) to a dilated annulus from dilatation of the left ventricle (from an imbalance between closing and tethering forces) or left atrial enlargement in patients with atrial fibrillation.

• #20 Mitral Regurgitation – Cardiovascular Disorders – Merck Manual Professional Edition

  https://www.merckmanuals.com/professional/cardiovascular-disorders/valvular-disorders/mitral-regurgitation

  Mitral regurgitation may be […] Common causes of chronic mitral regurgitation are intrinsic valve pathology (primary MR) or distortion of a normal valve by dilatation and impairment of the left ventricle and/or the mitral annulus (secondary MR). […] Secondary (functional) MR occurs when disease of the left ventricle or atrium impairs valve function. […] An increasingly recognized mechanism of secondary mitral regurgitation is atrial functional mitral regurgitation. This is caused by annular dilatation due to chronic atrial fibrillation with an enlarged left atrium. […] Complications of chronic MR include gradual enlargement of the left atrium (LA); LV enlargement and eccentric hypertrophy, which initially compensates for regurgitant flow (preserving forward stroke volume) but eventually decompensates (reducing forward stroke volume); atrial fibrillation, which may be further complicated by thromboembolism; and infective endocarditis.

• #21 Mitral Regurgitation – Cardiovascular Disorders – Merck Manual Professional Edition

  https://www.merckmanuals.com/professional/cardiovascular-disorders/valvular-disorders/mitral-regurgitation

  Mitral regurgitation may be […] Common causes of chronic mitral regurgitation are intrinsic valve pathology (primary MR) or distortion of a normal valve by dilatation and impairment of the left ventricle and/or the mitral annulus (secondary MR). […] Secondary (functional) MR occurs when disease of the left ventricle or atrium impairs valve function. […] An increasingly recognized mechanism of secondary mitral regurgitation is atrial functional mitral regurgitation. This is caused by annular dilatation due to chronic atrial fibrillation with an enlarged left atrium. […] Complications of chronic MR include gradual enlargement of the left atrium (LA); LV enlargement and eccentric hypertrophy, which initially compensates for regurgitant flow (preserving forward stroke volume) but eventually decompensates (reducing forward stroke volume); atrial fibrillation, which may be further complicated by thromboembolism; and infective endocarditis.

• #22 Mechanotransduction Mechanisms in Mitral Valve Physiology and Disease Pathogenesis

  https://pmc.ncbi.nlm.nih.gov/articles/PMC5744129/

  The mitral valve exists in a mechanically demanding environment, with the stress of each cardiac cycle deforming and shearing the native fibroblasts and endothelial cells. […] Mitral valve disease (MVD) has been linked to a variety of mechano-active genes ranging from extracellular components, mechanotransductive elements, and cytoplasmic and nuclear transcription factors. […] Understanding mechanosensing and transduction in mitral valve-specific cells may allow us to discover unique signal transduction pathways between cells and their environment, leading to cell or tissue specific mechanically targeted therapeutics for MVD. […] MVD results in altered mechanical and structural properties of the valve. […] Myxomatous mitral valves are characterized by leaflet enlargement, annular dilation, thickened and elongated chordae, GAG accumulation, loss of structure, increased compliance, and myxoid lesions.

• #23 Mechanotransduction Mechanisms in Mitral Valve Physiology and Disease Pathogenesis

  https://pmc.ncbi.nlm.nih.gov/articles/PMC5744129/

  The mitral valve exists in a mechanically demanding environment, with the stress of each cardiac cycle deforming and shearing the native fibroblasts and endothelial cells. […] Mitral valve disease (MVD) has been linked to a variety of mechano-active genes ranging from extracellular components, mechanotransductive elements, and cytoplasmic and nuclear transcription factors. […] Understanding mechanosensing and transduction in mitral valve-specific cells may allow us to discover unique signal transduction pathways between cells and their environment, leading to cell or tissue specific mechanically targeted therapeutics for MVD. […] MVD results in altered mechanical and structural properties of the valve. […] Myxomatous mitral valves are characterized by leaflet enlargement, annular dilation, thickened and elongated chordae, GAG accumulation, loss of structure, increased compliance, and myxoid lesions.

• #24

  https://www.jci.org/articles/view/22715/citations

  Mitral valve prolapse (MVP) is a common human phenotype, yet little is known about the pathogenesis of this condition. […] We thus hypothesized that increased TGF- signaling may contribute to the multisystem pathogenesis of MFS, including the development of myxomatous changes of the atrioventricular valves. […] Mitral valves from fibrillin-1deficient mice exhibited postnatally acquired alterations in architecture that correlated both temporally and spatially with increased cell proliferation, decreased apoptosis, and excess TGF- activation and signaling. […] In addition, TGF- antagonism in vivo rescued the valve phenotype, suggesting a cause and effect relationship. […] Expression analyses identified increased expression of numerous TGF-related genes that regulate cell proliferation and survival and plausibly contribute to myxomatous valve disease. […] These studies validate a novel, genetically engineered murine model of myxomatous changes of the mitral valve and provide critical insight into the pathogenetic mechanism of such changes in MFS and perhaps more common nonsyndromic variants of mitral valve disease.

• #25 Pathophysiology of valvular heart disease (Review)

  https://www.spandidos-publications.com/10.3892/etm.2016.3048

  Valvular heart disease (VHD) is caused by either damage or defect in one of the four heart valves, aortic, mitral, tricuspid or pulmonary. […] The pathogenesis of congenital and acquired CAVD is likely due to the interplay of genetic and environmental influences, even though the precise mechanisms are not known. […] Changes in the functionality and localization of matrix components potentially lead to VHD, since the proper organization of extracellular matrix (ECM) is essential in maintaining overall valve morphology and normal valve function. […] Genetic or acquired/environmental causes that disrupt the normal organization and composition of the ECM and communication between VECs and VICs alter valve mechanics and interfere with the valve leaflet function, culminating in heart failure.

• #26 Genomic expression patterns of mitral valve tissues from dogs with degenerative mitral valve disease in: American Journal of Veterinary Research Volume 67 Issue 8 ()

  https://avmajournals.avma.org/view/journals/ajvr/67/8/ajvr.67.8.1307.xml

  Our results provide insight into the genetic and molecular events that occur in dogs with DMVD by identifying a subset of 229 genes with an expression that is differentially regulated. […] On the basis of results of previous studies, we chose to assign each gene to 1 of 9 functional categories, and as such, we were able to recognize basic trends in core cellular functions as well as identify intriguing molecular pathways that would benefit from additional study. […] Inflammatory cell infiltrates are not routinely detected in myxomatous mitral valve leaflets during histologic examination. […] Results from our microarray study are interesting, in that our analysis indicated upregulation of numerous inflammatory cytokines (ie, IL-6, cyclooxygenase, and receptors for IL-1 and IL-10); adhesion molecules (ie, VCAM-1, ICAM-1, and monocyte chemoattractant protein); and the inflammatory marker, serum amyloid A.

• #27 Genomic expression patterns of mitral valve tissues from dogs with degenerative mitral valve disease in: American Journal of Veterinary Research Volume 67 Issue 8 ()

  https://avmajournals.avma.org/view/journals/ajvr/67/8/ajvr.67.8.1307.xml

  A striking finding of our study involved upregulation of the 5-HT2B receptor (3.9-fold increase). […] Our results reveal increased inflammatory cytokines, expression of endothelial adhesion molecules, and increased serotoninTGF- signaling in mitral valve tissues of affected dogs, compared with that of control dogs.

• #28

  https://journals.lww.com/mamc/fulltext/2015/01030/mechanisms_and_pathophysiology_of_mitral_valve.6.aspx

  The dynamic nature of the regurgitant orifice which decreases as the LV contracts further complicates elucidation of the mechanisms of MR. […] The MR results in volume overload of the LA and LV. The chronic LV volume overload in MR results in increasing annular dilatation that leads to cascading effect and further increases in MR that is why the terminology „MR begets MR.” […] In acute MR due to trauma, acute inferior or inferolateral wall MI or papillary muscle rupture, no compensatory mechanisms, and structural changes are present, and the regurgitant volume is imposed on a normal sized LA that causes a steep rise in LA pressure. […] The indices of systolic function of myocardium such as EF, fractional fiber shortening, and circumferential fiber shortening are inversely related to LV afterload.

• #29

  https://journals.lww.com/mamc/fulltext/2015/01030/mechanisms_and_pathophysiology_of_mitral_valve.6.aspx

  The dynamic nature of the regurgitant orifice which decreases as the LV contracts further complicates elucidation of the mechanisms of MR. […] The MR results in volume overload of the LA and LV. The chronic LV volume overload in MR results in increasing annular dilatation that leads to cascading effect and further increases in MR that is why the terminology „MR begets MR.” […] In acute MR due to trauma, acute inferior or inferolateral wall MI or papillary muscle rupture, no compensatory mechanisms, and structural changes are present, and the regurgitant volume is imposed on a normal sized LA that causes a steep rise in LA pressure. […] The indices of systolic function of myocardium such as EF, fractional fiber shortening, and circumferential fiber shortening are inversely related to LV afterload.

• #30 CV Physiology | Valvular Insufficiency (Regurgitation)

  https://cvphysiology.com/heart-disease/hd005

  Mitral valve regurgitation occurs when the mitral valve fails to close completely during ventricular systole, which causes blood to flow back (regurgitate) into the left atrium (LA) as the left ventricle (LV) contracts. […] During LV filling, the higher pressure of the LA leads to an increase in LV end-diastolic pressure (25 mmHg in this example) and LV end-diastolic volume. […] In acute mitral regurgitation (e.g., after sudden rupture of the chordae tendineae), the atrial pressure can become very elevated. […] In chronic mitral regurgitation, the left atrium adapts to the larger volume by dilating (anatomic remodeling), which increases its compliance. […] The backward flow of blood into the LA during ventricular systole results in a holosystolic murmur. […] Increased left atrial pressures can lead to pulmonary congestion and edema.

• #31 CV Physiology | Valvular Insufficiency (Regurgitation)

  https://cvphysiology.com/heart-disease/hd005

  Mitral valve regurgitation occurs when the mitral valve fails to close completely during ventricular systole, which causes blood to flow back (regurgitate) into the left atrium (LA) as the left ventricle (LV) contracts. […] During LV filling, the higher pressure of the LA leads to an increase in LV end-diastolic pressure (25 mmHg in this example) and LV end-diastolic volume. […] In acute mitral regurgitation (e.g., after sudden rupture of the chordae tendineae), the atrial pressure can become very elevated. […] In chronic mitral regurgitation, the left atrium adapts to the larger volume by dilating (anatomic remodeling), which increases its compliance. […] The backward flow of blood into the LA during ventricular systole results in a holosystolic murmur. […] Increased left atrial pressures can lead to pulmonary congestion and edema.

• #32 CV Physiology | Valvular Insufficiency (Regurgitation)

  https://cvphysiology.com/heart-disease/hd005

  Mitral valve regurgitation occurs when the mitral valve fails to close completely during ventricular systole, which causes blood to flow back (regurgitate) into the left atrium (LA) as the left ventricle (LV) contracts. […] During LV filling, the higher pressure of the LA leads to an increase in LV end-diastolic pressure (25 mmHg in this example) and LV end-diastolic volume. […] In acute mitral regurgitation (e.g., after sudden rupture of the chordae tendineae), the atrial pressure can become very elevated. […] In chronic mitral regurgitation, the left atrium adapts to the larger volume by dilating (anatomic remodeling), which increases its compliance. […] The backward flow of blood into the LA during ventricular systole results in a holosystolic murmur. […] Increased left atrial pressures can lead to pulmonary congestion and edema.

• #33 CV Physiology | Valvular Insufficiency (Regurgitation)

  https://cvphysiology.com/heart-disease/hd005

  Mitral valve regurgitation occurs when the mitral valve fails to close completely during ventricular systole, which causes blood to flow back (regurgitate) into the left atrium (LA) as the left ventricle (LV) contracts. […] During LV filling, the higher pressure of the LA leads to an increase in LV end-diastolic pressure (25 mmHg in this example) and LV end-diastolic volume. […] In acute mitral regurgitation (e.g., after sudden rupture of the chordae tendineae), the atrial pressure can become very elevated. […] In chronic mitral regurgitation, the left atrium adapts to the larger volume by dilating (anatomic remodeling), which increases its compliance. […] The backward flow of blood into the LA during ventricular systole results in a holosystolic murmur. […] Increased left atrial pressures can lead to pulmonary congestion and edema.

• #34 Mitral Stenosis: Background, Pathophysiology, Epidemiology

  https://emedicine.medscape.com/article/155724-overview

  Mitral stenosis (MS) is characterized by obstruction to left ventricular inflow at the level of mitral valve due to structural abnormality of the mitral valve apparatus. The most common cause of mitral stenosis is rheumatic fever. […] Acute insult leads to formation of multiple inflammatory foci (Aschoff bodies, perivascular mononuclear infiltrate) in the endocardium and myocardium. […] Whether the progression of valve damage is due to hemodynamic injury of the already affected valve apparatus or to the chronic inflammatory nature of the rheumatic process is unclear. […] Severe mitral stenosis occurs with a valve area of less than 1 cm2. As the valve progressively narrows, the resting diastolic mitral valve gradient, and hence left atrial pressure, increases. This leads to transudation of fluid into the lung interstitium and dyspnea at rest or with minimal exertion.

• #35 Mitral Stenosis Topic Review

  https://www.healio.com/cardiology/learn-the-heart/cardiology-review/topic-reviews/mitral-stenosis

  Over time, as mitral stenosis worsens and the mitral valve area decreases, right heart pressures increase to maintain cardiac output across the stenotic valve with a pressure gradient between the left atrium and the left ventricle. On exertion, with increases in cardiac output and increased flow through the mitral valve, the pressure gradient becomes exponentially larger, and pulmonary edema can occur. […] Thus, if the velocity (V) of flow is doubled, the transmitral pressure gradient increases by a factor of four. The resultant large increase in pulmonary and LA pressures is responsible for the exertional symptoms seen in mitral stenosis.

• #36 Mitral Stenosis Topic Review

  https://www.healio.com/cardiology/learn-the-heart/cardiology-review/topic-reviews/mitral-stenosis

  Over time, as mitral stenosis worsens and the mitral valve area decreases, right heart pressures increase to maintain cardiac output across the stenotic valve with a pressure gradient between the left atrium and the left ventricle. On exertion, with increases in cardiac output and increased flow through the mitral valve, the pressure gradient becomes exponentially larger, and pulmonary edema can occur. […] Thus, if the velocity (V) of flow is doubled, the transmitral pressure gradient increases by a factor of four. The resultant large increase in pulmonary and LA pressures is responsible for the exertional symptoms seen in mitral stenosis.

• #37 Mitral Valve Prolapse: Practice Essentials, Background, Pathophysiology

  https://emedicine.medscape.com/article/155494-overview

  Mitral valve prolapse (MVP) is characterized primarily by myxomatous degeneration of the mitral valve leaflets. In younger populations, there is gross redundancy of both the anterior and posterior leaflets and chordal apparatus. This is the extreme form of myxomatous degeneration, known as Barlow syndrome. In older populations, however, MVP is characterized by fibroelastic deficiency, sometimes with superimposed chordal rupture due to a lack of connective tissue support. […] These anatomic abnormalities result in malcoaptation of mitral valve leaflets during systole, resulting in regurgitation. Mitral annular dilatation may also develop over time, resulting in further progression of mitral regurgitation (MR). Acute severe MR results in congestive heart failure symptoms without left ventricular dilatation. Conversely, chronic or progressively severe MR can lead to ventricular dilatation and dysfunction, neurohormonal activation, and heart failure. Elevation in left atrial pressures can result in left atrial enlargement, atrial fibrillation, pulmonary congestion, and pulmonary hypertension.

• #38 Mitral Valve Prolapse: Practice Essentials, Background, Pathophysiology

  https://emedicine.medscape.com/article/155494-overview

  Mitral valve prolapse (MVP) is characterized primarily by myxomatous degeneration of the mitral valve leaflets. In younger populations, there is gross redundancy of both the anterior and posterior leaflets and chordal apparatus. This is the extreme form of myxomatous degeneration, known as Barlow syndrome. In older populations, however, MVP is characterized by fibroelastic deficiency, sometimes with superimposed chordal rupture due to a lack of connective tissue support. […] These anatomic abnormalities result in malcoaptation of mitral valve leaflets during systole, resulting in regurgitation. Mitral annular dilatation may also develop over time, resulting in further progression of mitral regurgitation (MR). Acute severe MR results in congestive heart failure symptoms without left ventricular dilatation. Conversely, chronic or progressively severe MR can lead to ventricular dilatation and dysfunction, neurohormonal activation, and heart failure. Elevation in left atrial pressures can result in left atrial enlargement, atrial fibrillation, pulmonary congestion, and pulmonary hypertension.

• #39 Pathophysiology of valvular heart disease (Review)

  https://www.spandidos-publications.com/10.3892/etm.2016.3048

  The histopathologic heterogeneity of CAVD indicates the involvement of diverse cell-dependent mechanisms that regulate calcium load on the valve leaflets, as well as the participation of different cell types, including interstitial cells, endothelial cells and cardiac chondrocytes, in valve biomineralization. […] Inflammation is known to play a significant role in many types of macrovascular calcification, including CAVD. […] Advances in genomic technologies have led to the identification of several genes that contribute to the normal development and function of the four heart valves and to the identification of many genetic abnormalities in some of these genes in congenital form of CAVD. […] The most common congenital valve anomalies are bicuspid aortic valve (BAV) and mitral valve prolapse (MVP).

• #40 Pathophysiology of valvular heart disease (Review)

  https://www.spandidos-publications.com/10.3892/etm.2016.3048

  The histopathologic heterogeneity of CAVD indicates the involvement of diverse cell-dependent mechanisms that regulate calcium load on the valve leaflets, as well as the participation of different cell types, including interstitial cells, endothelial cells and cardiac chondrocytes, in valve biomineralization. […] Inflammation is known to play a significant role in many types of macrovascular calcification, including CAVD. […] Advances in genomic technologies have led to the identification of several genes that contribute to the normal development and function of the four heart valves and to the identification of many genetic abnormalities in some of these genes in congenital form of CAVD. […] The most common congenital valve anomalies are bicuspid aortic valve (BAV) and mitral valve prolapse (MVP).

• #41 Mitral valve incompetence: epidemiology and causes

  https://www.escardio.org/Journals/E-Journal-of-Cardiology-Practice/Volume-16/Mitral-valve-incompetence-epidemiology-and-causes

  Mitral regurgitation (MR) is the second most frequent indication for valve surgery. The common causes of organic (primary) MR include prolapse syndrome, flail leaflet, rheumatic heart disease, coronary artery disease (CAD), infective endocarditis, certain drugs (some anorectic drugs), and collagen vascular disease. […] In primary MR, one or several components of the mitral valve apparatus are directly affected. […] The most frequent aetiology of mitral incompetence is degenerative (prolapse, flail leaflet). […] Myxomatous degeneration is the main aetiology of prolapsing valvar leaflets, explaining the fact that MVP is uncommon before adolescence. […] Primary MVP occurs with increased frequency in patients with Marfan syndrome and other connective tissue diseases (Ehlers-Danlos syndrome, osteogenesis imperfecta, dominant cutis laxa or pseudoxanthoma elasticum).

• #42

  https://www.jci.org/articles/view/22715

  Mitral valve prolapse (MVP) is a common human phenotype, yet little is known about the pathogenesis of this condition. MVP can occur in the context of genetic syndromes, including Marfan syndrome (MFS), an autosomal-dominant connective tissue disorder caused by mutations in fibrillin-1. Fibrillin-1 contributes to the regulated activation of the cytokine TGF-, and enhanced signaling is a consequence of fibrillin-1 deficiency. We thus hypothesized that increased TGF- signaling may contribute to the multisystem pathogenesis of MFS, including the development of myxomatous changes of the atrioventricular valves. […] Little is known about the precise pathogenetic sequence that culminates in either primary or Marfan-related myxomatous mitral valve disease. Increased production of both collagen, particularly type III collagen, and glycosaminoglycans has been documented in myxomatous valves, and some postulate that this may be the result of a leaflet response to repeated mechanical stress.

• #43

  https://www.jci.org/articles/view/22715

  The results of our expression analyses have allowed us to begin to explore pathogenetic mechanisms and candidate effectors involved in mitral valve disease in the context of excess TGF- signaling. One set of genes of interest are those that are regulated by TGF-, including IGH3, endothelin-1 (EDN1), and tissue inhibitor of metalloproteinase 1 (TIMP1). […] We therefore hypothesize that myxomatous changes of the mitral valve in MFS may manifest decreased cell adhesion and increased cell proliferation and survival due to excess IGH3, EDN1, and/or TIMP1 activity imposed by a deficiency of fibrillin-1. […] This work provides a novel context within which to further explore the pathogenesis of acquired myxomatous degeneration of the mitral valve in both Marfan syndrome and more common, non-syndromic variants of disease.

• #44 Degenerative Valve Disease: Classification, Diagnosis, and Treatment of Mitral Regurgitation | Today’s Veterinary Practice

  https://todaysveterinarypractice.com/cardiology/degenerative-valve-disease-classification-diagnosis-and-treatment-of-mitral-regurgitation/

  Degenerative valve disease (DVD) is the most common heart disease and the most common cause of congestive heart failure (CHF) in dogs. […] The mitral valve is most commonly and severely affected, although the tricuspid valve is concurrently involved in 30% of cases. […] DVD often progresses over many years, and morbidity is directly related to the degree of valvular insufficiency and subsequent volume overload to the heart. […] The degree of valvular insufficiency is affected by degree of structural change in the valve leaflets, integrity of the chordae tendineae, myocardial contractility, and chamber dilation. […] Secondary changes related to valvular insufficiency contribute to progressive valvular insufficiency. […] All of these changes lead to progressive valvular regurgitation and subsequent greater volume overload, triggering additional chamber dilation and eventually heart failure.

• #45 Degenerative Valve Disease: Classification, Diagnosis, and Treatment of Mitral Regurgitation | Today’s Veterinary Practice

  https://todaysveterinarypractice.com/cardiology/degenerative-valve-disease-classification-diagnosis-and-treatment-of-mitral-regurgitation/

  Degenerative valve disease (DVD) is the most common heart disease and the most common cause of congestive heart failure (CHF) in dogs. […] The mitral valve is most commonly and severely affected, although the tricuspid valve is concurrently involved in 30% of cases. […] DVD often progresses over many years, and morbidity is directly related to the degree of valvular insufficiency and subsequent volume overload to the heart. […] The degree of valvular insufficiency is affected by degree of structural change in the valve leaflets, integrity of the chordae tendineae, myocardial contractility, and chamber dilation. […] Secondary changes related to valvular insufficiency contribute to progressive valvular insufficiency. […] All of these changes lead to progressive valvular regurgitation and subsequent greater volume overload, triggering additional chamber dilation and eventually heart failure.

• #46 RNA sequencing provides novel insights into the pathogenesis of naturally occurring myxomatous mitral valve disease stage B1 in beagle dogs | PLOS One

  https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0300813

  Myxomatous mitral valve disease (MMVD) is a complex disease and shows variable progression from mild valve leakage to severe regurgitation, potentially leading to heart failure. […] The underlying pathophysiology of MMVD is primarily attributed to myxomatous degeneration of the mitral valve and associated chordae tendineae; additionally, the tricuspid valve can also be affected by myxomatous changes. […] Therefore, understanding the pathogenesis of canine MMVD necessitates a focus on the aging-related changes in the cardiovascular system. […] To address these knowledge gaps, we aimed to reveal the underlying pathogenesis of MMVD stage B1 by performing a comprehensive clinical evaluation along with the comparison of RNA-seq data to uncover gene expression disparities and potential molecular mechanisms.

• #47 RNA sequencing provides novel insights into the pathogenesis of naturally occurring myxomatous mitral valve disease stage B1 in beagle dogs | PLOS One

  https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0300813

  Myxomatous mitral valve disease (MMVD) is a complex disease and shows variable progression from mild valve leakage to severe regurgitation, potentially leading to heart failure. […] The underlying pathophysiology of MMVD is primarily attributed to myxomatous degeneration of the mitral valve and associated chordae tendineae; additionally, the tricuspid valve can also be affected by myxomatous changes. […] Therefore, understanding the pathogenesis of canine MMVD necessitates a focus on the aging-related changes in the cardiovascular system. […] To address these knowledge gaps, we aimed to reveal the underlying pathogenesis of MMVD stage B1 by performing a comprehensive clinical evaluation along with the comparison of RNA-seq data to uncover gene expression disparities and potential molecular mechanisms.

• #48 Heart: mitral valve degenerative disease in Dogs (Canis) | Vetlexicon

  https://www.vetlexicon.com/canis/cardiology/articles/heart-mitral-valve-degenerative-disease/

  MMVD has been studied for a long time and while the underlying cause of it remains unknown, the pathology of the disease has been well described. Histologic changes in this disease show accumulation of the mucopolysaccharides hyaluronic acid and chondroitin sulfate. […] Fibroblastic proliferation results in swirls and nodules in the expanded mucopolysaccharide matrix. The fibrosa layer degenerates with swelling, hyalinizination, and disintegration of the collagen bundles. […] Gross lesions become more severe with time. The lesions begin as small discrete nodules at the margins of the valve leaflets. At this stage, the valve is typically competent. When the nodules enlarge they also start to coalesce, forming irregular opacities at the tips of the leaflets. These lesions enlarge further and tend to bulge up on the atrial surface. Calcification and hemorrhage can be seen in the body of the valve.

• #49 Heart: mitral valve degenerative disease in Dogs (Canis) | Vetlexicon

  https://www.vetlexicon.com/canis/cardiology/articles/heart-mitral-valve-degenerative-disease/

  MMVD has been studied for a long time and while the underlying cause of it remains unknown, the pathology of the disease has been well described. Histologic changes in this disease show accumulation of the mucopolysaccharides hyaluronic acid and chondroitin sulfate. […] Fibroblastic proliferation results in swirls and nodules in the expanded mucopolysaccharide matrix. The fibrosa layer degenerates with swelling, hyalinizination, and disintegration of the collagen bundles. […] Gross lesions become more severe with time. The lesions begin as small discrete nodules at the margins of the valve leaflets. At this stage, the valve is typically competent. When the nodules enlarge they also start to coalesce, forming irregular opacities at the tips of the leaflets. These lesions enlarge further and tend to bulge up on the atrial surface. Calcification and hemorrhage can be seen in the body of the valve.

• #50 Heart: mitral valve degenerative disease in Dogs (Canis) | Vetlexicon

  https://www.vetlexicon.com/canis/cardiology/articles/heart-mitral-valve-degenerative-disease/

  MMVD has been studied for a long time and while the underlying cause of it remains unknown, the pathology of the disease has been well described. Histologic changes in this disease show accumulation of the mucopolysaccharides hyaluronic acid and chondroitin sulfate. […] Fibroblastic proliferation results in swirls and nodules in the expanded mucopolysaccharide matrix. The fibrosa layer degenerates with swelling, hyalinizination, and disintegration of the collagen bundles. […] Gross lesions become more severe with time. The lesions begin as small discrete nodules at the margins of the valve leaflets. At this stage, the valve is typically competent. When the nodules enlarge they also start to coalesce, forming irregular opacities at the tips of the leaflets. These lesions enlarge further and tend to bulge up on the atrial surface. Calcification and hemorrhage can be seen in the body of the valve.

• #51 Heart: mitral valve degenerative disease in Dogs (Canis) | Vetlexicon

  https://www.vetlexicon.com/canis/cardiology/articles/heart-mitral-valve-degenerative-disease/

  During the initial stages of MMVD, although there is gross thickening of the mitral valve, the valve is competent and there are no hemodynamic changes. The leaflets may begin to prolapse, or bow backward, into the left atrium in systole; however, they remain competent. […] As the degeneration progresses, the mitral valve and chordae tendineae continue to thicken, so that the leaflets no longer coapt properly. This leads to insufficiency across the valve, most commonly called mitral regurgitation (MR) when some of the blood from the left ventricle is pumped backwards into the left atrium instead of into the aorta in systole. […] As MMVD progresses, the MR will progress and so the compensatory cardiac changes will attempt to maintain normal cardiac output. There will be progressive left atrial dilation and eccentric hypertrophy of the left ventricle and as long as the metabolic demands of the body are met, there will be no signs of heart failure.

• #52 Heart: mitral valve degenerative disease in Dogs (Canis) | Vetlexicon

  https://www.vetlexicon.com/canis/cardiology/articles/heart-mitral-valve-degenerative-disease/

  During the initial stages of MMVD, although there is gross thickening of the mitral valve, the valve is competent and there are no hemodynamic changes. The leaflets may begin to prolapse, or bow backward, into the left atrium in systole; however, they remain competent. […] As the degeneration progresses, the mitral valve and chordae tendineae continue to thicken, so that the leaflets no longer coapt properly. This leads to insufficiency across the valve, most commonly called mitral regurgitation (MR) when some of the blood from the left ventricle is pumped backwards into the left atrium instead of into the aorta in systole. […] As MMVD progresses, the MR will progress and so the compensatory cardiac changes will attempt to maintain normal cardiac output. There will be progressive left atrial dilation and eccentric hypertrophy of the left ventricle and as long as the metabolic demands of the body are met, there will be no signs of heart failure.

• #53 Heart: mitral valve degenerative disease in Dogs (Canis) | Vetlexicon

  https://www.vetlexicon.com/canis/cardiology/articles/heart-mitral-valve-degenerative-disease/

  During the initial stages of MMVD, although there is gross thickening of the mitral valve, the valve is competent and there are no hemodynamic changes. The leaflets may begin to prolapse, or bow backward, into the left atrium in systole; however, they remain competent. […] As the degeneration progresses, the mitral valve and chordae tendineae continue to thicken, so that the leaflets no longer coapt properly. This leads to insufficiency across the valve, most commonly called mitral regurgitation (MR) when some of the blood from the left ventricle is pumped backwards into the left atrium instead of into the aorta in systole. […] As MMVD progresses, the MR will progress and so the compensatory cardiac changes will attempt to maintain normal cardiac output. There will be progressive left atrial dilation and eccentric hypertrophy of the left ventricle and as long as the metabolic demands of the body are met, there will be no signs of heart failure.

• #54 Heart: mitral valve degenerative disease in Dogs (Canis) | Vetlexicon

  https://www.vetlexicon.com/canis/cardiology/articles/heart-mitral-valve-degenerative-disease/

  Over time, while the cardiac compensation may maintain cardiac output at rest, it may be unable to do so with activity or stress. There will be inadequate perfusion to meet the increased metabolic demands of the body and the systemic compensatory mechanisms will become activated to maintain blood pressure. This likely begins to occur when the MR has become moderate to severe. The sympathetic nervous system and the renin-angiotensin-aldosterone system (RAAS) will be activated and lead to increases in preload and afterload.

• #55 Mitral Regurgitation – Cardiovascular Disorders – Merck Manual Professional Edition

  https://www.merckmanuals.com/professional/cardiovascular-disorders/valvular-disorders/mitral-regurgitation

  Mitral regurgitation may be […] Common causes of chronic mitral regurgitation are intrinsic valve pathology (primary MR) or distortion of a normal valve by dilatation and impairment of the left ventricle and/or the mitral annulus (secondary MR). […] Secondary (functional) MR occurs when disease of the left ventricle or atrium impairs valve function. […] An increasingly recognized mechanism of secondary mitral regurgitation is atrial functional mitral regurgitation. This is caused by annular dilatation due to chronic atrial fibrillation with an enlarged left atrium. […] Complications of chronic MR include gradual enlargement of the left atrium (LA); LV enlargement and eccentric hypertrophy, which initially compensates for regurgitant flow (preserving forward stroke volume) but eventually decompensates (reducing forward stroke volume); atrial fibrillation, which may be further complicated by thromboembolism; and infective endocarditis.

• #56 Mitral Regurgitation – Cardiovascular Disorders – Merck Manual Professional Edition

  https://www.merckmanuals.com/professional/cardiovascular-disorders/valvular-disorders/mitral-regurgitation

  In secondary MR, these medications can reduce the severity of MR and probably improve prognosis. […] Chronic primary mitral regurgitation that is severe needs intervention at the onset of symptoms or decompensation (LVEF 60% or LV end-systolic diameter 40 mm). […] In secondary mitral regurgitation, mitral valve replacement is preferred over repair with a downsized annuloplasty ring because mitral valve replacement results in less mitral regurgitation and heart failure 2 years after treatment. […] In about 50% of decompensated patients, prosthetic valve implantation markedly depresses ejection fraction because in such patients, ventricular function has become dependent on the afterload reduction of MR. […] Prognosis of mitral regurgitation varies by duration, severity, and cause. […] Some MR worsens and eventually becomes severe.

• #57 Mitral Stenosis: Background, Pathophysiology, Epidemiology

  https://emedicine.medscape.com/article/155724-overview

  Pulmonary hypertension may develop as a result of (1) retrograde transmission of left atrial pressure, (2) pulmonary arteriolar constriction, (3) interstitial edema, or (4) obliterative changes in the pulmonary vascular bed (intimal hyperplasia and medial hypertrophy). […] Approximately one third of patients with rheumatic mitral stenosis have depressed left ventricular systolic function as a result of chronic rheumatic myocarditis.

• #58 Mitral Stenosis: Background, Pathophysiology, Epidemiology

  https://emedicine.medscape.com/article/155724-overview

  Pulmonary hypertension may develop as a result of (1) retrograde transmission of left atrial pressure, (2) pulmonary arteriolar constriction, (3) interstitial edema, or (4) obliterative changes in the pulmonary vascular bed (intimal hyperplasia and medial hypertrophy). […] Approximately one third of patients with rheumatic mitral stenosis have depressed left ventricular systolic function as a result of chronic rheumatic myocarditis.

• #59

  https://www.jci.org/articles/view/22715

  The results of our expression analyses have allowed us to begin to explore pathogenetic mechanisms and candidate effectors involved in mitral valve disease in the context of excess TGF- signaling. One set of genes of interest are those that are regulated by TGF-, including IGH3, endothelin-1 (EDN1), and tissue inhibitor of metalloproteinase 1 (TIMP1). […] We therefore hypothesize that myxomatous changes of the mitral valve in MFS may manifest decreased cell adhesion and increased cell proliferation and survival due to excess IGH3, EDN1, and/or TIMP1 activity imposed by a deficiency of fibrillin-1. […] This work provides a novel context within which to further explore the pathogenesis of acquired myxomatous degeneration of the mitral valve in both Marfan syndrome and more common, non-syndromic variants of disease.

• #60 RNA sequencing provides novel insights into the pathogenesis of naturally occurring myxomatous mitral valve disease stage B1 in beagle dogs | PLOS One

  https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0300813

  Our work not only enhances the understanding of age-related MMVD progression but also establishes a foundation for advanced diagnostic and therapeutic strategies to improve canine cardiovascular health. […] The changes detected in cardiac markers and the identification of genes linked to ECM remodeling, prostaglandin metabolism, immune modulation, and IFN pathways enhance our understanding of age-related MMVD. […] The findings of this study not only provide valuable insights for future mechanistic studies but also offer a clinical means to more accurately identify MMVD stage B1 in dogs.

• #61 RNA sequencing provides novel insights into the pathogenesis of naturally occurring myxomatous mitral valve disease stage B1 in beagle dogs | PLOS One

  https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0300813

  Our work not only enhances the understanding of age-related MMVD progression but also establishes a foundation for advanced diagnostic and therapeutic strategies to improve canine cardiovascular health. […] The changes detected in cardiac markers and the identification of genes linked to ECM remodeling, prostaglandin metabolism, immune modulation, and IFN pathways enhance our understanding of age-related MMVD. […] The findings of this study not only provide valuable insights for future mechanistic studies but also offer a clinical means to more accurately identify MMVD stage B1 in dogs.

• #62 Mitral valve disease−morphology and mechanisms – Archive ouverte HAL

  https://hal.science/hal-01830969

  Mitral valve disease is a frequent cause of heart failure and death. Emerging evidence indicates that the mitral valve is not a passive structure, but even in adult life remains dynamic and accessible for treatment. […] This concept motivates efforts to reduce the clinical progression of mitral valve disease through early detection and modification of underlying mechanisms. Discoveries of genetic mutations causing mitral valve elongation and prolapse have revealed that growth factor signalling and cell migration pathways are regulated by structural molecules in ways that can be modified to limit progression from developmental defects to valve degeneration with clinical complications. […] Mitral valve enlargement can determine left ventricular outflow tract obstruction in hypertrophic cardiomyopathy, and might be stimulated by potentially modifiable biological valvular-ventricular interactions. Mitral valve plasticity also allows adaptive growth in response to ventricular remodelling. However, adverse cellular and mechanobiological processes create relative leaflet deficiency in the ischaemic setting, leading to mitral regurgitation with increased heart failure and mortality. […] Our approach, which bridges clinicians and basic scientists, enables the correlation of observed disease with cellular and molecular mechanisms, leading to the discovery of new opportunities for improving the natural history of mitral valve disease.

• #63 Mechanotransduction Mechanisms in Mitral Valve Physiology and Disease Pathogenesis

  https://pmc.ncbi.nlm.nih.gov/articles/PMC5744129/

  The mitral valve exists in a mechanically demanding environment, with the stress of each cardiac cycle deforming and shearing the native fibroblasts and endothelial cells. […] Mitral valve disease (MVD) has been linked to a variety of mechano-active genes ranging from extracellular components, mechanotransductive elements, and cytoplasmic and nuclear transcription factors. […] Understanding mechanosensing and transduction in mitral valve-specific cells may allow us to discover unique signal transduction pathways between cells and their environment, leading to cell or tissue specific mechanically targeted therapeutics for MVD. […] MVD results in altered mechanical and structural properties of the valve. […] Myxomatous mitral valves are characterized by leaflet enlargement, annular dilation, thickened and elongated chordae, GAG accumulation, loss of structure, increased compliance, and myxoid lesions.

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