Heart Failure Lecture 4 - Brock University

Heart Failure KINE 3P97 Val A. Fajardo, PhD Announcements § Last lecture before term test 1 § After reading week there will be a review session – come prepared with questions. Goals of today’s lecture 1. Refresher on normal cardiac function § Cardiac cycle § Cardiac output (stroke...

Heart Failure KINE 3P97 Val A. Fajardo, PhD Announcements § Last lecture before term test 1 § After reading week there will be a review session – come prepared with questions. Goals of today’s lecture 1. Refresher on normal cardiac function § Cardiac cycle § Cardiac output (stroke volume and heart rate) § Cardiac reserve (SERCA and phospholamban) 2. What is heart failure? § HFpEF vs HFrEF (what’s the difference?) § The changing landscape § HFpEF and diastolic dysfunction 3. Menopause and HFpEF § Role of estrogen deficiency § OVX mouse model What does your heart do? Heart Function § Oxygenate blood § Take deoxygenated blood from the body and pump it to the lungs to be oxygenated § Deliver oxygenated blood § Send oxygenated blood to the rest of the body § Each chamber has muscular walls § Left ventricle (LV) has the thickest walls § Has to create enough pressure and force to properly pump the blood through the body Body Body Lungs Lungs Lungs Lungs Body Body Diastole § Diastole occurs when the heart relaxes, allowing the heart to fill up passively with blood. § For the left ventricle, this can dictate how much blood gets sent out to the body (i.e., diastolic dysfunction and HFpEF). § Plus atrial kick (atrial systole) at the end of atrial diastole, but the majority of filling occurs passively. § Diastole = relaxation § “Under pressure” - in order for the ventricles to fill up passively, they must relax from their previous contraction (next slide). Pressure ↓ for passive filling. Systole § Systole occurs when the cardiac muscle contracts, pushing blood to the next chamber, out to the lungs or out to the rest of the body. § Systole = contraction § The left ventricle, for example, has to generate enough pressure to push out to the aorta and the rest of the body. How does the LV generate pressure? Pressure volume curves Focus on: - Ventricular pressure - Ventricular volume - Atrial pressure Cardiac cycle - Aortic pressure Isovolumic contraction LV is generating force (accumulating cross-bridges) What happens to volume? Once the LV hits 80 mmHg what happens to the aortic valve? What stimulates this contraction? Pressure volume curves Focus on: - Ventricular pressure - Ventricular volume - Atrial pressure - Aortic pressure LV ejection/systole What happens to LV pressure? What happens to LV volume? What happens to aortic valve pressure? Pressure volume curves Focus on: - Ventricular pressure - Ventricular volume - Atrial pressure - Aortic pressure Isovolumic relaxation What is happening to LV pressure? What is happening to LV volume? Once the LV hits ~10 mmHg what happens to the mitral valve? What causes this relaxation? Pressure volume curves Focus on: - Ventricular pressure - Ventricular volume - Atrial pressure - Aortic pressure Rapid inflow What happens to LV pressure vs. left atrial pressure? What is happening to LV volume? What happened to atrial pressure? Why? This is called the Early phase Can get the ‘E’ wave Pressure volume curves Focus on: - Ventricular pressure - Ventricular volume - Atrial pressure - Aortic pressure Diastasis Flat middle portion of diastole where initial filling has slowed...right before the atrial kick! What happens to LV pressure vs atrial pressure? (not shown here well at all) Mitral flow nearly ceases. Combined with the rapid inflow this is passive filling. Little & Oh, 2009. Circulation Pressure volume curves Focus on: - Ventricular pressure - Ventricular volume - Atrial pressure - Aortic pressure Atrial systole What happens to atrial pressure vs LV pressure? What is happening to LV volume? This atrial kick is known as the A wave E/A ratio and impaired relaxation Pressure volume curves Focus on: - Ventricular pressure - Ventricular volume - Atrial pressure - Aortic pressure Then start back at isovolumic contraction! For next class notice what happens to the pressure in the aorta throughout LV diastole…doesn’t just drop! Cardiac output A measure of the heart’s ability to pump blood out to the body! § CO = Stroke volume x heart rate § Stroke volume = how much blood pumped out of the LV in one beat (EDV – ESV) § Heart rate = how fast your heart beats per min § CO = ml x beats = ml / min beat min Couple of questions 1. Why does the heart need to pump blood to the body? 2. Is cardiac output static? Or does it change to meet demands? Cardiac reserve § Our heart’s ability to reach for a bit more and pump more blood out to the body. § Essentially an increase in cardiac output. § Fight or flight response – what is it? How does it work? § ↑ CO = ↑SV x ↑HR ↑ SA node firing = ↑ heart rate SA node is the pacemaker Automatic firing Beta-adrenergic stimulation increases rate of firing Pressure volume curves Focus on: - Ventricular pressure - Ventricular volume - Atrial pressure - Aortic pressure ECG – will be more closely spaced LV Volume and Pressure curves – both should expand ↑ stroke volume § ↑ cardiac contractility by increasing ↑ calcium release SERCA SR DHPR Ca2+ RyR Ca2+ ↑ SERCA mediated calcium uptake Activates the myofilaments (actin and myosin) ↑ SERCA mediated calcium uptake § ↑ Calcium store inside the sarcoplasmic reticulum § ↑ Releasable calcium ↑ Ca2+ ↑ SERCA mediated calcium uptake Phospholamban § SERCA inhibitor that physically interacts with SERCA § Highly expressed in cardiac muscle, especially in the LV § Prevents calcium binding, reduces SERCA’s affinity for calcium Phospholamban  (Asahi et al. 2002, J. Biol Chem) 10 100 1000 10000 (nM) § pCa is like pH – the negative logarithm of Ca2+ concentration. So a low pCa means high Ca2+ concentration. § rightward shift in the uptake-pCa curves indicates a reduction in SERCA’s apparent affinity for Ca2+. § Draw a line at 50% max calcium uptake. What do you notice about the solid red line (SERCA2) vs the dashed red line (SERCA2+PLN).  PLN KO Wild type § Knocking out phospholamban in the mouse heart produces the opposite effect – a leftward shift. § Now it takes less calcium to stimulate ½ maximal SERCA function! Phospholamban phosphorylation § ↑ phosphorylation of phospholamban at Ser16 and Thr17 causes its dissociation from SERCA § Relieves its inhibition on the pump MacLennan 2003 Nature Reviews Phospholamban pentamer § Phosphorylation à pentamer formation § Pentamer - 5 phospholamban units together…thought to be the storage form of phospholamban § It is the monomer (single phospholamban) that can bind to and inhibit SERCA § ↑ monomeric PLN = ↑ SERCA inhibition - More calcium can be pumped into the SR Kranias & Hajjar 2012 Circulation Research How do we phosphorylate/inactive PLN? Fight or Flight = ↑ Epinephrine/Norepinephrine § NE binds to its G-protein receptor and ↑cAMP to activate protein kinase A (PKA) § PKA phosphorylates phospholamban at Ser16 (serine amino acid at the 16th position from N- terminal end) ↑ Calcium in the cytosol (more active muscle) § PKA also phosphorylates DHPR and RyR § Activates calmodulin dependent kinase II (CaMKII) § CaMKII phosphorylates PLN at Thr17 (threonine amino acid at the 17th position from the N- terminal end) Mattiazzi and Kranias 2014 Frontiers in Pharmacology James & Robbins 2013 Circulation Research ↑ SERCA calcium uptake = ↑ SR Calcium load = ↑ Calcium release on next contraction ↑ SERCA function = ↑ Diastolic filling § ↑ Calcium uptake = ↑ muscle relaxation = ↑ passive filling (increase in E wave) § ↑ Amount of blood in the ventricles = ↑ “preload” = ↑ stroke volume ↑ Ca2+ ↑ SERCA mediated calcium uptake Pressure volume curves Focus on: - Ventricular pressure - Ventricular volume - Atrial pressure - Aortic pressure Increase in preload An increase in relaxation can allow for more early (E) phase filling. Can allow the mitral valve to open up sooner and allow for more rapid and passive filling. Actin-myosin are still relaxing during passive filling…so enhancing relaxation increases the left atria vs. left ventricle pressure gradient. As more volume fills up in the LV, what happens to the chamber?? Preload and cardiac contractility § ↑ Preload = ↑ Stretching of the myofilaments § ↑ myofilament (myosin and actin) overlap = ↑ crossbridge formation § ↓ space between myosin and actin (brings them closer) Length-tension relationship Look at myofilament overlap throughout the different phases. Which one produces most force and why? § ↓ SERCA pumps § ↓ PLN responsiveness § ↑ Calcium stored and release § ↓ Calcium in the SR § ↑ Diastolic filling and preload § ↓ Diastolic filling § ↑ Force production = ↑ stroke volume § ↓ Force produced = ↓ stroke volume (↑Beta-adrenergic drive) § Some PLN bound to SERCA § Some PLN not bound to SERCA MacLennan 2003 Nature Reviews Goals of today’s lecture 1. Refresher on normal cardiac function § Cardiac cycle § Cardiac output (stroke volume and heart rate) § Cardiac reserve (SERCA and phospholamban) 2. What is heart failure? § HFpEF vs HFrEF (what’s the difference?) § The changing landscape § HFpEF and diastolic dysfunction 3. Menopause and HFpEF § Role of estrogen deficiency § OVX mouse model  o A condition where the heart is unable to pump Heart failure enough blood to the body. o Highly lethal condition if not managed properly Two kinds of heart failure HF preserved EF (HFpEF) HF reduced EF (HFrEF) § Diastolic heart failure § Systolic heart failure § Ability to bring blood into the ventricle is impaired, but § Ability to bring blood into the ventricle is intact, but contractility is intact. contractility is impaired. § Can’t fill up the bottle but can squeeze it. § Can fill up the bottle (in fact volume has increased) but can’t squeeze it. § Most related to aging and is now more prevalent! § Most related to diseases such as dilated cardiomyopathy Ejection fraction § Amount of blood pushed out with each beat divided by the amount of blood that was in there to begin with. !"#$%& &'&()&* § 𝐸𝐹 = 𝑥100 +"),# -"#$%&./##&* § HFrEF: EF is < 40% - can’t contract strong enough to push an adequate amount of blood out. § HFpEF: EF > 50% (preserved as normal range is 55-70%) – can’t bring enough blood into the ventricles, so an insufficient amount of blood is pushed out to the body. § *Both cases lead to reduced stroke volume and cardiac output! Heart in action (high-frequency ultrasound) Mouse heart (beats 300-500 bpm) Short axis view (cross section of the heart) At the mid-papillary view TOP Bottom Capture this in M-mode (motion mode) Mouse heart (beats 300-500 bpm) Anterior wall Each hill and valley represents systole and diastole With this M-mode capture we can measure LV structure How thick the anterior and posterior walls are HFpEF has commonly been viewed as an expression of advanced hypertensive heart disease, with a cardiac phenotype characterized Posterior wall by an increase in wall thickness-to-chamber radius ratio (concentric hypertrophy). Conversely, HFrEF is typically associated with eccentric hypertrophy, characterized by an increase in cardiac chamber size without an accompanying increase in wall thickness.  Control Concentric hypertrophy Ahmad et al., 2022 Molecular Metabolism HFpEF HFrEF Capture this in M-mode (motion mode) Mouse heart (beats 300-500 bpm) Anterior wall Each hill and valley represents systole and diastole With this M-mode capture we can measure LV function ESV, EDV, Stroke volume (calculated) Heart rate through ECG LV internal diameter; d LV internal diameter; s Cardiac output (SV x HR) Ejection fraction (EDV-ESV/EDV) * 100 Fractional shortening (LVID;d – LVID;s / LVID;d) * 100 Posterior wall In HFrEF, stroke volume and ejection fraction decreases because contractility decrease. Think about how a strong/weak muscle would look! Capture this in M-mode (motion mode) Mouse heart (beats 300-500 bpm) Anterior wall In HFpEF, ejection fraction is preserved (> 50%). Fractional shortening is also preserved. So contractility is intact, yet SV has decreased. This is because the chamber volume has decreased meaning less blood can go in. Lowered end-diastolic volume Posterior wall ↓EDV (filling up water bottle) ↓SV (less water to begin with) ↓CO because CO = SV x HR Not only is the chamber thicker their ability to relax has been impaired à diastolic dysfunction Diastolic dysfunction § Impaired left ventricular relaxation with increased stiffness (decreased compliance) of the left ventricle 1. Impaired relaxation 2. Increased stiffness or decreased compliance *think pressure… Assessing diastolic function with PW mode § Pulse wave mode – sending pulses of sound to bounce off of moving red blood cells. § Positioned at the mitral valve, we can measure how fast blood is moving into the LV during diastole. § Blood into the LV and toward the probe depends on the ability of that left ventricle to relax and undergo diastole. § Better diastolic dysfunction = increased flow to the LV and toward the probe Measures of impaired relaxation § Isovolumic relaxation time (IVRT) § What happens if you have impaired relaxation? § E-wave (passive filling phase) E-wave A-wave § What happens if you have impaired relaxation? § A-wave (atrial kick) § What happens if you have impaired relaxation and passive filling? PW mode – E/A ratio and IVRT IVRT = isovolumic relaxation time, which happens right before the start of the E wave. Need to drop pressure below atrial pressure to open the mitral valve. E-wave = the part where LV is being passively filled and blood is flowing from the left atria to the ventricle This wave depends on LV pressure < atrial pressure A-wave = the second peak that is normally lower than the E-wave as it represents the atrial kick. E/A ratio = because most of the filling in a healthy heart occurs passively, the E/A ratio is > 1.0 Diastolic dysfunction: impaired relaxation § ↑ IVRT § ↓E/A ratio to values less than 1.0 § In the next slide, ask yourself, what happens to IVRT? What happens to the E/A ratio? § What happens to diastasis? Diastolic dysfunction with maternal obesity Ahmad et al., 2022 Molecular Metabolism Healthy Diastolic dysfunction Diastolic dysfunction: stiffness/compliance Deceleration time Deceleration time Ahmad et al., 2022 Molecular Metabolism Healthy Diastolic dysfunction Diastolic dysfunction: stiffness/compliance Deceleration time § Clinically non-invasive marker of left ventricular compliance or stiffness (faster time = stiff/less compliant ventricle) § The time it takes for the blood to stop flowing into the ventricle passively. When the pressures in the ventricle = pressure in the atria. Usually right before atrial systole. § If you stop faster, then you limit the amount of blood that flows into the ventricle passively. Analogy: you don’t want good firm brakes in Deceleration time the heart. § If you stop slower, then you allow for more time for the blood to flow into the ventricle passively. Analogy: squishy brakes are bad on the road, Healthy but good for the heart. The changing landscape of Heart failure! HFpEF HFrEF borderline Started my BSc MSc PhD Kinesiology Prof gig COVID-19 undergrad at Biomed Health Sci. Brock Q: what does this mean in terms of treatment development? 2013 Oktay et al. Curr Heart Fail Rep. Questions 1. What does this changing landscape mean in terms of treatment? 2. Why is HFpEF the most dominant form of heart failure now? Effects of aging on the SERCA pump § ↓ SERCA content § ↓ adrenergic sensitivity = ↓ PLN phosphorylation § ↑ structural damage to the pump from ↑ oxidative stress § ↓ SERCA function = ↓ calcium in SR = ↓ relaxation = ↓ diastolic filling § ↑ Diastolic dysfunction and HFpEF Aging and fibrosis § Data from several studies suggest that ↑ fibrosis is involved with pathophysiology of HFpEF § ↑ collagen deposition § ↑ myocardial stiffness contributes to diastolic dysfunction § ↑ myocardial stiffness reduces compliance § ↑ myocardial stiffness increases pressure in the ventricles, limiting diastolic filling § Aging increases cardiac fibrosis Goals of today’s lecture 1. Refresher on normal cardiac function § Cardiac cycle § Cardiac output (stroke volume and heart rate) § Cardiac reserve (SERCA and phospholamban) 2. What is heart failure? § HFpEF vs HFrEF (what’s the difference?) § The changing landscape § HFpEF and diastolic dysfunction 3. Menopause and HFpEF § Role of estrogen deficiency § OVX mouse model HFpEF in women § The aging population has changed the landscape of heart failure with most cases being HFpEF. § Epidemiological studies show that patients with HFpEF are more likely to be female. § 2:1 ratio female:male § Exploring the mechanisms behind these sex differences in HFpEF will help in developing new treatments. Any ideas?  Early life: maximize Adult life: maintain Older life: minimize Males vs Females What are the key differences that you can spot on this figure? Compston JE. Clin Endocrinology 1990; 33:653-662 Tadic et al., 2019 J. Cliniical Medicine  OVX OVX model § Rodent preclinical model where a mouse or rat undergoes ovariectomy § Causes an abrupt drop in estrogen levels § Mimics the effects of menopause on bone health and osteoporosis Dou et al., 2016 Nutrients What about the heart? § OVX and cardiac SERCA function – can exercise help? § 2009 Bupha-Intr