A previously healthy 52-year-old woman comes to the physician because of a 3-month history of chest pain on exertion. She takes no medications. Cardiopulmonary examination shows no abnormalities. Cardiac stress ECG shows inducible ST-segment depressions in the precordial leads that coincide with the patient's report of chest pain and resolve upon cessation of exercise. Pharmacotherapy with verapamil is initiated. This drug is most likely to have which of the following sets of effects? $$$ End-diastolic volume (EDV) %%% Blood pressure (BP) %%% Contractility %%% Heart rate (HR) $$$

No change no change no change no change

A 62-year-old man is brought to the emergency department because of a 4-hour history of abdominal pain, nausea, vomiting, and confusion. His wife reports that he had blurry vision on the way to the hospital. Two weeks ago, he lost his job and since then has been extremely worried about their financial situation and future. He has congestive heart failure and atrial fibrillation well controlled with combination medical therapy. His temperature is 36.5°C (97.7°F), pulse is 57/min and irregular, respirations are 14/min, and blood pressure is 118/63 mm Hg. The patient is oriented only to person. Serum studies show: Na+ 138 mEq/L Cl− 100 mEq/L K+ 5.3 mEq/L HCO3− 25 mEq/L Blood urea nitrogen 14 mg/dL Creatinine 0.9 mg/dL An ECG shows premature ventricular beats. The drug most likely responsible for this patient's symptoms has which of the following mechanisms of action?

Blockade of aldosterone receptors

Blockade of beta-adrenergic receptors

Inhibition of Na+-K+-2Cl--cotransporters

Contractility determinants for USMLE Step 2 CK: High-Yield Physiology Lessons

Contractility Basics - Calcium is King

Inotropy (Contractility): The intrinsic ability of the myocardium to contract, independent of preload and afterload.
Calcium's Role: The force of contraction is directly proportional to the intracellular Ca²⁺ concentration ($[Ca^{2+}]_i$).
- ↑ $[Ca^{2+}]_i$ leads to more $Ca^{2+}$ binding to Troponin C.
- This conformational change exposes actin-binding sites for myosin heads.
- Initiates actin-myosin cross-bridge cycling, causing muscle contraction.

Calcium handling in a cardiomyocyte

⭐ Contractility is represented by the slope of the end-systolic pressure-volume relationship (ESPVR). An increase in contractility shifts the curve up and to the left.

Autonomic & Rate Effects - The Neural Knobs

Sympathetic (β1) Stimulation: Increases contractility (positive inotropy).
Parasympathetic (M2) Stimulation: Opposes sympathetic effects via Gi protein, leading to ↓cAMP and reduced contractility.
Bowditch Effect (Treppe): An ↑ in heart rate leads to a gradual ↑ in intracellular $Ca^{2+}$ and contractility, as the $Na^+/K^+$ pump can't keep up, reducing $Na^+/Ca^{2+}$ exchanger function.

⭐ Phosphorylation of phospholamban removes its inhibition of SERCA2a, leading to faster calcium reuptake into the sarcoplasmic reticulum. This not only increases contractility but also improves relaxation (lusitropy).

Autonomic control of cardiac contractility via receptors

Pharmacologic Inotropes - The Pharmacy Pump-Up

Pharmacologic agents modulate myocardial contractility, a key determinant of cardiac output.

Inotrope Type	Mechanism & Examples
Positive	↑ Contractility - Digoxin: Inhibits Na⁺/K⁺-ATPase → ↑$[Na⁺]_i$ → ↓Na⁺/Ca²⁺ exchange → ↑$[Ca²⁺]_i$. - β-agonists (Dobutamine): ↑ cAMP. - PDE inhibitors (Milrinone): ↑ cAMP.
Negative	↓ Contractility - β-blockers: ↓ cAMP. - Non-dihydropyridine Ca²⁺ channel blockers (Verapamil, Diltiazem): Block L-type Ca²⁺ channels. - Class I antiarrhythmics.

⭐ Milrinone is an inodilator; it increases contractility (inotropy) by preventing cAMP breakdown in cardiac muscle and causes vasodilation by the same mechanism in smooth muscle.

Cardiomyocyte: Inotrope sites of action & calcium handling

Pathophysiology - Sick Heart Blues

Factors Decreasing Contractility:
- Acidosis: ↑ $H⁺$ ions compete with $Ca²⁺$ for binding to troponin C, reducing available binding sites.
- Hypoxia/Ischemia: ↓ ATP production impairs cross-bridge cycling and $Ca²⁺$ reuptake by SERCA.
- Hypercapnia: Elevated $CO₂$ leads to respiratory acidosis, compounding the effects of low pH.

⭐ In heart failure with reduced ejection fraction (HFrEF), there is a state of chronically decreased intrinsic contractility due to receptor downregulation and impaired signaling.

High‑Yield Points - ⚡ Biggest Takeaways

Contractility is the heart's intrinsic pumping force, independent of preload and afterload.

It's primarily driven by intracellular Ca²⁺ concentration; more Ca²⁺ means a stronger contraction.

Sympathetic stimulation (via β₁ receptors) and catecholamines are major positive inotropes, increasing cAMP and Ca²⁺.

Digoxin boosts contractility by inhibiting the Na⁺/K⁺-ATPase, leading to increased intracellular Ca²⁺.

Negative inotropes include β-blockers, calcium channel blockers, acidosis, and hypoxia.

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Contractility determinants