Materiały źródłowe

• #1 Heart Failure: Practice Essentials, Background, Pathophysiology

  https://emedicine.medscape.com/article/163062-overview

  Heart failure develops when the heart, via an abnormality of cardiac function (detectable or not), fails to pump blood at a rate commensurate with the requirements of the metabolizing tissues or is able to do so only with an elevated diastolic filling pressure. […] Heart failure is the pathophysiologic state in which the heart, via an abnormality of cardiac function (detectable or not), fails to pump blood at a rate commensurate with the requirements of the metabolizing tissues or is able to do so only with an elevated diastolic filling pressure. […] The common pathophysiologic state that perpetuates the progression of heart failure is extremely complex, regardless of the precipitating event. Compensatory mechanisms exist on every level of organization, from the subcellular all the way through to organ-to-organ interactions. Only when this network of adaptations becomes overwhelmed does heart failure ensue.

• #2 Pathophysiology of heart failure

  https://pmc.ncbi.nlm.nih.gov/articles/PMC7944197/

  Heart failure is an epidemic disease which affects about 1% to 2% of the population worldwide. Both, the etiology and phenotype of heart failure differ largely. Following a cardiac injury (e.g., myocardial infarction, increased preload or afterload) cellular, structural and neurohumoral modulations occur that affect the phenotype being present. These processes influence the cell function among intra- as well as intercellular behavior. In consequence, activation of the sympathoadrenergic and renin-angiotensin-aldosterone-system takes place leading to adaptive mechanisms, which are accompanied by volume overload, tachycardia, dyspnoea and further deterioration of the cellular function (vicious circle). There exists no heart failure specific clinical sign; the clinical symptomatic shows progressive deterioration acutely or chronically. As a measure of cellular dysfunction, the level of neurohormones (norepinephrine) and natriuretic peptides (e.g., NT-pro BNP) increase.

• #3 Heart Failure Pathogenesis Elucidation and New Treatment Method Development | JMA Journal

  https://www.jmaj.jp/detail.php?id=10.31662%2Fjmaj.2022-0106

  Heart failure (HF) is a leading cause of death worldwide. In Japan, the number of HF patients has increased with its aging population, resulting in HF pandemic. HF is the final stage of various cardiovascular diseases, including valvular heart disease, ischemic heart disease, atrial fibrillation, and hypertension. […] Understanding the molecular mechanisms underlying this process is crucial to elucidate HF pathophysiology. […] We demonstrated that ischemia and DNA damage are important in the progression of hypertrophy to HF. […] To realize precision medicines for HF, the underlying molecular mechanisms need to be elucidated. […] Understanding the molecular mechanisms underlying cardiac hypertrophy is crucial to elucidate HF pathophysiology. […] Various factors including hemodynamic stress, aging, neurohumoral factors, developmental abnormalities, cell death, mitochondrial disorders, myocardial ischemia, calcium regulation, catecholamine receptors, inflammation, metabolism, and oxidative stress are involved in HF development.

• #4 Pathophysiology of heart failure – Schwinger – Cardiovascular Diagnosis and Therapy

  https://cdt.amegroups.org/article/view/46185/html

  Heart failure is an epidemic disease which affects about 1% to 2% of the population worldwide. Both, the etiology and phenotype of heart failure differ largely. Following a cardiac injury (e.g., myocardial infarction, increased preload or afterload) cellular, structural and neurohumoral modulations occur that affect the phenotype being present. These processes influence the cell function among intra- as well as intercellular behavior. In consequence, activation of the sympathoadrenergic and renin-angiotensin-aldosterone-system takes place leading to adaptive mechanisms, which are accompanied by volume overload, tachycardia, dyspnoea and further deterioration of the cellular function (vicious circle). There exists no heart failure specific clinical sign; the clinical symptomatic shows progressive deterioration acutely or chronically.

• #5 Pathophysiology of heart failure

  https://pmc.ncbi.nlm.nih.gov/articles/PMC7944197/

  Identification of the pathophysiological mechanism leading to heart failure is crucial to choose adequate therapeutic options i.e., valve repair, treatment of rhythm disorders, pharmacological treatment. […] The understanding of the underlying pathophysiology of heart failure is essential to initiate the adequate therapeutic option individually for each patient. […] The phenotype of the heart may be predominantly excentric (e.g., following volume overload, myocardial infarction), concentric (e.g., following pressure overload, aortic stenosis) or a combination of both. The adaptive remodeling (change in LV mass, volume, structure) is influenced by the phenotype, comorbidities (e.g., diabetes), risk factors (e.g., hypertension) and by the damaging factors (e.g., myocardial stress following volume load after NSAR treatment; high heart rate). Chronic or acute injury (e.g., myocardial infarction) as well as overload (volume, pressure) of the heart will initiate structural and subsequent functional changes. In consequence physiological (mostly reversible) or pathological (e.g., fibrosis) adaptation occur and involve cardiomyocytes (hypertrophy, apoptosis, necrosis), fibroblasts (proliferation), endothelium and interstitium (extracellular matrix). These adaptive or maladaptive processes are the same, independent of the underlying pathological mechanism and involve the entire heart. […] The understanding of the underlying pathophysiology of heart failure is essential to initiate the adequate therapeutic option individually for each patient.

• #6 Pathophysiology of heart failure – Wikipedia

  https://en.wikipedia.org/wiki/Pathophysiology_of_heart_failure

  The main pathophysiology of heart failure is a reduction in the efficiency of the heart muscle, through damage or overloading. As such, it can be caused by a wide number of conditions, including myocardial infarction (in which the heart muscle is starved of oxygen and dies), hypertension (which increases the force of contraction needed to pump blood) and cardiac amyloidosis (in which misfolded proteins are deposited in the heart muscle, causing it to stiffen). […] The heart of a person with heart failure may have a reduced force of contraction due to overloading of the ventricle. In a healthy heart, increased filling of the ventricle results in increased contraction force (by the Frank-Starling law of the heart) and thus a rise in cardiac output. In heart failure, this mechanism fails, as the ventricle is loaded with blood to the point where heart muscle contraction becomes less efficient. This is due to reduced ability to cross-link actin and myosin filaments in over-stretched heart muscle.

• #7 Pathophysiology of Heart failure | PPT

  https://www.slideshare.net/slideshow/pathophysiology-of-heart-failure/73935073

  HEART FAILURE Defined as the pathophysiologic state in which impaired cardiac function is unable to maintain an adequate circulation for the metabolic needs of the tissues of the body. It may be acute or chronic. The term congestive heart failure (CHF) is used for the chronic form of heart failure in which the patient has evidence of congestion of peripheral circulation and of lungs. CHF is the end-result of various forms of serious heart diseases. […] Heart failure may be caused by one of the following factors, either singly or in combination: 1. Intrinsic pump failure 2. increased workload on heart 3. impaired filling of cardiac chambers […] The most common and most important cause of heart failure is weakening of the ventricular muscle due to disease so that the heart fails to act as an efficient pump. The various diseases which may culminate in pump failure by this mechanisms are as under: Ischaemic heart disease Myocarditis Cardiomyopathies Metabolic disorders e.g. beriberi Disorders of the rhythm e.g. atrial fibrillation and flutter.

• #8 Congestive Heart Failure Pathophysiology

  https://www.verywellhealth.com/congestive-heart-failure-pathophysiology-5205016

  Heart failure develops when there are changes to the structure of the heart muscle and it can’t pump blood as efficiently as it should. […] The damage to the heart may be due to coronary artery disease, high blood pressure, smoking, alcohol, diabetes, infection, or other conditions. […] Heart failure impacts about 6.5 million people in the United States, and it’s one of the most common reasons older adults get admitted to the hospital. […] As the heart becomes progressively weaker, a variety of symptoms are seen, including shortness of breath, weakness, fatigue, and edema.

• #9 Heart failure. Pathogenesis of heart failure and diagnosis of the incipient stage of heart failure

  https://popline.org/node/3219

  Heart failure may be classified according to the type of the primary load as follows: I. Increased heart-load 1. a) pressure load (load of the contractile myocardial function) – e.g. aortic stenosis, pulmonary stenosis, pulmonary hypertension, systemic hypertension; b) primary myocardial lesion (load of the contractile myocardial function) – e.g. myocardial ischaemia, myocardial infarction, cardiomyopathy; 2. Volume load (load of myocardial distensibility) – for instance in valvular insufficiency, -v shunt, anaemia. […] Definition of incipient heart failure is not a simple matter. Incipient means rather the beginning of a certain process which develops than a pathophysiologically expressed balanced state or clinical syndrome. […] Highly effective acute compensatory mechanisms designed to maintain blood supply to tissue capillaries are cardiac dilatation, tachycardia and elevation of myocardial contractility. However, these compensatory mechanisms gradually deteriorate and their compensatory power weakens.

• #10 Pathophysiology of Heart Failure | Thoracic Key

  https://thoracickey.com/pathophysiology-of-heart-failure/

  Despite repeated attempts to discover a unique pathophysiologic mechanism that precisely explains the clinical syndrome of heart failure, no single conceptual paradigm has withstood the test of time. […] This chapter focuses on the molecular and cellular changes that underlie heart failure with depressed systolic function, with an emphasis on the role of neurohormonal activation and left ventricular (LV) remodeling as the primary determinants for disease progression in heart failure. […] As shown in Figure 22-1A, heart failure may be viewed as a progressive disorder that is initiated after an index event either damages the heart muscle, with a resultant loss of functioning cardiac myocytes or, alternatively, disrupts the ability of the myocardium to generate force, thereby preventing the heart from contracting normally. […] Regardless of the nature of the inciting event, the feature that is common to each of these index events is that they all, in some manner, produce a decline in pumping capacity of the heart. […] With progression to symptomatic heart failure, however, the sustained activation of neurohormonal and cytokine systems leads to a series of end-organ changes within the myocardium referred to collectively as LV remodeling.

• #11 Heart Failure (HF) – Cardiovascular Disorders – MSD Manual Professional Edition

  https://www.msdmanuals.com/professional/cardiovascular-disorders/heart-failure/heart-failure-hf

  Heart failure (HF) is a syndrome of ventricular dysfunction. […] In heart failure, the heart may not provide tissues with adequate blood for metabolic needs, and cardiac-related elevation of pulmonary or systemic venous pressures may result in organ congestion. This condition can result from abnormalities of systolic or diastolic function or, commonly, both. […] In HFrEF (also called systolic HF), global LV systolic dysfunction predominates. The LV contracts poorly and empties inadequately, leading to increased diastolic volume and pressure and decreased ejection fraction ( 40%). […] Many defects in energy utilization, energy supply, electrophysiologic functions, and contractile element interaction occur, with abnormalities in intracellular calcium modulation and cAMP production. […] Diastolic dysfunction usually results from impaired ventricular relaxation (an active process), increased ventricular stiffness, valvular disease, or constrictive pericarditis.

• #12 Congestive Heart Failure Symptoms, Stages, & Classification – The Cardiology Advisor

  https://www.thecardiologyadvisor.com/features/congestive-heart-failure-symptoms-stages-classification/

  Congestive heart failure occurs when one or both of the large chambers of the heart, the ventricles, is unable to properly fill with or eject (pump) enough blood to supply the body with the oxygen it needs. Heart failure that is the result of an impairment in the ventricles ejecting blood is systolic heart failure. Congestive heart failure that is the result of an impairment in the ventricles ability to fill with blood is diastolic heart failure. […] Patients with Stage B heart failure are considered to have pre-HF. They have no present or previous symptoms of heart failure but do have one of the following: structural heart disease; increased ventricular filling pressures; or other risk factors. […] Patients with Stage C heart failure have symptomatic heart failure. They have structural heart disease with present or previous heart failure symptoms.

• #13 Heart Failure: Practice Essentials, Background, Pathophysiology

  https://emedicine.medscape.com/article/163062-overview

  In diastolic heart failure (heart failure with preserved ejection fraction [HFpEF]), the same pathophysiologic processes occur that lead to decreased cardiac output in systolic heart failure, but they do so in response to a different set of hemodynamic and circulatory environmental factors that depress cardiac output. […] In HFpEF, altered relaxation and increased stiffness of the ventricle (due to delayed calcium uptake by the myocyte sarcoplasmic reticulum and delayed calcium efflux from the myocyte) occur in response to an increase in ventricular afterload (pressure overload).

• #14 Heart Failure with Preserved Ejection Fraction: The Pathophysiological Mechanisms behind the Clinical Phenotypes and the Therapeutic Approach

  https://www.mdpi.com/1422-0067/25/2/794

  Heart failure (HF) with preserved ejection fraction (HFpEF) is an increasingly frequent form and is estimated to be the dominant form of HF. […] The current medical challenge is to develop effective therapeutic strategies, because patients suffering from HFpEF have symptoms and quality of life comparable to those with reduced ejection fraction, but the specific medication for HFrEF is ineffective in this situation; for this, we must first understand the pathological mechanisms in detail and correlate them with the clinical presentation. […] The etiology of HFpEF is unclear, and probably often multifactorial, but several culprits have been identified: microvascular lesions, low-grade systemic inflammation, and general oxidative stress (evolving in the context of comorbidities associated with endothelial dysfunction), all of these leading to myocardial remodeling and fibrosis.

• #15 CV Physiology | Pathophysiology of Heart Failure

  https://cvphysiology.com/heart-failure/hf003

  Diastolic dysfunction refers to the diastolic properties of the ventricle and occurs when the ventricle becomes less compliant (i.e., „stiffer”), which impairs ventricular filling. […] Both systolic and diastolic dysfunction lead to an increase in ventricular end-diastolic pressure, which serves as a compensatory mechanism through utilization of the Frank-Starling mechanism to augment stroke volume. […] Neurohumoral responses occur during heart failure. These include activation of sympathetic nerves and the renin-angiotensin system, and increased release of antidiuretic hormone (vasopressin) and atrial natriuretic peptide. The net effect of these neurohumoral responses is to produce arterial vasoconstriction (to help maintain arterial pressure), venous constriction (to increase venous pressure), and increased blood volume to increase ventricular filling.

• #16 CV Physiology | Pathophysiology of Heart Failure

  https://cvphysiology.com/heart-failure/hf003

  Cardiac dysfunction precipitates changes in vascular function, blood volume, and neurohumoral status. These changes serve as compensatory mechanisms to help maintain cardiac output (primarily by the Frank-Starling mechanism) and arterial blood pressure (by systemic vasoconstriction). However, these compensatory changes over months and years can worsen cardiac function. […] Changes in cardiac function associated with heart failure decrease cardiac output. This results from a decline in stroke volume that is due to systolic dysfunction, diastolic dysfunction, or a combination of the two. Briefly, systolic dysfunction results from a loss of intrinsic inotropy (contractility), which can be caused by disease-induced alterations in signal transduction mechanisms responsible for regulating inotropy.

• #17 Heart Failure (HF) – Cardiovascular Disorders – MSD Manual Professional Edition

  https://www.msdmanuals.com/professional/cardiovascular-disorders/heart-failure/heart-failure-hf

  Current data suggest that multiple comorbidities (eg, obesity, hypertension, diabetes, chronic kidney disease) lead to systemic inflammation, widespread endothelial dysfunction, cardiac microvascular dysfunction, and, ultimately, molecular changes in the heart that cause increased myocardial fibrosis and ventricular stiffening. […] In heart failure that involves left ventricular dysfunction, CO decreases and pulmonary venous pressure increases. […] In heart failure that involves right ventricular dysfunction, systemic venous pressure increases, causing fluid extravasation and consequent edema, primarily in dependent tissues (feet and ankles of ambulatory patients) and abdominal viscera. […] In HFrEF, left ventricular systolic function is grossly impaired; therefore, a higher preload is required to maintain CO.

• #18 CV Physiology | Pathophysiology of Heart Failure

  https://cvphysiology.com/heart-failure/hf003

  Neurohumoral activation is an important compensatory response, but it can also aggravate heart failure by increasing ventricular afterload (which depresses stroke volume) and increasing preload to the point where pulmonary or systemic congestion and edema occur. […] There is also evidence that other factors such as nitric oxide and endothelin (both of which are increased in heart failure) may play a role in the pathogenesis of heart failure. […] Some drug treatments for heart failure involve attenuating the neurohumoral changes. […] To compensate for reduced cardiac output during heart failure, feedback mechanisms within the body try to maintain normal arterial pressure. […] In heart failure, there is a compensatory increase in blood volume that serves to increase ventricular preload and thereby enhance stroke volume by the Frank-Starling mechanism.

• #19 Heart Failure (HF) – Cardiovascular Disorders – MSD Manual Professional Edition

  https://www.msdmanuals.com/professional/cardiovascular-disorders/heart-failure/heart-failure-hf

  With reduced CO, oxygen delivery to the tissues is maintained by increasing oxygen extraction from the blood and sometimes shifting the oxyhemoglobin dissociation curve to the right to favor oxygen release. […] As cardiac function deteriorates, renal blood flow decreases (due to low cardiac output). […] The renin-angiotensin-aldosterone-vasopressin (antidiuretic hormone [ADH]) system causes a cascade of potentially deleterious long-term effects. […] The failing heart and other organs produce tumor necrosis factor (TNF) alpha. […] Age-related changes in the heart and cardiovascular system lower the threshold for expression of heart failure. […] Anemia is common among patients with chronic heart failure and is frequently multifactorial.

• #20 Heart Failure: Practice Essentials, Background, Pathophysiology

  https://emedicine.medscape.com/article/163062-overview

  Most important among the adaptations are the following: The Frank-Starling mechanism, in which an increased preload helps to sustain cardiac performance; Alterations in myocyte regeneration and death; Myocardial hypertrophy with or without cardiac chamber dilatation, in which the mass of contractile tissue is augmented; Activation of neurohumoral systems. […] The release of norepinephrine by adrenergic cardiac nerves augments myocardial contractility and includes activation of the renin-angiotensin-aldosterone system [RAAS], the sympathetic nervous system [SNS], and other neurohumoral adjustments that act to maintain arterial pressure and perfusion of vital organs. […] In acute heart failure, the finite adaptive mechanisms that may be adequate to maintain the overall contractile performance of the heart at relatively normal levels become maladaptive when trying to sustain adequate cardiac performance.

• #21 Chronic Heart Failure – Heart Failure with Reduced Ejection Fraction Topic Review

  https://www.healio.com/cardiology/learn-the-heart/cardiology-review/topic-reviews/systolic-congestive-heart-failure

  Chronic heart failure (HF) results in the activation of multiple compensatory mechanisms in an attempt to maintain cardiac output. […] The two primary mechanisms considered neurohormonal responses are activation of the sympathetic nervous system (SNS) and activation of the renin-angiotensin-aldosterone system (RAAS). […] Activation of the RAAS contributes substantially to negative remodeling of the heart, resulting in cardiac function. […] Both A-type (ANP) and B-type (BNP) natriuretic peptide have beneficial hemodynamic effects in HF and represent a compensatory pathway. […] Endothelin also promotes remodeling and vasoconstriction; however, clinical trials of endothelin inhibitors have not demonstrated a convincing long-term benefit, and thus the role of endothelin remains unclear.

• #22 Heart Failure: Practice Essentials, Background, Pathophysiology

  https://emedicine.medscape.com/article/163062-overview

  Systolic and diastolic heart failure each result in a decrease in stroke volume. […] Although there are commonalities in the neurohormonal responses to decreased stroke volume, the neurohormone-mediated events that follow have been most clearly elucidated for individuals with systolic heart failure. […] The ensuing elevation in plasma norepinephrine directly correlates with the degree of cardiac dysfunction and has significant prognostic implications. […] Norepinephrine, while directly toxic to cardiac myocytes, is also responsible for a variety of signal-transduction abnormalities, such as downregulation of beta1-adrenergic receptors, uncoupling of beta2-adrenergic receptors, and increased activity of inhibitory G-protein. […] Changes in beta1-adrenergic receptors result in overexpression and promote myocardial hypertrophy.

• #23 Heart Failure: Practice Essentials, Background, Pathophysiology

  https://emedicine.medscape.com/article/163062-overview

  ANP and BNP are endogenously generated peptides activated in response to atrial and ventricular volume/pressure expansion. […] Their hemodynamic effects are mediated by decreases in ventricular filling pressures, owing to reductions in cardiac preload and afterload. […] Other vasoactive systems that play a role in the pathogenesis of heart failure include the ET receptor system, the adenosine receptor system, vasopressin, and tumor necrosis factor-alpha (TNF-alpha). […] Elevated levels of ET-1 closely correlate with the severity of heart failure. […] TNF-alpha has been implicated in response to various infectious and inflammatory conditions. […] In individuals with systolic dysfunction, therefore, the neurohormonal responses to decreased stroke volume result in temporary improvement in systolic blood pressure and tissue perfusion. However, in all circumstances, the existing data support the notion that these neurohormonal responses contribute to the progression of myocardial dysfunction in the long term.

• #24 CV Physiology | Sympathetic Activation in Heart Failure

  https://cvphysiology.com/heart-failure/hf004

  Sympathetic activation of the heart causes an increase in heart rate and inotropy through the release of norepinephrine, which binds to 1-adrenoceptors. […] The increase in inotropy by sympathetic activation, however, may not restore normal inotropy in ventricles having systolic dysfunction because inotropic responses are also blunted because of the down regulation of 1-adrenoceptors. […] Sympathetic activation has other important effects which can be deleterious, including ventricular hypertrophy, enhanced arrhythmogenesis, and molecular and biochemical changes that lead to further dysfunction. […] Therefore, although sympathetic activation plays a compensatory role in the failing heart, there is considerable evidence that prolonged sympathetic activation exacerbates heart failure. […] Enhanced sympathetic outflow to the kidneys causes an increase in renin release.

• #25 Heart Failure: Practice Essentials, Background, Pathophysiology

  https://emedicine.medscape.com/article/163062-overview

  Research indicates that local cardiac Ang II production (which decreases lusitropy, increases inotropy, and increases afterload) leads to increased myocardial energy expenditure. […] Ang II has also been shown in vitro and in vivo to increase the rate of myocyte apoptosis. […] Ang II also mediates myocardial cellular hypertrophy and may promote progressive loss of myocardial function. […] In the failing heart, increased myocardial volume is characterized by larger myocytes approaching the end of their life cycle. […] As heart failure advances, there is a relative decline in the counterregulatory effects of endogenous vasodilators, including nitric oxide (NO), prostaglandins (PGs), bradykinin (BK), atrial natriuretic peptide (ANP), and B-type natriuretic peptide (BNP). […] This decline occurs simultaneously with the increase in vasoconstrictor substances from the RAAS and the adrenergic system, which fosters further increases in vasoconstriction and thus preload and afterload.

• #26 CV Physiology | Sympathetic Activation in Heart Failure

  https://cvphysiology.com/heart-failure/hf004

  Plasma renin activity, therefore, is elevated in heart failure patients, in part, because of increased sympathetic activity. […] Increased renin release causes increased formation of angiotensin II and subsequent formation of aldosterone. […] These circulating hormones cause sodium and water retention by the kidneys that increases blood volume. […] Angiotensin II also has direct vasoconstrictor actions on blood vessels, which contribute to the increase in systemic vascular resistance. […] These hormones also stimulate cardiac remodeling that occurs during chronic heart failure. […] Although the actions of these hormones serve as important compensatory responses to heart failure, over-activation can have deleterious long-term actions.

• #27 Beta Blockers in Heart Failure Management – The Cardiology Advisor

  https://www.thecardiologyadvisor.com/features/beta-blockers-in-heart-failure/

  Beta blockers in heart failure with reduced ejection fraction are the standard of care for patients with this condition. […] For patients with HFrEF, beta blockers can boost clinical status by improving left ventricular function as well as reducing symptoms of heart failure, and the risk of hospitalization and mortality. […] During heart failure, chronic -adrenergic receptor activation leads to excess stimulation of catecholamines, eventually decreasing norepinephrine levels and leading to myocardial apoptosis and fibrosis. […] By blocking -adrenergic receptors, beta blockers impede adrenergic activation on the heart, thereby decreasing heart rate, blood pressure, and cardiac output. […] High-quality evidence from multiple randomized controlled trials (RCTs) indicates that beta blockers can improve left ventricular function and heart failure symptoms.

• #28 Heart failure – McMaster Pathophysiology Review

  https://www.pathophys.org/heartfailure/

  Continuous sympathetic activation results in downregulation of -adrenergic receptors with decreased sensitivity to circulating catecholamines and less inotropic response. […] Increased heart rate augments metabolic demands and can further reduce performance by increasing myocardial cell death. […] Increased circulating volume and preload ultimately overwhelm Frank-Starling mechanism and hearts ability to maintain forward flow, resulting in worsening of lung vasculature congestion. […] Increased total peripheral resistance results in higher afterload, impeding the left ventricles stroke volume and reducing cardiac output. […] Chronically elevated angiotensin II and aldosterone trigger production of cytokines, which activate macrophages an stimulate fibroblasts resulting in adverse heart remodelling.

• #29 Heart failure – McMaster Pathophysiology Review

  https://www.pathophys.org/heartfailure/

  In addition to global mechanical dysfunction in heart failure, another key player in this process may be dysfunction at a cellular level. […] Myocyte loss resulting from insults such as MI or exposure to cardiotoxic drugs. […] Apoptosis (programmed cell death) from elevated catecholamines, angiotensin II, inflammatory cytokines, and mechanical strain from increased wall stress. […] Changes activated in expression of contractile proteins, ion channels, enzymes, receptors and secondary messengers. […] Reduced cellular ability to maintain calcium homeostasis. […] Changes in handling of high-energy phosphates. […] These mechanisms attempt to maintain sufficient blood pressure to perfuse vital organs by compensating for the decrease in cardiac output that occurs in heart failure. […] In heart failure, a decreased stroke volume results in reduced chamber emptying, with higher than normal diastolic volume.

• #30 Heart failure – McMaster Pathophysiology Review

  https://www.pathophys.org/heartfailure/

  This induces a greater stroke volume for the subsequent contraction to help empty the ventricle and preserve forward cardiac output. […] However this mechanisms has limits, and at markedly elevated diastolic volumes, the stretch of myofibers becomes too great and suboptimal for generating a strong contraction. […] In response to a sustained increase in pressure and chamber radius, hypertrophy of the ventricular myocytes is stimulated. […] The increased mass of muscle fibers serves to maintain contractile force and counteract the elevated ventricular wall stress. […] Unfortunately, despite these compensatory mechanisms, there is progressive decline in the hearts ability to contract and relax in the face of persistent hemodynamic challenges. […] Furthermore, chronic activation of the above mechanisms ultimately becomes maladaptive and induces further worsening of cardiac performance.

• #31 Azthena logo with the word Azthena

  https://www.news-medical.net/health/Heart-Failure-Pathophysiology.aspx

  Heart failure is a condition where the heart fails to pump and circulate an adequate supply of blood to meet the requirements of the body. The muscles of the heart become less efficient and damaged, leading to overload on the heart. […] One example is heart muscle damage caused by a heart attack or myocardial infarction. In myocardial infarction, there is a lack of blood supplied to the heart muscles causing them to be starved of oxygen and leading to death of the muscle tissue. The muscles then fail to function normally, increasing the risk of heart failure. […] Cardiac muscle diseases such as amyloidosis or cardiomyopathy also damage the heart muscles and can lead to heart failure. […] The muscle contraction of the heart may weaken due to overloading of the ventricle with blood during diastole. In a healthy individual, an overloading of blood in the ventricle triggers an increases in muscle contraction, to raise the cardiac output. This is called the Frank-Starling law of the heart. In heart failure, however, this mechanism fails due to weakened cardiac muscles which results in a failure of the heart to pump an adequate amount of blood.

• #32

  https://myhealth.alberta.ca/Health/pages/conditions.aspx?hwid=aa86963

  Heart failure means that your heart muscle doesn’t pump as much blood as your body needs. […] Compensation may help your body adjust to the effects of heart failure in the short term. But over time it can make heart failure worse by further enlarging the heart and reducing how well the heart can pump. […] When the body thinks it needs more fluid in its blood vessels, it releases specific chemicals (renin, angiotensin, and aldosterone) that cause the blood vessels to constrict. […] Your heart’s goal in compensating for heart failure is to maintain your cardiac output. […] To maintain your cardiac output, your heart can try to beat faster (increase your heart rate) or pump more blood with each beat (increase your stroke volume). […] Beating faster helps to maintain cardiac output as the stroke volume falls. But a faster heart rate can be counterproductive because it allows less time for the ventricle to fill with blood after each heartbeat.

• #33 heart failure | Calgary Guide

  https://calgaryguide.ucalgary.ca/?s=heart+failure

  Left Heart Failure: Pathophysiology (Neurohormonal Activation) Definition of heart failure: Myocardial dysfunction (systolic or diastolic) results in decreased CO, such that the heart cannot meet the body’s metabolic demands or can only do so at elevated filling pressures […] Heart: Activation of fibroblasts 4 collagen synthesis and hypertrophy […] Heart: Increase HR to maintain normal CO […] Maladaptive Response: t preload (EDV), volume overload […] Maladaptive Response: Adverse LV remodelling […] Maladaptive Response: t myocardial oxygen demand and 4, diastolic time 4, contractility of the heart 4, coronary blood flow 4 myocardial ischemia […] Blood backs up into lungs perfusion of blood throughout the body inability of the heart to meet metabolic demands Congestive Heart Failure

• #34 Heart Failure: Practice Essentials, Background, Pathophysiology

  https://emedicine.medscape.com/article/163062-overview

  The primary myocardial response to chronic increased wall stress is myocyte hypertrophy, death/apoptosis, and regeneration. […] The reduction of cardiac output following myocardial injury sets into motion a cascade of hemodynamic and neurohormonal derangements that provoke activation of neuroendocrine systems, most notably the above-mentioned adrenergic systems and RAAS. […] The release of epinephrine and norepinephrine, along with the vasoactive substances endothelin-1 (ET-1) and vasopressin, causes vasoconstriction, which increases calcium afterload and, via an increase in cyclic adenosine monophosphate (cAMP), causes an increase in cytosolic calcium entry. […] The increased calcium entry into the myocytes augments myocardial contractility and impairs myocardial relaxation (lusitropy).

• #35 Heart Failure with Preserved Ejection Fraction: The Pathophysiological Mechanisms behind the Clinical Phenotypes and the Therapeutic Approach

  https://www.mdpi.com/1422-0067/25/2/794

  These detrimental elements seem to participate fundamentally in the pathogenesis of the disease. […] The initial model indicated for HFpEF in descriptive studies was that of a ventricle of normal size but with hypertrophied walls (concentric left ventricular hypertrophy). […] The development of diastolic dysfunction, in patients with HFpEF, does not affect the final filling volume of the LV, but this filling is difficult, as abnormally high filling pressures are required. […] The pericardial sac contributes to the good functioning of the heart through multiple roles, one of them being the limitation of the distension of the ventricular filling; this correlated with the venous return contributing to the increase in the intracardiac pressure. […] Increased filling pressure in the LV is responsible for most of the symptoms in HFpEF.

• #36 Heart Failure with Preserved Ejection Fraction: The Pathophysiological Mechanisms behind the Clinical Phenotypes and the Therapeutic Approach

  https://www.mdpi.com/1422-0067/25/2/794

  Patients diagnosed with HFpEF frequently associate with reduced central aortic compliance and increased peripheral arterial stiffness. […] The common element of the two vascular alterations (micro- and macro-vascular) is endothelial dysfunction. […] The mechanism of endothelial dysfunction is the known one, mediated by the decrease in available nitric oxide (NO) by decreasing the activity of nitric oxide synthase 3 (NOS3) in endothelial cells or endothelial NO synthase (eNOS). […] The presence and severity of endothelial dysfunction in patients with HFpEF contribute to a worse prognosis due to higher rates of acute cardiovascular events, a worse quality of life due to more severe symptoms, and reduced exercise capacity. […] The aging process of the heart can be accelerated by the presence of HFpEF. […] The lack of distinct mechanisms should make us understand that HFpEF is not a disease in itself, but a multifaceted clinical syndrome, characterized by heterogeneous clinical manifestations, encumbered by many comorbidities and systemic multiorgan damage.

• #37 Pathophysiology of Heart Failure | Thoracic Key

  https://thoracickey.com/pathophysiology-of-heart-failure/

  A growing body of experimental and clinical evidence suggests that heart failure progresses as a result of the overexpression of biologically active molecules that are capable of exerting deleterious effects on the heart and circulation. […] The portfolio of compensatory mechanisms that have been described thus far includes activation of the adrenergic nervous systemic system and the renin-angiotensin system (RAS), which are responsible for maintaining cardiac output through increased retention of salt and water; peripheral arterial vasoconstriction and increased contractility; and inflammatory mediators that are responsible for cardiac repair and remodeling. […] The decrease in cardiac output in heart failure activates a series of compensatory adaptations that are intended to maintain cardiovascular homeostasis. […] One of the most important adaptations is activation of the sympathetic (adrenergic) nervous system, which occurs early in the course of heart failure. […] The ongoing XR-1 trial (NCT01484288) is using an implantable barostimulation device that activates the carotid baroreceptors to decrease sympathetic activation in patients with symptomatic heart failure, to determine whether this will restore the sympathovagal imbalance.

• #38 The pathophysiology of heart failure – PubMed

  https://pubmed.ncbi.nlm.nih.gov/22227365/

  Heart failure is a clinical syndrome that results when the heart is unable to provide sufficient blood flow to meet metabolic requirements or accommodate systemic venous return. […] Heart failure results from injury to the myocardium from a variety of causes including ischemic heart disease, hypertension, and diabetes. […] As the heart fails, patients develop symptoms which include dyspnea from pulmonary congestion, and peripheral edema and ascites from impaired venous return. […] There are several compensatory mechanisms that occur as the failing heart attempts to maintain adequate function. These include increasing cardiac output via the Frank-Starling mechanism, increasing ventricular volume and wall thickness through ventricular remodeling, and maintaining tissue perfusion with augmented mean arterial pressure through activation of neurohormonal systems.

• #39 The pathophysiology of heart failure – PubMed

  https://pubmed.ncbi.nlm.nih.gov/22227365/

  Although initially beneficial in the early stages of heart failure, all of these compensatory mechanisms eventually lead to a vicious cycle of worsening heart failure. […] Despite significant understanding of the underlying pathophysiological mechanisms in heart failure, this disease causes significant morbidity and carries a 50% 5-year mortality.

• #40 A self-reinforcing cycle hypothesis in heart failure pathogenesis | Nature Cardiovascular Research

  https://www.nature.com/articles/s44161-024-00480-6

  Heart failure is a progressive syndrome with high morbidity and mortality rates. Here, we suggest that chronic exposure of the heart to risk factors for heart failure damages heart mitochondria, thereby impairing energy production to levels that can suppress the hearts ability to pump blood and repair mitochondria (both energy-consuming processes). As damaged mitochondria accumulate, the heart becomes deprived of energy in a self-reinforcing cycle, which can persist after the heart is no longer chronically exposed to (or after antagonism of) the risk factors that initiated the cycle. Together with other previously described pathological mechanisms, this proposed cycle can help explain (1) why heart failure progresses, (2) why it can recur after cessation of treatment, and (3) why heart failure is often accompanied by dysfunction of multiple organs. Ideally, therapy of heart failure syndrome would be best attempted before the self-reinforcing cycle is triggered or designed to break the self-reinforcing cycle.

• #41 Heart Failure: Practice Essentials, Background, Pathophysiology

  https://emedicine.medscape.com/article/163062-overview

  The increase in afterload and myocardial contractility (known as inotropy) and the impairment in myocardial lusitropy lead to an increase in myocardial energy expenditure and a further decrease in cardiac output. […] The increase in myocardial energy expenditure leads to myocardial cell death/apoptosis, which results in heart failure and further reduction in cardiac output, perpetuating a cycle of further increased neurohumoral stimulation and further adverse hemodynamic and myocardial responses. […] In addition, the activation of the RAAS leads to salt and water retention, resulting in increased preload and further increases in myocardial energy expenditure. […] The concept of the heart as a self-renewing organ is a relatively recent development. […] This imbalance of hypertrophy and death over regeneration is the final common pathway at the cellular level for the progression of remodeling and heart failure.

• #42

  https://www.jci.org/articles/view/62834

  Ca2+ cycling refers to the release and reuptake of intracellular Ca2+ that drives muscle contraction and relaxation. In failing hearts, Ca2+ cycling is profoundly altered, resulting in impaired contractility and fatal cardiac arrhythmias. The key defects in Ca2+ cycling occur at the level of the sarcoplasmic reticulum (SR), a Ca2+ storage organelle in muscle. Defects in the regulation of Ca2+ cycling proteins including the ryanodine receptor 2, cardiac (RyR2)/Ca2+ release channel macromolecular complexes and the sarcoplasmic/endoplasmic reticulum Ca2+ ATPase 2a (SERCA2a)/phospholamban complex contribute to heart failure. […] It is now generally accepted that defective SR Ca2+ handling plays an important role in HF pathophysiology. This defective SR Ca2+ handling is characterized chiefly by leaky RyR2 channels, due to stress-induced dissociation of the stabilizing RyR2 subunit calstabin2 (also known as FKBP12.6) resulting in a diastolic SR Ca2+ leak, reduced SR Ca2+ content, and decreased Ca2+ transient. Compounding this problem is impaired SR Ca2+ uptake due to reduced activity of SERCA2a, as a consequence of both reduced SERCA2a expression and increased inhibition of the pump by phospholamban. Thus, these two major players in cardiac EC coupling, the SR Ca2+ release channel (RyR2) and the SR Ca2+ uptake pump (SERCA2a), conspire to deplete the SR of Ca2+ and lead to impaired cardiac contractility.

• #43 Mechanism for pathogenesis of heart failure • healthcare-in-europe.com

  https://healthcare-in-europe.com/en/news/mechanism-for-pathogenesis-of-heart-failure.html

  A weak heart is unable to pump an adequate amount of blood around the body. […] A research group from the Clinic for Internal Medicine III in the Faculty of Medicine at Kiels Christian Albrecht University (CAU) and Schleswig-Holstein University Hospital (Kiel Campus) has discovered a previously unknown heart muscle protein and also described a new mechanism by which heart failure can develop. […] At the molecular level, one thing is common to all forms of heart failure: a disruption to the calcium metabolism of heart muscle cells. […] Myoscape binds to a specific calcium channel on the heart muscle and thus has a significant effect on its function. […] In the absence of Myoscape, heart muscle cells in the model system develop a serious impairment of calcium channel metabolism, ultimately leading to progressive heart failure.

• #44

  https://www.jci.org/articles/view/62834

  The search for novel therapeutics for HF has led investigators to examine the mechanisms underlying HF with the hope that this approach will uncover potential therapeutic targets to slow HF progression, improve quality of life, and reduce mortality. Much attention has been paid to understanding the role of defects in Ca2+ regulation in HF. This is because, as noted above, Ca2+ is the signal that regulates cardiac muscle contraction. Cardiac contractility is determined by the amplitude and kinetics of Ca2+ cycling, which in turn are regulated by phosphorylation and dephosphorylation of key proteins involved in excitation-contraction (EC) coupling by kinases and phosphatases. […] The RyR2 leak is caused by stress-induced remodeling of the RyR2 macromolecular complex due to PKA hyperphosphorylation, nitrosylation, and oxidation of the channel that results in depletion of calstabin2, phosphatases and PDE4D3 from the RyR2 channel in HF. Depletion of PDE4D3 and phosphatases results in elevated levels of cAMP at RyR2 and a decreased rate of dephosphorylation of a hyperphosphorylated channel, promoting further PKA hyperphosphorylation. The depletion of the channel subunit calstabin2 from the channel results in destabilization of the channel closed state and the diastolic SR Ca2+ leak that reduce the SR Ca transient, resulting in impaired contractility and trigger fatal cardiac arrhythmias.

• #45 Mechanism for pathogenesis of heart failure • healthcare-in-europe.com

  https://healthcare-in-europe.com/en/news/mechanism-for-pathogenesis-of-heart-failure.html

  The binding of Myoscape and another protein called actinin 2 stabilises the calcium channel in the heart muscle cell at the correct position in the cell membrane. […] In the absence of Myoscape, the calcium channel is removed from the cell membrane and heart failure then develops. […] We believe that we have here discovered a critical new mechanism for the genesis of heart failure.

• #46 Molecular Mechanisms Underlying Heart Failure and Their Therapeutic Potential

  https://www.mdpi.com/2073-4409/14/5/324

  Heart failure (HF) is a prominent fatal cardiovascular disorder afflicting 3.4% of the adult population despite the advancement of treatment options. Therefore, a better understanding of the pathogenesis of HF is essential for exploring novel therapeutic strategies. Hypertrophy and fibrosis are significant characteristics of pathological cardiac remodeling, contributing to HF. The mechanisms involved in the development of cardiac remodeling and consequent HF are multifactorial, and in this review, the key underlying mechanisms are discussed. These have been divided into the following categories thusly: (i) mitochondrial dysfunction, including defective dynamics, energy production, and oxidative stress; (ii) cardiac lipotoxicity; (iii) maladaptive endoplasmic reticulum (ER) stress; (iv) impaired autophagy; (v) cardiac inflammatory responses; (vi) programmed cell death, including apoptosis, pyroptosis, and ferroptosis; (vii) endothelial dysfunction; and (viii) defective cardiac contractility. Preclinical data suggest that there is merit in targeting the identified pathways; however, their clinical implications and outcomes regarding treating HF need further investigation in the future. Herein, we introduce the molecular mechanisms pivotal in the onset and progression of HF, as well as compounds targeting the related mechanisms and their therapeutic potential in preventing or rescuing HF. This, therefore, offers an avenue for the design and discovery of novel therapies for the treatment of HF.

• #47 Molecular Mechanisms Underlying Heart Failure and Their Therapeutic Potential

  https://www.mdpi.com/2073-4409/14/5/324

  The initial activation of these pathways can induce cardiomyocyte growth and survival, angiogenesis, antioxidant generation, and mitochondrial biogenesis. However, sustained stimulation has deleterious effects and triggers the activation of other molecular mechanisms, contributing to cell death, mitochondrial dysfunction, reactive oxygen species (ROS) production, and impaired Ca2+ handling. […] Fibrosis is an important characteristic of pathological cardiac remodeling, which causes ventricular stiffness due to the accumulation of extracellular matrix proteins in the interstitial or perivascular regions of the heart, which negatively impacts the systolic and diastolic functions. […] Dysregulation of mitochondrial dynamics is a key hallmark in HF. Abnormal mitochondrial dynamics, encompassing both fission and fusion processes, are increasingly recognized as critical contributors to cardiovascular disease (CVDs).

• #48 Molecular Mechanisms Underlying Heart Failure and Their Therapeutic Potential

  https://www.mdpi.com/2073-4409/14/5/324

  Dysregulation of mitochondrial dynamics is a key hallmark in HF. […] The heart is a metabolically demanding organ, relying heavily on a constant supply of ATP to fuel its contractile function. Mitochondria are the primary source of ATP, which produce more than 95% of the ATP in the myocardium and account for nearly 30% of cardiomyocyte volume. […] In HF, particularly under metabolic stresses like diabetes or obesity, there is often a shift away from efficient FAO toward glycolysis. […] In HF, oxidative stress also contributes to myocardial tissue damage, which is evident in both the myocardium and plasma and is closely associated with LV dysfunction in patients with HF. […] The role of high-mobility group box 1 (HMGB1) is significant in the pathogenesis of heart failure. […] The transcriptional activation of GDF15 emerges mainly via p53-dependent mechanisms in HF.

• #49 Activation of cytokines as a mechanism of disease progression in heart failure | Annals of the Rheumatic Diseases

  https://ard.bmj.com/content/59/suppl_1/i90

  The scientific quest for the basic mechanism(s) responsible for the development and progression of congestive heart failure in humans has been practically exhaustive; none the less, the mechanisms responsible for the decompensation of myocardial function after myocardial injury or haemodynamic overloading, or both, have remained elusive. […] More recently, it has become evident that another class of biologically active molecules, generally referred to as cytokines are also important in heart failure.

• #50 Adipokines Pathogenesis in Heart Failure – ScienceOpen

  https://www.scienceopen.com/hosted-document?doi=10.15212/CVIA.2024.0065

  Inflammation is a major factor in the pathophysiology of HF. […] The inflammatory cytokine is tumor necrosis factor-alpha that affects cardiac dysfunction and cardiac remodeling, has been associated with the development of HF. […] TNF-α increases LV dysfunction in pacing-induced HF, partly by mediating local loss of mitochondrial activity, and increases in oxidative stress and myocyte apoptosis. […] The severity of HF is associated with the pro-inflammatory cytokine TNF-α and one of its downstream mediators, interleukin-6, which therefore might potentially serve as biomarkers.

• #51 Adipokines Pathogenesis in Heart Failure – ScienceOpen

  https://www.scienceopen.com/hosted-document?doi=10.15212/CVIA.2024.0065

  Many studies have reported that obesity causes heart failure (HF) pathogenesis. […] The elevated circulating levels of angiopoietin-like protein 2 (ANGPTL2) observed in patients with HF suggest potential links among elevated ANGPTL2 levels, metabolic disturbances, and inflammation. […] C1q/TNF-related protein 3 and C1q/TNF-related protein 9 are diminished in patients with HF with reduced ejection fraction, in proportion to disease severity, and are associated with elevated morbidity and mortality. […] In addition, fibroblast growth factor 21 (FGF21) has been suggested to be involved in the pathophysiology of diastolic HF. […] Osteopontin has also been reported to be upregulated in patients with HF and therefore might potentially serve as a novel prognostic biomarker in patients with chronic HF.

• #52 Adipokines Pathogenesis in Heart Failure – ScienceOpen

  https://www.scienceopen.com/hosted-document?doi=10.15212/CVIA.2024.0065

  A considerable number of patients with community-acquired HF have elevated tumor necrosis factor-alpha, which is associated with significantly diminished survival and significantly elevated risk of HF. […] Obesity can exacerbate HF because of altered heart and blood flow, as well as elevated likelihood of other risk factors. […] Direct cardiac lipotoxicity is another disorder in which lipid buildup in the heart can cause cardiac failure, even in the absence of additional risk factors. […] However, this article discusses few major adipokines such as angiopoietin-like protein 2 (ANGPTL2), C1q complement/tumor necrosis factor-associated proteins (CTRPs), fibroblast growth factor 21 (FGF21), osteopontin (OPN), and tumor necrosis factor-alpha (TNF-α) in the pathogenesis of HF. […] ANGPTL2 is known to contribute to chronic inflammation and has been implicated in HF development.

• #53 Molecular Mechanisms Underlying Heart Failure and Their Therapeutic Potential

  https://www.mdpi.com/2073-4409/14/5/324

  In HF, patient biopsies reveal downregulation of autophagy-related proteins, such as Beclin1 and LC3II, indicating reduced autophagosome formation and, thus, autophagy. […] Apoptosis is a form of programmed cell death arising in response to specific danger signals indicative of a harmful and dysfunctional intra- and extracellular environment. A key feature of HF, particularly HFrEF, is the loss of cardiomyocytes via apoptosis, contributing to a significant loss in the amount of contractile myocardial tissue, thereby exacerbating disease development. […] In failing human hearts, increased activated caspase-9, caspase-3, and cytosolic cytochrome c have been observed, suggesting that there was increased apoptosis. […] Pyroptosis is clearly implicated in the pathogenesis of HF as many studies on human hearts have revealed an increase in caspase-1, IL-1β, and IL-18, correlating with the development of the disease. […] The failing heart is in an altered redox state that overproduces ROS, as mentioned above. The recent literature suggests that the abnormal cardiovascular phenotype seen in HF is mainly due to imbalances between cardiac oxidative stress and NO bioavailability.

• #54 Pathophysiology of heart failure – Schwinger – Cardiovascular Diagnosis and Therapy

  https://cdt.amegroups.org/article/view/46185/html

  Identification of the pathophysiological mechanism leading to heart failure is crucial to choose adequate therapeutic options i.e., valve repair, treatment of rhythm disorders, pharmacological treatment. […] The main structural alteration in HFrEF is eccentric remodeling accompanied with chamber dilatation and often volume-overload leading to forward failure typically as consequence of large anterior myocardial infarction. The volume overload is most often the result of permanent neurohumoral activation (RAA-System). HFpEF shows impaired ventricular relaxation and/or filling, increased ventricular stiffness and thus elevated filling pressure accompanied by pressure overload. […] Chronic or acute injury (e.g., myocardial infarction) as well as overload (volume, pressure) of the heart will initiate structural and subsequent functional changes. In consequence physiological (mostly reversible) or pathological (e.g., fibrosis) adaptation occur and involve cardiomyocytes (hypertrophy, apoptosis, necrosis), fibroblasts (proliferation), endothelium and interstitium (extracellular matrix). These adaptive or maladaptive processes are the same, independent of the underlying pathological mechanism and involve the entire heart. […] The understanding of the underlying pathophysiology of heart failure is essential to initiate the adequate therapeutic option individually for each patient.

• #55 Pathophysiology of heart failure with reduced ejection fraction: Hemodynamic alterations and remodeling – UpToDate

  https://www.uptodate.com/contents/pathophysiology-of-heart-failure-with-reduced-ejection-fraction-hemodynamic-alterations-and-remodeling

  Pathophysiology of heart failure with reduced ejection fraction: Hemodynamic alterations and remodeling […] Heart failure (HF) is a clinical syndrome caused by impairment of ventricular filling or ejection of blood, which results in the inability of the heart to provide adequate perfusion to the tissues while maintaining normal cardiac filling pressures. HF is associated with a variety of interrelated structural, functional, and neurohumoral alterations with beneficial as well as maladaptive effects. […] This topic will discuss the hemodynamic and remodeling aspects of the pathophysiology of HF, particularly HF with reduced ejection fraction (HFrEF; left ventricular ejection fraction [LVEF] ≤40 percent) and HF with mid-range ejection fraction (HFmrEF; LVEF 41 to 49 percent). The pathophysiology of neurohormonal alternations in HF, the diagnosis and management of HFrEF and HFmrEF, and the pathogenesis of HF with preserved ejection fraction (HFpEF, LVEF ≥50 percent) are discussed separately.

• #56 CV Physiology | Pathophysiology of Heart Failure

  https://cvphysiology.com/heart-failure/hf003

  The result of humoral activation is an increase in renal reabsorption of sodium and water, which increases blood volume to help maintain cardiac output; however, the increased volume can be deleterious because it raises venous pressures, which can lead to pulmonary and systemic edema. […] Therefore, most patients in heart failure are treated with diuretic drugs to reduce blood volume and venous pressures to reduce edema. […] Both systolic and diastolic heart failure lead to changes in systemic vascular resistance, blood volume, and venous pressures. These changes can be examined graphically by using cardiac and vascular function curves. […] The increase in systemic vascular resistance increases the afterload on the left ventricle, which can further depress its output.

• #57 Causes and pathophysiology of high-output heart failure – UpToDate

  https://www.uptodate.com/contents/causes-and-pathophysiology-of-high-output-heart-failure

  While most patients with heart failure (HF), with either reduced or preserved ejection fraction, have low or normal cardiac output accompanied by elevated systemic vascular resistance, a minority of patients with HF present with a high-output state with low systemic vascular resistance. […] This topic will discuss the causes and pathophysiology of high-output HF. […] High-output HF is an uncommon type of HF. The prevalence of this disorder is uncertain, particularly since the potential contributory role of high-output syndromes to HF may not be appreciated in many cases. […] Although high-output states are uncommon as a sole cause of HF, they may more commonly contribute to HF in patients with underlying cardiovascular disease and reduced myocardial reserve. […] In a Mayo Clinic series of 120 consecutive patients with high-output HF diagnosed between 2000 and 2014, the most common causes were obesity (31 percent), liver disease (22.5 percent), arteriovenous shunts (22.5 percent), lung disease (16 percent), and myeloproliferative disorders (8 percent).

• #58 High output heart failure: A review of clinical status – epidemiology, pathophysiology, diagnosis, prognosis and clinical management

  https://www.oatext.com/high-output-heart-failure-a-review-of-clinical-status-epidemiology-pathophysiology-diagnosis-prognosis-and-clinical-management.php

  The clinical syndrome of heart failure (HF) has traditionally been associated with low or normal cardiac output accompanied by increased systemic vascular resistance. […] In these patients, the pathophysiological hallmark is decreased systemic vascular resistance. […] Understanding its pathophysiology, diagnosis and clinical management has become very important. […] The pathophysiology of high-output cardiac state and the associated clinical HF with or without the presence of underlying heart disease is largely unique to the underlying aetiology. […] However, reduced systemic vascular resistance due to arteriovenous shunting or peripheral vasodilation or both is the hallmark of physiological dysregulation in patients with high-output HF. […] The activation of RAAS increases intravascular blood volume in the acute and sub-acute settings but chronic activations can result into a progressive decline in cardiac function.

• #59 High output heart failure: A review of clinical status – epidemiology, pathophysiology, diagnosis, prognosis and clinical management

  https://www.oatext.com/high-output-heart-failure-a-review-of-clinical-status-epidemiology-pathophysiology-diagnosis-prognosis-and-clinical-management.php

  Over time, the dilatation exceeds and holds more blood volume than the heart can effectively pump, leading to HF. […] The condition lacks clinical trial data and in the absence of a remediable cause, therapeutic options are limited and many of the accepted therapies for low-output HF are contra-indicated.

• #60 Molecular Mechanisms of the Failing Heart | JAPSC Journal

  https://www.japscjournal.com/articles/molecular-mechanisms-failing-heart-fatal-regression

  Heart failure (HF) is one of the most common causes of death, and the number of HF patients is increasing worldwide due to population ageing. The pathogenesis of HF has been extensively studied by many researchers with a focus on cardiomyocytes, but its complex pathophysiology has yet to be elucidated. […] Non-cardiomyocytes account for 70% of the cells that comprise the heart, and there is close communication between non-cardiomyocytes and cardiomyocytes, suggesting that non-cardiomyocytes might play a pivotal role in the development of HF. […] The pathogenesis of HF has been extensively studied by many researchers with a focus on cardiomyocytes, but cardiomyocytes constitute only 20-30% of cells forming the heart, with 70% being non-cardiomyocytes, such as endothelial cells, fibroblasts, smooth muscle cells, pericytes and blood cells. This highlights the potentially pivotal role of non-cardiomyocytes in HF development.

• #61 Molecular Mechanisms of the Failing Heart | JAPSC Journal

  https://www.japscjournal.com/articles/molecular-mechanisms-failing-heart-fatal-regression

  Endothelial dysfunction is believed to be deeply involved in the pathophysiology of cardiovascular diseases (CVD). […] Endothelial dysfunction is caused by an imbalance between endothelium-derived vasodilatory and vasoconstrictive actions, leading to reduced flow-mediated vasodilation and an inability to meet the oxygen demands of the heart. […] Endothelial dysfunction impairs antithrombotic activity and induces inflammation. […] The senescence of endothelial cells is deeply linked to HF, and preventing vascular senescence may become a new therapeutic intervention for HF. […] Thus, endothelial cells play pivotal roles in the pathogenesis of HF, not only by forming blood vessels that carry oxygen and nutrients, but also by secreting various factors. […] Cardiac fibroblasts affect cardiac myocytes and play critical roles in the pathogenesis of HF, as well as fibrosis, and suggests that the interaction between cardiac fibroblasts and myocytes is a novel target for HF. […] Although the pathogenesis of HF has been extensively studied with a focus on cardiomyocytes, 70% of the cells in the heart are non-cardiomyocytes, and the interactions between many cell types, including cardiomyocytes and noncardiomyocytes, have been elucidated.

• #62 Genome-wide association and Mendelian randomisation analysis provide insights into the pathogenesis of heart failure | Nature Communications

  https://www.nature.com/articles/s41467-019-13690-5

  Heart failure (HF) is a leading cause of morbidity and mortality worldwide. A small proportion of HF cases are attributable to monogenic cardiomyopathies and existing genome-wide association studies (GWAS) have yielded only limited insights, leaving the observed heritability of HF largely unexplained. […] We report results from a GWAS meta-analysis of HF comprising 47,309 cases and 930,014 controls. Twelve independent variants at 11 genomic loci are associated with HF, all of which demonstrate one or more associations with coronary artery disease (CAD), atrial fibrillation, or reduced left ventricular function, suggesting shared genetic aetiology. […] Functional analysis of non-CAD-associated loci implicate genes involved in cardiac development (MYOZ1, SYNPO2L), protein homoeostasis (BAG3), and cellular senescence (CDKN1A). Mendelian randomisation analysis supports causal roles for several HF risk factors, and demonstrates CAD-independent effects for atrial fibrillation, body mass index, and hypertension. These findings extend our knowledge of the pathways underlying HF and may inform new therapeutic strategies.

• #63

  https://www.jci.org/articles/view/189335

  Heterozygous truncating variants in the sarcomere protein titin (TTN) are the most common genetic cause of heart failure. […] Truncation variants in the gene TTN encoding titin are the most common cause of familial dilated cardiomyopathy (DCM), with both haploinsufficiency and poison peptide implicated as contributory mechanisms of disease. […] Two nonmutually exclusive hypotheses have been developed to explain DCM pathogenesis for TTNtvs, namely, haploinsufficiency and poison peptide. […] Full-length TTN is decreased in TTNtv DCM hearts compared with non-TTNtv DCM hearts, and truncated TTN proteins have been shown to incorporate into sarcomeres in patients with DCM. […] The work of Kim et al. suggests a pathogenic contribution of the intron 1 TTN rare variant and highlights a major limitation of current clinical testing, namely that this variant would have never been found with current clinical panel testing. […] Given that poison peptides likely play some role in the pathogenicity of TTNtv DCM, whether through direct effects on the myofilament and/or through accumulation of cellular aggregates, there is also a potential downside to this strategy.

• #64 Genome-wide association and Mendelian randomisation analysis provide insights into the pathogenesis of heart failure | Nature Communications

  https://www.nature.com/articles/s41467-019-13690-5

  HF is a complex disorder with an estimated heritability of ~26%. […] We hypothesised that a GWAS of HF with greater power would provide an opportunity for: (i) discovery of genetic variants modifying disease susceptibility in a range of comorbid contexts, both through subtype-specific and shared pathophysiological mechanisms, such as fluid congestion; and (ii) provide insights into aetiology by estimating the unconfounded causal contribution of observationally associated risk factors by Mendelian randomisation (MR) analysis. […] We conducted a GWAS comprising 47,309 cases and 930,014 controls of European ancestry across 26 studies from the Heart Failure Molecular Epidemiology for Therapeutic Targets (HERMES) Consortium. […] We identified 12 independent genetic variants, at 11 loci associated with HF at genome-wide significance (P<5×10^−8), including 10 loci not previously reported for HF.

• #65 Genome-wide association and Mendelian randomisation analysis provide insights into the pathogenesis of heart failure | Nature Communications

  https://www.nature.com/articles/s41467-019-13690-5

  We highlight the results for these loci in our reporting of subsequent analyses to identify candidate genes. Notably, genetic associations with DCM at the BAG3 locus have been reported previously. […] We identify 12 independent variant associations for HF risk at 11 genomic loci by leveraging genome-wide data on 47,309 cases and 930,014 controls, including 10 loci not previously associated with HF. The identified loci were associated with modifiable risk factors and traits related to LV structure and function, and include the strongest associations signals from GWAS of CAD (9p21, LPA), AF (PITX2) and BMI (FTO). […] We use genetic causal inference and conditional analysis to explore the syndromic heterogeneity and causal biology of HF, and to provide insights into aetiology. Mendelian randomisation analysis confirms previously reported casual effects for BMI and provides evidence supporting the causal role of several observationally linked risk factors, including AF, elevated blood pressure (DBP and SBP), LDL-C, CAD, TGs and T2D.

• #66 An Overview of the Mechanism behind Excessive Volume of Pericardial Fat in Heart Failure

  https://www.jomes.org/journal/view.html?uid=1030&vmd=Full

  Heart failure (HF) is a clinical syndrome characterized by myocardial dysfunction leading to inefficient blood filling or ejection. Regardless of the etiology, various mechanisms, including adipokine hypersecretion, proinflammatory cytokines, stem cell proliferation, oxidative stress, hyperglycemic toxicity, and autonomic nervous system dysregulation in the pericardial fat (PCF), contribute to the development of HF. […] The PCF acts as neuroendocrine tissue that is closely linked to myocardial function and acts as an energy reservoir. This review aims to summarize each mechanism associated with PCF in HF. […] PCF has been directly associated with cardiovascular outcomes and risk factors due to its direct effects on the myocardium, and an increased PCF volume is associated with myocardial dysfunction in heart failure (HF).

• #67 An Overview of the Mechanism behind Excessive Volume of Pericardial Fat in Heart Failure

  https://www.jomes.org/journal/view.html?uid=1030&vmd=Full

  Dysregulation of this balance between sympathetic and parasympathetic activity can contribute to development and progression of HF. […] An increased PCF volume is closely associated with dysregulation of autonomic nervous activity, which can lead to increased risk of HF and mortality. […] Excessive deposition of PCF, particularly in the form of epicardial and pericardial adipocytes, can have detrimental effects on the heart and contribute to the development of HF.

• #68 Investigating SGLT2 Inhibitors in Heart Failure

  https://www.uspharmacist.com/article/investigating-sglt2-inhibitors-in-heart-failure

  Sodium glucose cotransporter 2 inhibitors (SGLT2i) were recently included in the treatment guidelines due to reduced hospitalizations for HF and cardiovascular (CV) mortality in patients with HFpEF. Aside from adequate blood pressure control, SGLT2i are the only direct therapy recognized in the guidelines to reduce mortality in HFpEF. These agents work by blocking the SGLT2 protein in the proximal tubule of the nephron, reducing the amount of reabsorbed glucose and sodium into the blood. This inhibition results in glycosuria and resulting natriuresis, ultimately lowering serum glucose concentrations. While the antihyperglycemic outcome achieved with these agents is important, several cardioprotective effects of SGLT2i have been proven in HF patients regardless of the presence of diabetes. These favorable effects include blood pressure lowering, natriuresis and diuresis, improved cardiac energy metabolism, prevention of inflammation, improved glucose control, and weight loss. Several potential mechanisms have been proposed, targeting HF risk factors to produce cardioprotective effects.

• #69 Diuretics and Heart Failure: Background, Technical Considerations, Outcomes

  https://emedicine.medscape.com/article/2145340-overview

  Diuretics reduce intravascular volume, leading to a decrease in central venous pressure, right and left heart filling pressures, and pulmonary vascular pressures. Venous capacitance increases, and intrapulmonary fluid returns to the circulation. The left ventricular volume is smaller, and cardiac output typically increases. In the setting of mitral regurgitation, the reduced left ventricular volume improves mitral leaflet coaptation and decreases the regurgitant volume. […] Diuretic use in the heart failure patient does carry certain risks. Various electrolyte abnormalities can occur. Inhibition of the Na-K-2Cl channel leads to increased sodium delivery to the distal tubule and cortical collecting duct. […] Diuretic use can lead to worsening renal function. Whether higher diuretic doses directly lead to the development of renal failure (cardio-renal syndrome) or are simply a marker for patients at risk is debatable. […] Numerous studies have determined that activation of these pathways contributes to the pathophysiology of heart failure, thus potentially undermining the benefits of diuretic use. This mechanism may also explain why various studies have failed to show a mortality benefit from diuretics use.

• #70 Right-Sided Heart Failure: Left-Sided Heart Failure, Symptoms

  https://my.clevelandclinic.org/health/diseases/21494-right-sided-heart-failure

  Treatment is directed at the cause of your heart failure, and not all causes of right-sided heart failure are curable. But you can treat heart failure and improve your symptoms. Often, a combination of lifestyle changes, medications and heart devices can help you manage heart failure and live an active life. […] Cardiac rehabilitation, or rehab, is a program supervised by health professionals. It can help slow the progression of heart failure. […] For many people, the right combination of therapies and lifestyle changes can slow or stop the disease and improve symptoms. They can lead full, active lives.

• #71 Beta Blockers in Heart Failure Management – The Cardiology Advisor

  https://www.thecardiologyadvisor.com/features/beta-blockers-in-heart-failure/

  Beta blockers are the mainstay heart failure treatment for patients with an LVEF of up to 40%, as seen in HFrEF. […] In recent guidelines for managing heart failure, it is recommend that all patients receive treatment with 1 of the 3 beta blockers shown to reduce mortality: bisoprolol fumarate, carvedilol, or metoprolol succinate.

• #72 Investigating SGLT2 Inhibitors in Heart Failure

  https://www.uspharmacist.com/article/investigating-sglt2-inhibitors-in-heart-failure

  The cardioprotective effects of SGLT2i in HFrEF have been proven regardless of diabetes status. The Cardiovascular and Renal Outcomes in Patients with Heart Failure (EMPEROR-Reduced) and the Dapagliflozin in Patients with Heart Failure and Reduced Ejection Fraction (DAPA-HF) trials were elemental in expanding the use of SGLT2i in patients with HFrEF but without diabetes. Dapagliflozin and empagliflozin both demonstrated a significant reduction in CV death. In addition, empagliflozin was superior in reducing hospitalizations for HF, and dapagliflozin decreased rates of worsening HF. These results prompted inclusion of SGLT2i to the HFrEF guidelines as first-line agents with a class I recommendation in stage C or D HFrEF. This was a significant addition to HFrEF treatment; however, the results cannot be extrapolated to HFpEF patients due to the background characteristics of the trial populations.

• #73 Investigating SGLT2 Inhibitors in Heart Failure

  https://www.uspharmacist.com/article/investigating-sglt2-inhibitors-in-heart-failure

  The results of the above SGLT2i trials have provoked recent changes to the AHA/ACC HF guidelines with regard to the management of HFpEF. Updates to the guidelines now give SGLT2i in HFpEF a 2a recommendation, the highest class of recommendation given to any agent for the treatment of HFpEF. Other guideline recommendations for HFpEF include diuretics for congestion and symptom improvement, as well as MRAs, angiotensin receptor blockers, and angiotensin receptor-neprilysin inhibitors to reduce hospitalizations in those particularly with an LVEF on the lower end of the spectrum. The addition of the above pharmacologic therapy recommendations is huge in the HFpEF subset, as previously practitioners were left with limited event-driven data in this population. […] SGLT2i have shown a reduction in the composite of CV death and hospitalizations for HF in patients with HFpEF. The EMPEROR-Preserved trial helped to gain initial utilization of these agents in patients with a preserved EF and inclusion in guidelines, while the DELIVER trial suggested that the benefits are generalizable to be a class-wide effect. SGLT2i present a desirable therapy option for an increasingly prevalent disease state that previously had few pharmacologic options. The benefits of SGLT2i provide a treatment option for HFpEF patients with minimal adverse effects, and overall they were well tolerated. Further studies in HFpEF patients are needed with power to show a reduction in CV death with these agents; however, they are generally safe and provide several advantages in HF, irrespective of LVEF.

• #74 Molecular Mechanisms Underlying Heart Failure and Their Therapeutic Potential

  https://www.mdpi.com/2073-4409/14/5/324

  Understanding the pathogenesis of HF is vital for the development of successful therapeutic strategies. In this review, we aim to discuss the principle molecular mechanisms contributing to HF and thus highlight potential targets for the treatment of this disease. […] Pathological cardiac structural remodeling is a pivotal hallmark of HF. In response to acute pathological stress, cardiac muscles attempt to tackle the increased workload or injury via compensated hypertrophy. Here, the ventricles thicken without hampering their volumetric capacity. A key feature of adaptive hypertrophy is that cardiac output (CO) remains unimpaired, and the observed structural changes can return to normal following the removal of the stressful stimulus. However, prolonged stress induced by risk factors, including aging, diabetes, and hypertension, has deleterious effects, triggering alterations in key signal transduction and metabolic pathways and causing pathological hypertrophy, fibrosis, and apoptosis.

• #75 Heart Failure Pathogenesis Elucidation and New Treatment Method Development | JMA Journal

  https://www.jmaj.jp/detail.php?id=10.31662%2Fjmaj.2022-0106

  The mechanism underlying this limitation of angiogenesis is unknown. Persistent hypoxia in cardiomyocytes during the chronic phase suggests that some factors promote Hif1a degradation in cardiomyocytes. p53, a known Hif-degrading factor, is activated in failing cardiomyocytes. […] DNA damage is also an important factor in human heart disease. […] Despite several studies outlining the importance of DNA damage in various heart diseases, we have not fully elucidated the specific molecular mechanisms underlying DNA damage involved in HF development and progression. […] HF pathogenesis is primarily associated with genetic and environmental factors.

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