Left Ventricular Pump Function

Michael R. Pinsky, MD, Dr hc Department of Critical Care Medicine University of Pittsburgh Left Ventricular Pump Function

• Maintain a constant and high organ input pressure • Eject into a low compliance high resistance arterial circuit • Transfer all blood received with a minimal back pressure • Match to venous return on a beat-to-beat basis Bedside Assessment of Ventricular Pump Function Assessing Left Ventricular Performance Commonly Used Measures of Cardiovascular Function:

Heart Rate Cardiac Output Stroke Volume LV ejection fraction Frank-Starling Relationship

• Frank: Force of fiber contraction proportional to length prior to excitation • Frank. Z Biol 32:370-437, 1895 • Starling: Fiber length proportional to end-diastolic volume • Patterson & Starling. J Physiol (Lon) 48:465-513,1914 • Frank-Starling: Systolic function proportional to end- diastolic volume Primacy of Preload in Determining Systolic Performance Otto Frank Isometric contractions of a frog at increasing filling pressures Frank O, Z Biol 1895; 32:370 Ernest Starling Stroke volume increases with end-diastolic volume

End-diastolic Volume

Increased End-diastolic Volume

Patterson & Starling. J Physiol 48:357-87, 1914 Starling versus Anrep Heterometric v. Homeometric of the

Increased Preload Starling EDV Preload Heart Rate Anrep Contractility

ESV Increased Contractility

Sudden increase and decrease in venous return Rosenblueth et al. Arch Int Physiol 67: 358, 1959 Frank-Starling Relationship

LV Ejection Hyper-effective Phase Indies:

Ejection Fraction Stroke Volume Stroke Work Hypo-effective LV dP/dt

Vcf Preload (end-diastolic volume)

Sarnoff & Berglund. Circulation 9:706-18, 1954 Frank-Starling Relationship Is heart A “better” than heart B? A

B Stroke Volume Stroke

Preload (end-diastolic volume) Arterial pressure increases with end-diastolic volume

Patterson & Starling. J Physiol (London) 48:357-79, 1914 Inherent Weaknesses with Using Stroke Volume as a Measure of Cardiac Contractility

• Stroke volume is altered by Ejection Pressure • Increasing arterial pressure decreases stroke volume • Decreasing arterial pressure increases stroke volume • Stroke volume is altered by Heart Rate • Tachycardia decreases stroke volume (less filling time) • Bradycardia increases stroke volume (more filling time) • Chronotropy For a constant end-diastolic volume: • Increasing heart rate increases stroke volume • Decreasing heart rate decreases stroke volume Ventricular Function

Muscular Work LV ejection: volume under pressure

Stroke Work = Developed Pressure x Stroke Volume

Minute Work = Stroke Work x Heart Rate Frank-Starling Relationship

A

B Stroke Work Stroke

Preload (end-diastolic volume) Wiggers CJ, Circulation 5:321-48, 1952 LV Pressure-Volume Loop End-systole Ejection (stroke volume) Aortic Valve Opening LV Isometric Isometric Pressure Relaxation Contraction (mm Hg)

Mitral Valve End-diastole Opening Diastolic filling

LV Volume (mL) Patterson & Starling. J Physiol 48:465-513,1914 Determinants of LV Function Preload End-diastolic volume Afterload Systolic wall stress Contractility Intrinsic myocardial performance Heart Rate Chronotropy

Patterson & Starling. J Physiol 48:357-79, 1914 Frank-Starling Relation Primacy of PRELOAD in determining ventricular systolic performance

Preload is determined by systemic venous return Preload is the primary determinant of cardiac output

LV Preload equals LV end-diastolic volume

Patterson & Starling. J Physiol 48:465-513,1914 LV Pressure-Volume Relations Diastolic Filling

LV Diastolic Compliance = P/ V Pressure End-diastolic P/V Relation Increased (mm Hg) Stiffness

P V

LV Volume (mL) Pinsky Intensive Care Med 29:175-8, 2003 Isometric LV Ejection

End-Systolic Developed Pressure LV Pressure (mm Hg) A B C

LV Volume (mL) Suga et al. Circ Res 32:314-322, 1973 Isometric LV Ejection

End-Systolic Pressure- Volume Relationship

LV Pressure (mm Hg) A B C

LV Volume (mL) Suga et al. Circ Res 32:314-322, 1973 LV Ejection from a Common EDV

End-Systolic Pressure- C Volume Relationship

LV B Pressure (mm Hg) A

LV Volume (mL) Suga et al. Circ Res 32:314-322, 1973 Isometric LV Contraction or Ejection

Suga et al. Circ Res 32:314-322, 1973 The Slope of the End-Systolic Pressure-Volume Relationship (ESPVR) is proportional to contractility

• The ESPVR is relatively insensitive to loading conditions • Independent of prior end-diastolic volume • Independent of subsequent ejection pressure • Increasing ESPVR is increased contractility • Decreasing ESPVR is decreased contractility

Suga et al. Circ Res 32:314-322, 1973 LV Pressure-Volume loops at variable venous return before and after epinephrine

Suga et al. Circ Res 32:314-322, 1973 Effect of Changes in Contractility on the End-Systolic Pressure-Volume Relationship Decreased Contractility Increased Contractility

Augmented Normal LV Pressure Failure (mm Hg)

LV Volume (mL) Suga et al. Circ Res 32:314-322, 1973 The Functional Basis for Left Ventricular Contraction and ESPVR

LV pressure-volume histories at differing preloads and afterloads LV Pressure

LV Volume On the Nature of LV Contraction Sequential P/V Loops during IVC Occlusion

IVC LV Occlusion Pressure

LV Volume End-Systolic Pressure Volume Relationship (generated by IVC occlusion)

Ees IVC Occlusion

Ejection

Diastolic compliance On the Nature of LV Contraction Iso-chronic lines at 20 ms intervals

200 140 100 80

ESPVR 60

LV 40 Pressure 20

LV Volume Suga et al. Circ Res 32:314-322, 1973 On the Nature of LV Contraction

Iso-chronic lines at 20 ms intervals Baseline Increased Inotrophy (Epinephrine infusion) 100 80 60 200 140100 40 80 60 P P 40 20 20

Volume Volume Suga et al. Circ Res 32:314-322, 1973 Time-Varying Elastance (Et) Instantaneous LV Pressure/Volume Relations

Increased Contractility

(Epinephrine) (mmHg/ml)

Normal LV P/V P/V LV Contractility (Baseline)

Time (sec) Suga et al. Circ Res 32:314-322, 1973 On the Nature of LV Contraction

Time-Varying Elastance (Et) • Shortening proceeds uniformly from start to end of systole independent of either pressure or volume • Time post-initiation of systole defines a pressure- volume domain which is independent of history

• Increased contractility increases Et throughout systole • Increased contractility decreases the time to end- systole Suga et al. Circ Res 32:314-322, 1973 Time-varying Elastance

(Et)

• All events characterized by the Frank- Starling Relationship can be explained

completely by the concept of Et • Preload “appears” to be determining

systolic function because Et has an increasing slope over time

Suga et al. Circ Res 32:314-22, 1973 On the Nature of LV Contraction Time varying Elastance and the Frank-Starling Relationship 200 140 100 80 60 40

20

Pressure

Ejection Indices

Volume A B A B EDV Stroke volume, ejection fraction, dP/dt All increase with increasing EDV Cardiac Contractility

Contractility proportional to the rate and amount of Ca+2 flux into the sarcolema of the contracting myocytes

All known positive inotropes increase Ca+2 flux All known negative inotropes decrease Ca+2 flux Cardiac Contractility

Since Ca+2 is essential for contraction, is Ca+2 a positive inotrope? Yes and No

Where the Ca+2 goes is as important as how much Ca+ there is available Cardiac Contractility

Changes in contractility reflect LONG TERM adaptations to external stress (Anrep effect) Cardiac Contractility

• Autonomic Tone Exercise, Stress; Diabetes • Coronary Blood Flow • Kojima et al. Am J Physiol 264:H183-9, 1993 • Serum ionic Ca+2 • Marquez et al. Anesthesiology 65:457-61, 1986 • Local Catecholamine Stores Chronic stress • Catecholamine Receptors Sepsis • Extrinsic Catecholamine Supplements Assessing LV Contractility at the Bedside

• LV dP/dt at 20 or 30 mmHg • Prior to aortic value opening • Preload, heart rate and afterload dependent

• Can radial arterial dP/dtmax reflect LV contractility? • Reflected pressure waves distort arterial pressure • Compliance and inertance alter peripheral pressure

• Compared LV dP/dtmax with femoral and radial arterial dP/dtmax as contractility, preload and afterload systematically altered in pigs

Monge Garcia et al. Crit Care 22 325, 2018 Changes in Radial Artery dP/dtmax Tracks Changes in Ees

DVasomotor D Volume D Contractility

Monge Garcia et al. Crit Care 22 325, 2018 Determinants of Afterload

LaPlace’s Law LV Wall Stress

Tension = Px r r P Maximal tension at maximal P x r which usually occurs at the opening of the aortic value: EDV, diastolic pressure Chronotropy

Increases in heart rate increase Ca+2 influx into the sarcolema of the myocytes increasing force of contraction

Bers. Nature 415:198-205, 1998

Optimal heart rate? > 60 but < 120 Effect of Changes in Heart Rate on Contractility Force-Frequency Relationship

Liu et al. Circulation 88:1893-906, 1993 Effect of Changes in Heart Rate on Contractility Force-Frequency Relationship

70 min-1 100 min-1 70 min-1 100 min-1

Chronotropy Diastolic Dysfunction 130 min-1 160 min-1 120 min-1 150 min-1

Liu et al. Circulation 88:1893-906, 1993 What is heart failure? Heart failure as a state in which the heart is unable to meet the demands for blood flow without excessive use of the Frank-Starling mechanism, that is the increase in stroke volume associated with increased preload.

Sagawa, Maughan, Suga, Sunagawa. Cardiac Contraction and the Pressure- Volume Relationship. Oxford University Press, 1988 Heart failure Type 1: increased loading Type 2: altered inotropic state Type 3: altered lusitropic state Type I: Heart failure because of an increase in loading conditions

Preload: valvular incompetence, arterio-venous fistulas, anemia, sepsis, hypervolemia, beri beri Afterload: hypertension, aortic stenosis, sepsis Type II: Heart failure because of a decreased contractility

Myocardial infarction Ischemic heart disease Dilated cardiomyopathy infections, metabolic alterations, toxic conditions, collagen vascular disease Idiopathic dilated cardiomyopathy Type III heart failure: restriction to ventricular filling: Diastolic Dysfunction

Internal: Hypertrophic cardiomyopathy Restrictive cardiomyopathy Incomplete relaxation External: Tamponade Right ventricular dilatation/hypertrophy Functional tamponade (PEEP) Sepsis Clinical Applications of LV Pressure-Volume Relations

Acute Myocardial Ischemia • Useful in understanding the pathophysiolgy of acute myocardial ischemia • Explains rationale for pharmacological approaches to optimize ventricular pump function Effect of Acute Myocardial Ischemia on Left Ventricular Pressure-Volume Relationship Ischemia

LV Ees Ees Pressure Acute LV (mm Hg) Failure

Ischemia

LV volume (mL) Effect of Inotropic Support following Acute Myocardial Ischemia

Ees

LV Ees Pressure (mm Hg) Dobutamine

LV volume (mL) Effect of Vasodilator Therapy & Inotropic Support following Acute Myocardial Ischemia

Ees Ees Decreased LV LV ejection Pressure Pressure (mm Hg)

Nitroprusside

LV volume (mL) Transesophageal Echocardiography-ABD and LV Pressure

Gorcsan et al. Circulation 1994;89:180-90 LV Contractile Reserve in Sepsis Decreased Adrenergic Depressed Responsiveness? 30 contractility? *

20

Baseline E’es Dobutamine 10

0 P < 0.05 Day 1 Day 5 Day 9 n = 10

Cariou et al. Intensive Care Med 34: 917-22, 2008 Effect of Pressure and Volume

Loading on MVO2 and SWlv Pressure load Volume load SWlv MVO2

Cardiac Output Relation Between the LV Pressure-Volume Loop,

MVO2, and Cardiac Efficiency

The hidden mechanical Elastance-Defined work of the LV Potential Work

Stroke Pressure Work

PE

Volume Suga et al.Am J Physiol 240:H39-H44, 1981 The LV Pressure-Volume Area (PVA)

Strok PVA PVA

e LV LV

Work Pressure

Pressure PE

MVO LV Volume LV Volume 2

Suga et al.Am J Physiol 240:H39-H44, 1981 The LV Pressure-Volume Area (PVA)

Suga et al.Am J Physiol 240:H39-H44, 1981 Relation Between the LV Pressure-Volume Loop,

MVO2, and Cardiac Efficiency

MVO2 A >> MVO2 B

A

B LV Pressure LV

LV Volume Relation Between the LV Pressure-Volume Loop,

MVO2, and Cardiac Efficiency

Two P/V loops: Same SW (area) Different PVA & Different MVO 2 MVO2 A >> MVO2 B

A A

B B

LV Pressure LV LV Pressure LV

LV Volume LV Volume The LV Pressure-Volume Area (PVA) and LV Ejection Efficiency

Suga et al.Am J Physiol 240:H39-H44, 1981 Myocardial Efficiency

Myocardial Efficiency = SW/(PVA) x HR

A Goal of Hemodynamic Therapy: Maximize the Extrinsic Work While Minimizing Elastance-Defined Potential Work and Heart Rate Myocardial Efficiency

Myocardial Efficiency = SW/(PVA) x HR

Vasodilator therapy Inotropic support that reduces EDV VentricularParameters Function

Left Ventricular Pressure 0 0 Ees ≈ ESP/ESV Left Ventricular Volume PE Ees SVlv SW SW/(SW+PE) LVefficiency = SW+ PE=LV PVA= MVO 2 Ventricular Pump Function Conclusions

Cardiac output and stroke volume are insensitive measures of intrinsic contractility Difficult to assess cardiac contractility by a single data set, need to follow trends and response to interventions

Time-varying elastance, end-systolic elastance, and preload-recruitable stroke work are the standards for assessing intrinsic

Radial arterial dP/dtmax trends LV Ees