Introduction_to_cardiac_pathophysiology_01.07.24

Introduction to Cardiac Pathophysiology

• Course offered at Georg-August-Universität Göttingen

• Presenter: PD Dr. med. Belal A. Mohamed

• Areas of expertise: Cardiology and Pneumology

Cardiomyocyte Function

• Definition: Striated myofiber responsible for heart contraction and relaxation.

  • Contraction: Pumps blood into the vascular system.

  • Relaxation: Allows passive filling of the ventricles.

Structural Overview of Cardiomyocytes

• Cardiac Sarcomere: Composed of multiprotein complexes with approximately 200 proteins aligned longitudinally, giving cardiac muscle its striated appearance (Pinotsis, Trends Biochem Sci. 2009).

Sarcoplasmic Reticulum (SR)

• Function: Surrounds myofibrils and serves as the primary internal Ca2+ store.

• Components:

  • Mitochondria

  • Myofibrils

  • Sarcolemma

  • T Tubules and Terminal Cisternae

Cardiac Transverse-Tubule Structure

• Description: Sarcolemma extending into the myocyte, forming a branched, interconnected network (Juan M. Pascual, Scott T. Brady, Basic Neurochemistry 2012).

T-Tubules & Sarcoplasmic Reticulum Interaction

• Role: Positioning voltage-gated L-type Ca2+ channels opposite Ryanodine Receptors (RyRs) for efficient excitation-contraction (EC) coupling.

Cardiac Excitation–Contraction Coupling Mechanics

Diastole Phase

• Ca2+ is resequestered resulting in:

  • Decreased Ca2+ binding to troponin C

  • Relaxation through removal mechanisms:

    • Extracellularly via

      • Na+/Ca2+ exchange

      • Ca2+ -ATPase

    • SR via SERCA2a

    • Mitochondria via MCU

Systole Phase

• Triggered by depolarization:

  • Opening of LTCC → Influx of Ca2+ →

  • Activation of RyR2 → Release of Ca2+ from SR →

  • Binding to troponin C → Cross-bridging of actins/myosins → Contraction

Voltage-gated L-type Ca2+ Channels (LTCCs)

• Function: Opens with membrane depolarization leading to Ca2+ influx, which initiates contraction.

• Types: Seven types, with CaV1.2 being predominant in cardiac myocytes.

Regulation of LTCCs by Kinases

• PKA: Activates via β-adrenergic stimulation leading to increased Ca2+ influx and contractility.

• PKG: Direct phosphorylation decreases activity, lowering Ca2+ influx and contractility.

• CaMKII: Enhances channel activity and Ca2+ influx, promoting positive inotropy.

Ryanodine Receptors (RyRs)

• Isoform: Three mammalian isoforms with RyR2 being predominant in cardiac myocytes.

• Gating Mechanics:

  • Systole: Ca2+ binding opens RyR, releasing SR Ca2+.

  • Diastole: Closure prevents SR Ca2+ release.

Ca2+ Handling During Relaxation

• Extrusion Mechanisms:

  • Into the SR via SERCA

  • Extracellularly via Na+/Ca2+ exchanger and Ca2+ ATPase

  • Into mitochondria via MCU

Ca2+ Removal and Exchange Mechanisms

• ATP-dependent pumps: Maintain ionic gradients critical for maintaining function during relaxation and contraction cycles.

  • Na+/Ca2+ exchanger (NCX): Transports 3 Na+ in for 1 Ca2+ out under normal conditions.

Ca2+ Reuptake into SR

• Mechanism: Via SERCA pump which exists in three isoforms, where SERCA2a is the principal isoform in cardiac tissue.

SERCA Regulation by Phospholamban (PLB)

• PLB: When active, inhibits SERCA2a activity; phosphorylation leads to its dissociation and increased SERCA activity.

Myocardial Remodeling

• Definition: Structural changes post-injury affecting heart size, mass, structure, and function.

  • Types of Stress:

    • Ischemic (e.g., myocardial infarction)

    • Non-ischemic (e.g., hemodynamic stress)

• Adaptive vs. Maladaptive Responses:

  • Initial adaptive remodeling may lead to heart failure if no intervention occurs.

Cardiac Stress Types

• Concentric Hypertrophy: Response to pressure overload conditions.

• Eccentric Hypertrophy: Response to volume overload conditions.

• Ischemic Heart Diseases: Manifestations of myocardial stress.

Overview of Cardiac Stress Responses

• Volumes and pressures stimulate remodeling which could be adaptive initially but lead to maladaptive features if unchecked.

Natriuretic Peptides in Cardiac Function

• Secretion Dynamics: Triggered by atrial distension, hypoxia, endothelial stimulation, and other factors.

• Physiological Roles: Regulate blood pressure and fluid balance, opposing RAAS activity, promoting natriuresis and vasodilation.

Pathophysiology of Ischemic Heart Disease

• Causes & Risk Factors: Including atherosclerosis, hypertension, and diabetes leading to myocardial ischemia.

Clinical Manifestations of Myocardial Ischemia

• Typical symptoms include chest pressure, pain radiating to adjacent areas, and potential loss of consciousness.

Diagnosis of Myocardial Infarction (MI)

• Elevated levels of cardiac-specific biomarkers (e.g., troponins, CK-MB) indicating cardiac muscle injury.

Treatment Strategies for Myocardial Infarction

• Immediate reperfusion is critical to restore blood flow, utilizing drugs or surgical interventions to salvage heart tissue.