Chronic Heart Failure Background and Drugs PDF 2024

Chronic Heart Failure BPS 338 1/29/2024 Richard T Clements Richard T. Clements PhD Assistant Professor Biomedical and Pharmaceutical Sciences Office 495P/ Lab 470 [email protected] Outline Background: Physiology Pathophysiology of HF HFrEF and HFpEF...

Chronic Heart Failure BPS 338 1/29/2024 Richard T Clements Richard T. Clements PhD Assistant Professor Biomedical and Pharmaceutical Sciences Office 495P/ Lab 470 [email protected] Outline Background: Physiology Pathophysiology of HF HFrEF and HFpEF Hemodynamics Neurohormonal hypotheses SNS/RAAS hypertrophy/ fibrosis Compensatory responses  Drugs to treat HF b-blockers ACEi/ATRB ARNI SGLT2i vericiguat MRA Loop Diuretics Hydralazine/Nitrates Inotropes  Chronic Heart Failure Heart failure (HF) is a progressive clinical syndrome that can result from any changes in cardiac structure or function that impair the ability of the ventricle to fill with or eject blood.  Cardiac Physiology: Cardiac Output CO = HR * SV SV determined by preload, afterload, and contractility Determinants of Cardiac Output: Afterload Preload Contractility Heart Rate Cardiac Cycle  Ejection Fraction The amount of blood ejected from the heart (stroke volume) divided by the amount of blood in the heart at diastole (EDV) expressed as %  Symptoms of HF Inability of the heart to maintain adequate cardiac output Fatigue dizziness, Muscle weakness/ exercise intolerance Shortness of breath Increased filling pressures can lead to additional complications Pulmonary edema: high vascular pressures in the lung result in fluid leak into air space Peripheral edema Ascites  Types of HF Heart Failure with reduced ejection fraction: HFrEF a.k.a Systolic Heart Failure Heart Failure with preserved Ejection Fraction: HFpEF a.k.a Diastolic Heart Failure Although different in hemodynamics and cardiac remodeling both have lower SV and CO.  HFrEF (systolic dysfunction) – reduced contractility causing reduced SV and EF. EDV is increased. HFpEF – although SV is lower leading to lower CO. EF is normal due to reduced EDV. EF=SV/EDV HFrEF and HFpEF both have less CO. HFrEF HFpEF  HFrEF and Frank-Starling Mechanism HFrEF: Impaired contractile function of the myocardium. Reduced CO for given preload/pressure  HFpEF and increased diastolic pressure. HFpEF – associated with stiffer ventricles and/or impaired relaxation signaling function Increased LVEDP for a given volume. Decreased LVEDV and SV Pressure Volume Loops PV loops in Heart Failure Summary of pressure – volume changes in HF Although may have elements of diastolic dysfunction in HFrEF and vice versa. Spectrum Especially as disease progresses/end stage. Vasodilation and HF Vasodilation reduces afterload In HF the heart is unable to maintain CO Decreased SV for a given afterload compared to normal Decreasing afterload increases the amount able to be pumped out at a given force. Increases CO Causes of HFrEF Major causes of reduced EF Structural abnormalities Previous MI – infarct/damaged myocardium Coronary Artery Disease Diabetes Metabolic Syndrome Lipids Inflammation O2 disruptions Hypertension Genetic cardiomyopathies Myocardial damage - Toxicity  Causes of HFpEF Not entirely clear disease mechanism Factors Obesity Hypertension CAD Diabetes Metabolic syndrome Kidney disease COPD Sleep Apnea Anemia  Neurohormonal hypothesis of CHF CHF is a progressive disease process exacerbated in the long term by compensatory mechanisms to increase CO. Initial injury or structural/ signaling alterations to decrease CO. Low CO elicits reflex response (baroreceptor) Increased SNS and RAAS activation to increase CO Results in remodeling and progressively declining function. Progressive Injury in HF Different stages of heart failure  Summary of CHF Two major classifications HFrEF (systolic) – reduced EF and stroke volume, increased volumes Heart cannot pump strongly enough to meet CO HFpEF (diastolic) - preserved EF, lower SV, lower volumes, higher pressures Heart is too stiff to fill properly to meet CO Both associated with fatigue, exercise intolerance, congestion etc.. Is a progressive disease which involves numerous factors: Major cause of damage is overactivation of the SNS system for prolonged periods Can have significant changes over time: Compensated: able to meet CO demands despite poor performance Decompensated: no longer able to adequately provide CO.  Myocardial Hypertrophy Hypertrophy in HF is abnormal growth of cardiomyocytes Not proliferation but growth of cells Differences in hypertrophic signals in HFpEF and HFrEF: Hypertrophic responses common to both Differences are incompletely understood but intensive subject of cardiac research. Fibrosis and Cardiac Remodeling and HF Fibrosis and ECM deposition is a major component of cardiac remodeling in addition to hypertrophy Deposition of ECM molecules promote fibrosis. Fibrotic hearts are stiffer, less elastic Contractile function is impaired depending on severity. Cardiac Fibroblasts drive Myocardial Fibrosis Cardiac Tissue: Green: Myocytes Red : Fibroblasts Blue: Nuclei Hypertrophy and Fibrosis Complex Interplay mediating Fibrosis Increased ECM: collagen, etc. Pro-fibrotic signals and mediators: TGF/CTGF Inflammatory Cytokines Growth Factors ET-1, Ang II, others…  Pathological Hypertrophy and Fibrosis Signaling Complicated interplay of many different cascades Do not worry about details here Recognize Pathways driven by: AngII Adrenergic Signals Mechanical Forces Opposed by Natriuretic Peptides  Angiotensin II Nervous System Thirst Vasopressin release SNS activation Potent vasoconstrictor (increase Baroreflex modulation renal pressures) Stimulation of aldosterone release Heart Inotropy from adrenal glands (fluid Hypertrophy retention) Fibrosis Reduced perfusion Direct effects on cardiomyocyte, hypertrophy Blood vessels: Direct effects on fibroblast Increased contraction Impaired vasodilation proliferation/fibrosis Enhance atherosclerosis Enhance SNS activity Kidney: Most adverse effects of AngII Renal vasoconstriction mediated by AT1R Increased fluid reabsorption Renin release Aldosterone release  AngII and vasoconstriction Ang II is a potent vasoconstrictor. Effects mediated by activation of AT1R (GPCR) AngIIR activation increase Ca++/MLCK and Rho GTPase cascades to increase MLC phosphorylation I.V. Ang II infusion  Ang II and hypertrophy/fibrosis AngII stimulates cardiomyocyte hypertrophy and remodeling Effects both direct and mediated by pressure overload due to elevated constriction. AngII via AT1R activates numerous growth/proliferative signaling cascades. Alters gene expression (fetal gene expression) and can impair contractile function Vessel rarefaction Same amount of vessels for larger cells. Pathological hypertrophy can impair contractile function Fibrosis can increase stiffness promote arrythmia Ang II induces fibroblast proliferation and fibrosis Ang II is also associated with increased fibroblast proliferation Ang II – induces many fibrotic mediators causing increased deposition of ECM Collagens, Fibronectin, Laminins, etc… Increased fibrosis can increase LV stiffness Increased aortic stiffness and pulse pressure also. Red myocytes Blue fibrosis  Major Effects of Ang II: Vasoconstriction Activation of SNS Hypertrophic and fibrosis signaling Volume retention  2016 AHA/ACC guidelines Goals of Therapy Limit/slow myocardial remodeling Limit neurohormonal response ACEi/ARNI/B-blocker Reduce BP/afterload Reduce volume retention Overall - improve CO long-term  2022 AHA/ACC guidelines Goals of Therapy: from outset Limit/slow myocardial remodeling B-blocker , ARNI, SGLT2i, MRA Limit neurohormonal response ACEi/ARNI/B-blocker Reduce BP/afterload ACEi, ARNI, Nit/hydral Reduce volume retention loop diuretics, MRA, ARNI, SGLT2i Overall - improve CO long-term NYHA stages of Heart Failure  Summary: signaling causes of CHF Fibrosis is a major problem in CHF Caused by ECM deposition of cardiac fibroblasts and myocytes in heart impairing function SNS (adrenergic signaling) overactivation promotes fibrosis Ang II activation promotes fibrosis Inflammatory signals promote fibrosis/injury Multitude of fibrosis signaling pathways in common: TGF, cytokines, MAP kinases, etc… (details are not important here – recognize driven by AngII and B-AR) Hypertrophy in CHF also a major problem Many of the signaling cascades in myocytes driving hypertrophy Similar to fibrosis signals. Hypertrophy driven by SNS, AngII, Aldosterone, etc..  Drugs to treat HF b-blockers ACEi/ATRB ARNI SGLT2i vericiguat MRA Loop Diuretics Hydralazine/Nitrates Inotropes  ACEi/ATRB ACEi: Block angiotensin converting enzyme (ACE) which generates AngII from AngI. ATRB (Angiotensin Receptor Blocker): Blocks intracellular signaling via the receptor ACEi and ATRB have similar effects with exception of increased Bradykinin (dilator) Increased Bradykinin causes cough.  Angiotensin II Nervous System Thirst Vasopressin release SNS activation Potent vasoconstrictor (increase Baroreflex modulation renal pressures) Stimulation of aldosterone release Heart Inotropy from adrenal glands (fluid Hypertrophy retention) Fibrosis Reduced perfusion Direct effects on cardiomyocyte, hypertrophy Blood vessels: Direct effects on fibroblast Increased contraction Impaired vasodilation proliferation/fibrosis Enhance atherosclerosis Enhance SNS activity Kidney: Most adverse effects of AngII Renal vasoconstriction mediated by AT1R Increased fluid reabsorption Renin release Aldosterone release  ACEi and ATRB STARTING DOSE TARGET DOSE IMPORTANT ADVERSE EFFECTS, INTERACTIONS, AND CLASS/Drug HALF-LIFE (h) (mg) (mg) CONTRAINDICATIONS ACE inhibitors Captopril 1.7 3 × 6.25 3 × 50 Adverse effects: Cough (~5%), ↑ serum creatinine ( 50%, possibility of renal artery stenosis), hyperkalemia, hypotension, angioedema Lisinopril 13 1 × 2.5–5 1 × 20–35 Interactions: Increased rate of hyperkalemia in + + Ramipril 13–17 1 × 2.5 1 × 10 combination with K -sparing diuretics, K supplements, Trandolapril 15–23 1 × 0.5 1×4 cyclosporine, NSAIDs (PD), reduced efficacy in + combination with NSAIDs (PD), ↑ [Li ] in serum (PK), ↑ hypoglycemic risk in combination with insulin or oral antidiabetics; increased effect in renal insufficiency (PK) Contraindications: Bilateral renal artery stenosis Angiotensin receptor blockers Candesartan 9 1 × 4–8 1 × 32 Adverse effects: Similar to ACEi, but no cough Losartan 6–9 1 × 50 1 × 150 Interactions and contraindications: As ACEI Valsartan 6 2 × 40 2 × 160  Summary: ACEi in HF Major benefits include: Decreased vasoconstriction limiting afterload and improving CO. Ca/MLCK/RhoK cascades Limit cardiac hypertrophic responses leading to maladaptive remodeling AT1R – driven gene expression Stimulation of SNS activity Limit cardiac fibroblast proliferation leading to impaired mechanical function, increased stiffness and propensity for arrythmia AT1R- driven gene expression – ECM proteins Decrease volume overload due to fluid retention Decrease Na excretion Decrease aldosterone Decrease SNS activity : further RAAS activation  Aldosterone and HF Aldosterone part of the RAAS system Even with ACEi additional mechanisms for making Aldosterone Aldosterone can also enhance fibrosis (myocardial, renal, and vascular) Aldosterone: Increase Na+ and water reabsorption to concentrate urine in cortical collecting duct of kidney (K+ sparing 1 2 diuretic) 3 1)Activation, preservation, synthesis of Na channels 2)Activation, preservation, redistribution of Na+/K+ ATPase 3)Activation, preservation, synthesis of lumen K+ channels 4) Alter permeability and cellular respiration Overall effect to increase Na retention, increase blood volume and contribute to overload.  Aldosterone and Fibrosis Aldosterone binds and inhibits MR MR can act as a transcriptional regulator to promote fibrosis/hypertrophy response in heart/other tissues. Non-transcriptional effects via transactivation of other receptors to increase ROS and fibrosis. MR antagonists spironolactone and eplerenone LBD and DBD are specific domains of MR  Summary : MRA: spironolactone and eplerenone MRA have been shown to improve survival in HFrEF Spironolactone – nonspecific steroid receptor blocker: side effects gynecomastia and dysmenorrhea Eplerenone: specific MRA K+ sparing diuretic Blocks aldosterone effects in kidney Reduces blood volume : decrease afterload Still used with ACEi due to aldosterone “escape” with ACEi Alternative pathways to make aldosterone get upregulated in the presence of an ACEi Limit fibrosis and remodeling in cardiac cells ARNI- Angiotensin Receptor Blocker and Neprilysin Inhibitor Entresto, LCZ696 or sacubitril/valsartan Sacubitril (neprilysin inhibitor) Valsartan (ATRB) Newer drug approved recently that is thought to exert majority of effects through elevation of natriuretic peptides. ANP, BNP. Inhibition of ATR Demonstrated improved survival over enalapril alone (ACEi) in HFrEF  Neprilysin Neprilysin is an ectoenzyme that degrades numerous vasoactive peptides Neprilysin Degrades: Natriuretic Peptides ANP BNP Bradykinin ET-1 Ang-II Others  Natriuretic Peptides (NPs) have multiple protective effects Atrial and Brain natriuretic peptides (ANP, BNP) have multiple protective responses in CHF Decrease blood volume and Na (natriuresis) Direct vasodilator Made in response to stretch of the heart.  NP receptors and vessels NPRA and B: Have a guanylate cyclase built into the receptor Make cGMP Activates PKG Promotes vasodilation in smooth muscle Is anti-fibrotic/ hypertrophy in other cell types – fibroblasts and myocytes  Major anti-fibrotic effects of ANP/BNP are via increased cGMP Activation of NP-R’s activates pGC in fibroblasts/myocytes is antifibrotic. NPs are vasodilatory also via pGC and PKG pGC is particulate guanylate cyclase  ANP and BNP have opposing effects to Ang II ANP/BNP production and ARB are complementary and beneficial in CHF Also recognize NP’s and AngII have opposing effects on SNS  Sacubitril/Valsartan and side effects Angioedema – acute increases in endothelial permeability caused by excessive bradykinin due to neprilysin inhibition. Also concern as serious side effect with ACEi as they also increase bradykinin Hypotension Neprilysin causes increases in other vasoactive mediators: AngII (solved by ARB), ET-1 (potent vasoconstrictor) Summary Sac/Val (ARNI) Therapeutic effects Inhibits Neprlysin and blocks Ang receptor: Increases NP levels. Promotes vasodilation in smooth muscle via increased NPs: Reduces BP and afterload Works through cGMP/PKG Antagonizes SNS stimulation/activation via NP’s NPs have anti-fibrosis signaling. Antagonizes AngII mediated signaling (valsartan) Antifibrotic and anti-hypertrophic signaling via NP’s Promotes natriuresis (Na excretion) via NPs Reduce preload/afterload positive mechanical effects on heart.  Vericiguat – soluble guanylate cyclase activator (sGC) riociguat Demonstrated to improve survival in HFrEF patients Activates soluble guanylate cyclase to produce cGMP (similar to NP receptors) cGMP promotes vasodilation in vascular smooth muscle cells NO/cGMP promotes antifibrotic signaling in cardiac fibroblasts No signaling/production impaired in many disease states Not to be use with PDE5i!! Same rationale as NO donors. b-blockers and HF Why use a b-blocker in chronic heart failure? bAR – increase contractility, HR and CO b-blockers decrease contractility and lower HR. acute effects to decrease CO Was counterintuitive and met with skepticism in the 80’s/90’s when developed. Neurohormonal hypothesis of heart failure – 90’s-2000s Overactivation of SNS and RAAS Inhibition can stabilize cardiac function and limit remodeling. Limits progressive decline in function due to inhibition of b-AR signaling in heart as well as hemodynamic alterations to worsen failure (afterload, etc) b-blocker inhibition and HF B-blockers will also reduce contractility (Ventricular cardiomyocytes) and slow HR (SA node) Chronically increased HR and contractility due to SNS overactivation may contribute to pathological remodeling, cell death and impaired contraction  b-AR has additional cascades to promote hypertrophy and fibrosis. b-AR has additional cascades to promote hypertrophy and fibrosis: This is distinct signals from Ca++ increases and HR Some mediated by PKA, some not Know B-AR signaling promotes fibrosis in the heart b-blockers and heart failure b1 - selective Metoprolol t1/2 3-5 hours (prolonged release formulation must be used – important to keep relatively constant dose of B-blockers) Bisprolol t1/2 10-12 hours b and a1: Carvedilol: t1/2 6-10h – twice daily dose Alpha blockade may be beneficial for decreasing afterload/hypertrophy/fibrosis b1 selective and NO-mediated dilation: Nebivolol (Europe, not approved in US for HF) NO donor activity may promote dilation and anti-fibrosis signaling  b- blockers Need to be started at low dose (~1/8 target) and slowly ramped up Acute negative inotropic effects Reductions in CO Hypotension If introduced slowly over weeks/months compensatory mechanisms can avoid large decreases in CO that would be associated with initial high doses If started slowly well tolerated: major benefit thought to limit chronic SNS damage and cardiac remodeling Reduction in HR may improve energetics/metabolism Don’t confuse with acutely decompensated heart failure treatment b-agonists/inotropes  b-Blockers Summary I b-blockers mainly improve CHF by reducing chronic SNS signaling which causes myocardial remodeling (hypertrophy and fibrosis) Summary: therapeutic effects of b-blockers Reverse or halt remodeling of LV (Neurohormonal hypothesis) Decrease hypertrophy and LV mass Improve shape (sphericity) Decrease myocyte apoptosis/necrosis (catecholamine-induced) Reduce LVESV and LVEDV Increase EF ~5% Slow HR – but not relevant to CHF Reduce O2 consumption - SIHD Antiarrhythmic - AAD Limit renin release – reduce volume retention Lower BP and afterload (especially carvedilol – a anatagonist) SGLT2 inhibitors Sodium GLucose co-Transporter 2 inhibitors: Reduce hyperglycemia by promoting renal excretion Numerous additional effects associated with improvement in heart failure: HFrEF and HFpEF Direct effects on heart are multifactorial and may involve multiple off- target effects Normalization of renal function can significantly improved overloaded hearts (reduce preload/afterload)  SGLT2i and HF Numerous recent clinical trials for SGLT2 inhibitors and heart failure SGLT2 inhibitors effective in HFrEF and HFpEF. ~15% reduction in hospitalization for HF and death. One of first evidence based medications for HFpEF Beneficial effects of SGLT2 inhibitors in the kidney 1.With hyperglycemia there is too much Na reabsorption in proximal tubule 2.inhibiton of SGLT2 normalizes luminal Na 3. Increased sodium in the distal tubule causes afferent vasoconstriction to reduce glomerular pressure SGLT2 inhibitors and the heart : possible direct effects NCX – normally exchanges Na (in) and Ca (out) If there is too much Na+ inside can run in reverse or not as fast as usual SGLT1 is on cardiomyocyte membrane – brings Na+ inside NHE1 brings Na+ inside SGLT2i inhibits both thus reducing intracellular Na+ Decreased Na+ allows NCX to work normally to expel Ca++. the picture shows NCX in reverse mode because of too much Na+ May also raise mito Ca++ - thus driving ATP  SGLT2 Summary SGLT2 inhibitors may have numerous additional therapeutic effects in cardiomyocytes: Decrease fibrosis signaling Normalize cardiomyocyte Ca++ handling (SGLT1 and NHE) Improve cardiac mitochondrial function Improved BP and vasodilation (secondary to hyperglycemia and Ca++?) Kidney-mediated effects Lower hyperglycemia Reduce RAAS and SNS signaling Improve TGF Reduce volume Loop Diuretics furosemide, torsemide, bumetanide Inhibit the Na+, K+ 2Cl- symporter in the ascending loop of Henle. These diuretics also increase K+ excretion which can lead to hypokalemia (this is in contrast to spironolactone and eplerenone Decreases volume retention and decreases preload improving cardiac output Loop Diuretics furosemide, torsemide, bumetanide Inhibit the Na+, K+ 2Cl- symporter in the ascending loop of Henle. These diuretics also increase K+ excretion which can lead to hypokalemia (this is in contrast to spironolactone and eplerenone) Decreases volume retention and decreases preload improving cardiac output May need increased dosing in CKD to be effective Summary Loop Diuretics Decreases volume retention Decreases preload/afterload improving volume overload/remodeling and CO (afterload) Often used in conjunction with K+ sparing diuretics (MRA’s) Concern for hypokalemia as target is Na+, K+, Ca++ co transporter.  Nitrates/Hydralazine Pure vasodilators have not been very effective in HF studies (reflex tachycardia?) ISDN and Hydralazine combination. ISDN dilates veins and conduit arterioles: Decreases preload/venous pressure. Hydralazine dilates arterioles Activation of K+ channels (pro-dilatory) Limits Ca++ release (IP3 receptor) Limits reactive oxygen species (pro-contractile) May promote local vasodilator production (VEGF,PGI2) ISDN alone is subject to nitrate tolerance Possibly due to ROS scavenging effects of hydralazine. 20mg ISDN/37.5 mg hydralazine – 2 tablets , 3x day.  NO can be scavenged by ROS. Creates formation of RNS which can damage cells and possibly lead to nitrate tolerance Hydralazine diminishes ROS thereby increasing NO signaling and itself promotes dilation  Vasodilation and HF Vasodilation reduces afterload In HF the heart is unable to maintain CO Decreased SV for a given afterload compared to normal Decreasing afterload increases the amount able to be pumped out at a given force. Increases CO  Hydralazine/ISDN ISDN: slow release NO to promote vasodilation Hydralazine: likely mechanism scavenging of ROS which will promote NO efficacy, limit tolerance Hydralazine/ISDN:. Benefit was restricted to African-American cohort. conferred a 43% survival benefit in CHF Approved by FDA in 2006. First ethnically restricted approval Differences in racially based treatment differences unknown. Hypotension major adverse effect related to vasodilation.  Inotropes and HF Inotropes are generally not used and only in specific situations Digoxin – a cardiac glycoside, inhibits the Na+/K+ ATPase. Has a very narrow therapeutic window for beneficial vs detrimental/toxic effects (.5-.8ng/ml therapeutic, >1.2 ng/ml detrimental) Elevates intracellular Ca++ via NCX (opposite mechanism of Ranolazine)  Additional Inotropes Omecamtiv mecarbil: A novel myosin activator currently being tested for chronic HF Increases cardiac contraction without modulating Ca++ or other signaling pathways, ATP consumption Promotes interaction of myosin and actin for greater force generation Goal: to promote contraction without negative signaling associated with other inotropes: unclear.  Summary CHF therapeutics Limit myocardial remodeling: B-blockers – block SNS stimulation/remodeling ACEi/ATRB – limit AT1R dependent remodeling ARNI – enhance NP signaling MRA – aldosterone dependent fibrosis Promote vasodilation/decrease afterload: ACEi/ATRB – limit angII mediated vasoconstriction ARNI – NPs promote vasodilation/cGMP signaling Hydralazine/ISDN – direct vasodilation B-blockers: Decrease HR Reduce volume/decrease preload Loop diuretics – Na+, K+, 2Cl- furosemide, tosemide Aldosterone inhibitors (MRA) – Na+ channel expression/activity. ACEi/ATRB ARNI- NPs cause excretion of Na+ (natriuresis) Unclear/multifactorial: SGLT2i Things to know: The mechanisms leading to HF Neurohormonal hypothesis: Overactivation of SNS and RAAS leading to progressively worse function Afterload and remodeling/fibrosis Drugs/mechanisms and beneficial effects specific to CHF ACEi/ATRB ARNI – sacubitril/valsartan b-blockers MRA SGLT2i Loop Diuretics Hydralazine/ISDN Cardiac Amyloidosis A condition where misfolded proteins get deposited in the heart and disrupt cardiac function Can lead to further progressive remodeling similar to other types of heart failure  Multiple types of amyloidosis Amyloid Transthyretin (ATTR) – Transthyretin a protein made in liver and secreted that transports thyroid hormone and retinol (Vitamin A). Subtypes: Hereditary (between 1:100k and 4% depending on region: West Africa/Portugal) Wild-type (later onset) subtypes: unclear, estimates as high as 20% in men over 80. Amyloid Light Chains (AL) – This is related to production of immune modulating light chains (bone marrow derived cells). Can also be associated with immune/blood –related cancers. ~1:65k Numerous additional cardiac amyloidoisis mutations(very rare) including: Apolipoproteins, Fibrinogen, Gelsolin  Symptoms of cardiac amyoidoisis Very similar to HFpEF Increased cardiomyocyte hypertrophy Reduced EDV and increased EDP Reduced cardiac output Ineffective HF treatments (ACEi, ARB, b-blockers) Shortness of breath Mismatch with LV wall thickness/QRS voltage Fatigue Edema Arrythmia Additional orthopedic and nervous system problems Kidney and liver problems Trantheyretin (TTR) misfolding  Tafamadis and ATTR-CM Tafamadis is small molecule developed in the late 90’s early 2000’s to specifically bind and stabilize TTR tetramers. Approved in 2019 for treatment of ATTR in US. Decreases all cause mortality by ~ 30% Cost of treatment somewhat controversial : ~225,000/year. Mechanism of Tafamadis  Summary - ATTR - Cardiac Amyloidopathy ATTR has similar presentation to HFpEF Caused by deposition of misfolded TTR proteins in the mycocardium TTR is a circulating protein made by liver and is stable as a tetramer Tafamadis reduces amyloid deposition by stabilizing the tetramer confirmation of TTR. TTR can be caused by misfolding of wt proteins – associated with age, or by mutations in the TTR gene which can result in ATTR much earlier.  Practice Question Why use b-blockers in SIHD: A: Limit fibrotic signaling B: Decrease arrythmia by lowering heart rate C: Decrease cardiac contractility and heart rate to lower O2 demand D all of the above  Practice Question Why use b-blockers in CHF: A: Limit fibrotic signaling B: Decrease arrythmia by lowering heart rate C: Decrease cardiac contractility and heart rate to lower O2 demand D All of the above  What are the beneficial effects of ACEi in CHF? A: Decrease fibrosis signaling B: Decrease blood volume through Na excretion C: Increase vasodilation D: All of the above  What signaling cascade is protective in CHF in multiple cell types and is activated by ARNI and vericiguat? A – cAMP/PKA B – NO/cGMP/PKG C – MLCK and MYPT D – All of the above  Why lower heart rate in SIHD (multiple multiple choice) A: Increase time between beats to avoid arrythmia B: Lower oxygen demand C: Increase diastolic filling time D: Increase oxygen supply  What is the major difference between verapamil and nifedipine for SIHD? A – Nifedipine decreases cardiac contraction verapamil does not B – Nifedipine lowers heart rate verapamil increases heart rate C – Nifedipine may increase heart rate and verapamil lowers heart rate D - Nifedipine constricts veins and verapamil dilates veins Why are diuretics beneficial in CHF? A. Increase preload to increase CO B. Decrease preload to modulate remodeling C. Increase NPs to promote cardioprotective signaling D. Increase contractility to increase CO HFrEf and Treatment Aldosterone and Na+ retention Aldosterone binding to mineralocorticoid receptor (MR) in kidney. activation, preservation, synthesis of Na channels (1-3) Activation, preservation, redistribution of Na+/K+ ATPase (4-6) Alter permeability and respiration (7,8) Overall effect to increase Na retention, increase blood volume and contribute to overload. Goodman and Gilman Figure 25-6 HFpEF and treatment Progression of HF and Adaptation  b-agonists – only used in acute severely decompensated HF Used in settings of acute and severe cases of lowered CO. Severe hypotension Cardiac arrest Cardiogenic shock Myocardial stunning and post-cardiac surgery low output syndrome Not desirable for long term treatment of HF Desensitization of bAR signaling Increased O2 demand Can make the heart ischemic Increased afterload due to effects on aAR Promote remodeling Beneficial effects of Natriuretic peptides (ANP, BNP) are via cGMP  cGMP activates PKG signaling PKG activation counteracts many of the detrimental constriction and fibrosis signaling cascades discussed. Vericiguat: a sGC activator Combination therapy and cardiac function I= inotrope V=vasodilator D= diuretic  SGLT2 : similar but opposite mechanism to Digitalis in regards to Ca++ Inotropes are generally not used and only in specific situations Digoxin – a cardiac glycoside, inhibits the Na+/K+ ATPase. Has a very narrow therapeutic window for beneficial vs detrimental/toxic effects (.5-.8ng/ml therapeutic, >1.2 ng/ml detrimental) Elevates intracellular Ca++ via NCX (opposite mechanism of Ranolazine)  b1AR mechanism of modulating Ca++ release : PKA PKA can increase Ca++ release through direct modulation of Ca++ release through RyR, and external Ca++ channels. However, Ca++ stores need to be replenished and increased so PKA phosphorylates and inhibits PLB PLB normally inhibits SERCA. pPLB no longer inhibits SERCA and SR Ca++ stores increase Subsequent Ca++ release from SR is increased. Other kinases are involved in this coordinated response: ex CamKII, but PKA is major player.