246 Pathophysiology heart disease

Question 1

What types of heart disease due to impeded cardiac filling result in heart failure that result ?

Answer 1

Pericardial disease with restricted filling:

• Pericardial effusion with tamponade
• constrictive pericarditis

Valvular inflow obstruction:

• Atrioventricular valve stenosis
• Other anatomic obstructions e.g. cor triatriatum, neoplasm, granuloma

Intrinsic myocardial disease with impaired diastolic function:

• HCM
• RCM

Question 2

What are examples of heart failure resulting from increased resistance to ejection?

Answer 2

Increased resistance to ejection of blood (afterload): - Outflow tract obstruction: Pulmonic and subvalvular aortic stenosis, hypertrophy obstructive cardiomyopathy - Thromboembolism - Pulmonary hypertension

Question 3

What are examples of heart failure resulting from impaired ejection or volume overload?

Answer 3

• primary/secondary myocardial disease with impaired systolic function: DCM, Ischemia, infectious, nutritional, toxin - Misdirected blood flow from volume overload: Valve insufficiency, left to right shunts, arteriovenous fistulas - Chronic high-output states: thyrotoxicosis, chronic aneamia

Question 4

What are examples of heart failure resulting from arrhythmias and conduction disorders?

Answer 4

• Sustained tachyarrhythmias: supraventricular tachycardia, atrial fibrillation - Chronic bradyarrhythmias: complete heart block.

Question 5

What does SNS activation do to the heart during heart failure?

Answer 5

1. Increases HR (ventricular contractility) by affecting rate of SA nodal depolarisation and 2. Decrease systolic duration. This is to restore CO back toward normal desite depressed SV.
   - Stimulation of beta-adrenergic receptors increases firing rate of SA nodal cells by increasing slow inward calcium current Ical. SNS activation shifts the activation curve of inward pacemaker current, If, to positive voltages via Gs-dependent stimulation of adenylyl cyclase.

Question 6

What is the SNS effect on myocardial contractility?

Answer 6

• myocardial contractility (intrinsic force of contraction of myocardium independent of loading conditions) is increased by adrenergic nervous stimulation, circulating catecholamines, HR, and to some extent afterload.
• Action of stimulatory Gs protein, beta-adrenergic stimulation leads to activation of adenylyl cyclase and formation of cyclic AMP (cAMP), which activates protein kinase A (PKA) - Activated PKA phosphorlylates a number of proteins (L-type calcium channels, ryanodine, phospholamban, and SERCA2) that facilitate calcium transport across sarcolemma, augment calcium-induces calcium released by sarcoplasmic reticulum (SR), and increase calcium re-uptake by the SR. - Protein kinase A increases activity of variety of proteins that augment rate and force of myofilament contraction (troponin I and myosin-binding protein C)

Question 7

RAAS activation

Answer 7

• Reduced CO and activation of SNS in HF leads to activation of RAAS - stimuli for release of renin from juxtoglomerular cells = decreased renal perfusion, reduced sodium reabsorption by renal tubules, and beta1-adrenergic stimulation. - low-sodium diets, dehydration, blood loss, and vigorous exercise all stimulate renin release from juxtaglomerular apparatus.

Question 8

Neurohormonal alterations of renal function

Answer 8

The inadequate CO is sensed by arterial baroreceptoors and leads to sustained activation of SNS and RAAS - Decreased renal perfusion and increased real SN-mediated vasoconstriction causes decreased renal blood flow and increased sodium and water retention. - ATII => increases thirst and stimulates aldosterone release and ADH => both of which cause water retention. - NE -> stimulates release of ADH - These alterations = diminished/redistributed renal blood flow, reduced sodium excretion, and increased plasma levels of ADH with water. The Na and H2O retention leads to elevated venous pressures and development of oedema and effusion.

Question 9

Natriuretic peptides

Answer 9

• ANP and BNP oppose the actions of RAAS. - Act via A-type natriuretic peptide receptor, NPR-A to cause natriuresis and diuresis to inhibit tubular sodium transport in inner medullary collecting duct of the kidney. - The receptor mediates vasorelaxation of systemic and pulmonary arterioles -> to decreases systemic and pulmonary vascular resistance. -Also inhibit release of renin and aldosterone - NPR-B preferentially mediates vasodilation from locally produced CNP -NPR-C clears mature ANP and BNP from circulation - ANP and BNP are cleared from membrane bound neutral endopeptidase which cleaves them into inactive fragments. - Neutral endopeptidase and NPR-C have greater affinity for ANP, and so BNP has longer half-life. - N-terminal fragments of proANP and proBNP are removed slowly from circulation as these peptides depend on renal excretion.

Question 10

arginine vasopressin (AVP)/Antidiuretic hormone (ADH)

Answer 10

-

Question 11

arginine vasopressin (AVP)/Antidiuretic hormone (ADH)

Answer 11

• ADH - nonapeptide with arginine at 8th position. -provasopressin from preprovasopressin is produced in hypothalamus. Provasopressin becomes vasopressinin vesicles that are transported along azos to posterior pituitary, where they are secretory granules containing the active peptide within the nerve endings. - Plasma osmolality & hypovolaemis stimulate release from neurohyophysis - Low plasma volume = strest receptors in atria and large veins decrease firing rate, and stimulate AVP release. - SNS and ATII stimulate AVP release.

Question 12

Neurohormonal alterations of peripheral vasculature

Answer 12

• autonomicNS and autroregulatory mediators maintain sstemic blood pressure. - Adrenergic nervous system plays a role in redirecting blood to vital centres (brain & heart) causing increased peripheral vascular resistance. - Down regulation of parasympathetic tone, upregulation of RAAS, increased endothelin and AVP and alteration of blood to specific vascular beds

Question 13

Endothelin

Answer 13

vascular tone modulated by endothelium-derived vasodilators, NO and prostacyclin, and complex actions of potent endothelium-derived vasoconstricting peptide, endothelin. - Endothelins come from larger peptides produced by vascular enothelial cells (e.g. myocytes), in a sequence of steps analogous to the described for natriuretic peptides. - preproendothelin becomes inactive proendothelin, and temred big endothelin which is cleaved N-terminus by endothelial converting enzyme (ECE) to create mature active Endothelin-1 (ET-1) - ET-1 mRA expression and ET-1 production stimulated by hypoxia and emchanical factors, including stretch and low shear stressl by vasoactive sustances such as ATII, AVP, NE, and bradykinin, and growth factors and cytokines including transforming growth factor beta, tnf-a, and interleukin-1

Question 14

Endothelin

Answer 14

vascular tone modulated by endothelium-derived vasodilators, NO and prostacyclin, and complex actions of potent endothelium-derived vasoconstricting peptide, endothelin. - Endothelins come from larger peptides produced by vascular enothelial cells (e.g. myocytes), in a sequence of steps analogous to the described for natriuretic peptides. - preproendothelin becomes inactive proendothelin, and termed ‘big endothelin’ which is cleaved N-terminus by endothelial converting enzyme (ECE) to create mature active Endothelin-1 (ET-1) - ET-1 mRA expression and ET-1 production stimulated by hypoxia and mechanical factors, including stretch and low shear stresl by vasoactive substances such as ATII, AVP, NE, and bradykinin, and growth factors and cytokines including transforming growth factor beta, tnf-a, and interleukin-1

Question 15

Endothelin

Answer 15

vascular tone modulated by endothelium-derived vasodilators, NO and prostacyclin, and complex actions of potent endothelium-derived vasoconstricting peptide, endothelin. - Endothelins come from larger peptides produced by vascular enothelial cells (e.g. myocytes), in a sequence of steps analogous to the described for natriuretic peptides. - preproendothelin becomes inactive proendothelin, and termed ‘big endothelin’ which is cleaved N-terminus by endothelial converting enzyme (ECE) to create mature active Endothelin-1 (ET-1) - ET-1 mRA expression and ET-1 production stimulated by hypoxia and mechanical factors, including stretch and low shear stress by vasoactive substances such as ATII, AVP, NE, and bradykinin, and growth factors and cytokines including transforming growth factor beta, tnf-a, and interleukin-1

Question 16

NO and adrenomedullin

Answer 16

• NO is produced in endothelial cells from L-arginine via the action of endothelial nitric oxide synthase (eNOS), diffuses into smooth muscle cells and contributes to vasodilation - NO increases intracellular cGMP levels in vascular smooth muscle cells by activating soluble guanylate cyclase and activates potassium channels, leading to hyperpolarisation of the cell and vasodilation. - Heart failure: impaired endothelial cell function causes decreased NO synthesis, contributing to vasoconstriction

Question 17

Cytokine and Integrin signaling

Answer 17

• Cytokines (protein regulatory factors) = water soluble signaling proteins or glycoproteins produced by a wide variety of cell type used extensively in cellular communications - cytokines exhibit endocrine, paracrine, and autocrine actions via membrane-bound receptors that up and down-regulate expression of genes and transcription factors, thereby acting as potent modifiers of protein synthesis. - increased IL-1, IL-6, and TNF-a identified in human patients with CHF and regarded as important negative prognostic indicators. - increased TNF-a levels act to depress myocardial function, and chronic elevations of TNF-a promote apoptosis.

Question 18

Cardiac remodeling: Myocyte and nonmyocyte alterations

Answer 18

• pathologic cardiac remodeling shares adaptive processes and signaling pathways of physiologic remodeling with irreversible remodeling, reduced systolic or diastolic performance, and cardiac decompensation. Meerson and colleages identified 3 phases to hypertrophic response: 1) initial stage where hypertrophy develops in response to increased wall stress 2) compensated stage where wall stress is normalised by hypertrophic response, 3) exhaustion phase characterised by cardiomyocyte death, development of myocardial fibrosis, ventricular dilation, and reduced cardiac output. Compensatory and adaptive remodelling processes are transformed when hemodynamic stresses are prolonged in duration or excessive in magnitude, when physiologic patters of neurohormonal activation are excessively modified (RAAS, NE, ET-1) and when vascular remodelling exerts its toll on myocardial perfusion

Question 19

Define cardiac failure:

Answer 19

• The pathophysiological state where the heart is impaired in its ability to eject or receive blood, and this becomes so severe it overwhelms the compensatory mechanisms of the cardiovascular system.
• Heart failure is present when abnormal cardiac function results in either retention of sodium and water and elevated venous and capillary pressures (CHF or backward failure) or inadequate cardiac output (low output heart failure or forward failure)