Chapter 28 — Exercises

Natriuretic Peptides: The Heart Failure Biomarkers That Became Treatments

These exercises are for working through, not for grading. Items marked † are extended — they take longer, they usually require you to hold two things in mind at once, and they are the ones worth doing if you only do a few.

No answers are given here. Several items have more than one defensible answer, and for those the reasoning is the point. Nothing in this chapter or these exercises is medical advice, and none of it should be used to make a decision about your own treatment or anyone else's.

Part A — The heart as an endocrine organ (§28.1–28.2)

A. In one sentence, state what de Bold's 1981 experiment showed, and name the control condition that made the result interpretable.

B. Why was the discovery of a cardiac hormone delayed by the way organs were categorized in textbooks? Give one other example from elsewhere in biology where a category obscured a function.

C. Most endocrine glands respond to a chemical input. Cardiac muscle responds to a mechanical one. List three consequences of that difference for how the signal behaves over a day.

D. Fill in the following table from memory, then check it against §28.2.

E. ANP is stored preformed in granules; BNP is transcribed on demand. Explain why that makes ANP the better physiological signal and BNP the better measurement.

F. The natriuretic peptide receptors are not G-protein-coupled receptors. What are they, what second messenger do they produce, and why does that second messenger matter later in the chapter?

G. NPR-C binds all three family members and does not signal. Give it a one-sentence job description, and name one drug strategy elsewhere in the chapter whose effect it partly explains.

H. † The natriuretic peptide system and the renin-angiotensin-aldosterone system are described as counterweights. Draw the two systems as opposing arrows acting on four variables — blood volume, vascular tone, sodium retention, and cardiac remodeling — and mark which system is winning in established heart failure. Then state what your diagram implies about where a drug could usefully intervene.

I. † Section 28.2 describes natriuretic peptide resistance: high circulating levels with a blunted effect. Name the three contributing mechanisms given in the text. Then explain why this phenomenon should have lowered anyone's prior expectation for the strategy in §28.5 — and say clearly why lowering a prior expectation is not the same as having evidence.

Part B — The measurement (§28.3)

J. Draw the processing of proBNP, labeling both products, and mark which is biologically active and which is the more practical measurement. Explain the irony.

K. Why are BNP and NT-proBNP results not interchangeable numbers? What is the single practical consequence for anyone reading a result on a laboratory report?

L. A test with high sensitivity and moderate specificity is best used in one particular way. State which way, and translate that into a plain sentence you could say to a patient about what a low result means and what a high result does not mean.

M. For each confounder, state the direction it pushes a natriuretic peptide result and give the mechanism where the chapter offers one: age, kidney impairment, obesity, atrial fibrillation.

N. † Of the four confounders in M, one is uniquely dangerous because it pushes the number in the direction that produces false reassurance. Identify it, explain why the direction matters more than the magnitude, and describe the clinical situation in which the error would be most costly.

O. The chapter says a natriuretic peptide result is "an aid to judgment and not a verdict." Give two examples from outside cardiology — one from another area of medicine, one from anywhere else — where a validated input to a decision has been treated as the decision.

P. † An echocardiogram and an NT-proBNP measurement both bear on heart failure. Write a short paragraph explaining what question each one answers that the other cannot, and describe a clinical situation in which the blood test is more useful than the imaging, and one in which the reverse holds.

Part C — The central distinction (§28.4)

Q. State the three claims about the natriuretic peptide system that the chapter distinguishes. For each, name the study design that settles it and the answer that design produced.

R. Explain, in your own words, why a diagnostic accuracy study can never establish that a treatment works — no matter how many patients it enrolls.

S. "Accuracy studies deal in sensitivity and specificity; outcome trials deal in event rates and hazard ratios." Write one sentence describing a claim that tries to pay in the wrong currency, and name the fallacy.

T. The fourth claim — titrating therapy toward a biomarker target — failed. Give the chapter's explanation for why, and say what that explanation implies about when biomarker-guided strategies would be expected to help.

U. † Rule 3 of the rating system says never upgrade a rating with mechanism. The ⚠️ Hype Check in §28.4 argues that a better mechanism should make you more careful, not less. Reconstruct that argument in three or four sentences, then find one claim from an earlier chapter of this book where the same warning applies.

V. † Write a 📊 Evidence Rating block, in the book's four-line format, for a claim the chapter does not rate: "NT-proBNP measurement improves outcomes in patients presenting to an emergency department with breathlessness." Note carefully that this is neither the diagnostic claim nor the titration claim. Be explicit about what study design would settle it and whether you believe that study exists.

Part D — Nesiritide (§28.5)

W. Nesiritide is recombinant human BNP — the actual sequence, not an analog. Explain why that fact, which sounds like an advantage, turned out to be irrelevant to the outcome.

X. List the endpoints the approval rested on. Classify each using Chapter 5 §5.6's vocabulary.

Y. The chapter insists that the outcome trial demonstrated absence of benefit rather than presence of harm. Explain the difference and why conflating them misrepresents the record.

Z. † A second peptide, tested independently in acute heart failure, improved hemodynamics and failed to improve cardiovascular mortality. Explain what two independent failures of the same strategy establish that one failure would not, and state the limit of that inference.

AA. † The nesiritide ❌ and the ❌ ratings you have met in Part III of this book look identical on the page and mean different things. Write a short paragraph distinguishing "evidence present and negative" from "evidence largely absent," and explain why a reader is worse off if a rating system cannot tell them apart.

Part E — Neprilysin and ARNI (§28.6–28.7)

AB. Neprilysin has many substrates. List those given in the chapter and, for each, state whether raising it is helpful, harmful, or unclear in heart failure.

AC. Explain in two sentences why a neprilysin inhibitor given alone could worsen heart failure.

AD. Why must the partner drug be an angiotensin receptor blocker rather than an ACE inhibitor? Name the peptide at the center of the answer and the adverse effect it causes.

AE. † Compare neprilysin inhibition with the DPP-4 inhibitors of Chapter 7 §7.6. Identify what is architecturally identical, then state the structural ceiling that both share. Finally, explain why the heart failure story inverted the expected ordering of "supply" and "preserve" — and give the explanation you find most persuasive, with your reason.

AF. PARADIGM-HF used enalapril rather than placebo as its comparator. Explain why that choice makes the result more impressive and, separately, what it prevents the trial from telling you.

AG. † The trial included a run-in period and was stopped early. Each is a legitimate design feature and each has a known effect on how the result should be read. Explain both effects, state the direction each biases the reported result, and say whether either changes your confidence in the direction of the finding.

AH. † On sacubitril/valsartan, BNP rises while NT-proBNP falls in a patient who is improving. Explain the molecular reason. Then explain why this single fact is a good summary of the whole chapter, referring to the biomarker-versus-therapy distinction in §28.4.