Chapter 28 — Quiz

Natriuretic Peptides: The Heart Failure Biomarkers That Became Treatments

Twenty-two questions. Mixed format: multiple choice, true/false with justification, and short answer. Answer key at the bottom — resist it until you have written something down for every item, including the ones you are unsure about. The unsure ones are where the learning is.

1. De Bold's 1981 experiment showed that injecting extract of which tissue produced rapid natriuresis in rats?

  • A. Ventricular myocardium
  • B. Atrial myocardium
  • C. Renal cortex
  • D. Pituitary

2. Which control made that experiment interpretable?

  • A. Injecting saline
  • B. Injecting extract of ventricular tissue, which did not produce the effect
  • C. Measuring urine output before injection
  • D. Using a second species

3. True or false, with one sentence of justification: The "B" in BNP stands for "brain" because the peptide is produced primarily in the central nervous system.

4. Match each peptide to its principal source.

Peptide Source
ANP ventricular myocardium
BNP endothelium and chondrocytes
CNP atrial myocardium

5. The natriuretic peptide receptors NPR-A and NPR-B are unusual among peptide receptors because:

  • A. They are intracellular
  • B. Their intracellular domain is itself a guanylyl cyclase
  • C. They require a co-receptor
  • D. They are ion channels

6. What second messenger do NPR-A and NPR-B produce?

  • A. cAMP
  • B. Calcium
  • C. cGMP
  • D. Inositol trisphosphate

7. NPR-C differs from NPR-A and NPR-B in that it:

  • A. Binds only CNP
  • B. Signals through a G protein instead of a cyclase
  • C. Does not signal at all; it internalizes and degrades its ligands
  • D. Is found only in the kidney

8. Name the four physiological effects of natriuretic peptide signaling given in §28.2, and state which hormonal system each one opposes.

9. proBNP is cleaved into two fragments. Which of the following correctly describes them?

  • A. BNP is inactive and long-lived; NT-proBNP is active and short-lived
  • B. BNP is active and short-lived; NT-proBNP is inactive and longer-lived
  • C. Both are active; only one is measurable
  • D. Both are inactive; the precursor is the active molecule

10. True or false, with justification: A BNP result and an NT-proBNP result can be compared directly against the same reference range.

11. For a test with high sensitivity and moderate specificity, the strongest clinical use is:

  • A. Ruling a condition in
  • B. Ruling a condition out
  • C. Monitoring response to therapy
  • D. Population screening

12. For each confounder, state whether it raises or lowers measured natriuretic peptide levels: (a) advanced age, (b) chronic kidney disease, (c) obesity, (d) atrial fibrillation.

13. Which confounder is most likely to produce false reassurance, and why?

14. Nesiritide is best described as:

  • A. A synthetic analog of BNP with modified residues
  • B. Recombinant human BNP, identical in sequence to the natural peptide
  • C. A small-molecule BNP receptor agonist
  • D. An inhibitor of BNP degradation

15. The approval of nesiritide rested principally on:

  • A. Reduced 30-day mortality
  • B. Reduced heart failure rehospitalization
  • C. Reduced pulmonary capillary wedge pressure and improved short-term dyspnea
  • D. Improved ejection fraction over one year

16. The large randomized outcome trial of nesiritide in acute decompensated heart failure found:

  • A. A significant increase in 30-day mortality
  • B. A significant reduction in rehospitalization
  • C. No meaningful effect on death or rehospitalization at 30 days, and more hypotension
  • D. Significant improvement in dyspnea at 6 and 24 hours

17. Explain in two or three sentences why inhibiting neprilysin alone could worsen heart failure. Name the specific peptide responsible.

18. Sacubitril/valsartan must not be co-administered with an ACE inhibitor, and a washout is required when switching. The reason is:

  • A. Additive hypotension
  • B. Compounded bradykinin accumulation and angioedema risk
  • C. Competition for the same transporter
  • D. Additive hyperkalemia

19. In PARADIGM-HF, the comparator was:

  • A. Placebo
  • B. Enalapril
  • C. Valsartan alone
  • D. Standard care with no study drug

20. State the primary composite endpoint of PARADIGM-HF, the approximate hazard ratio, and one reason the trial was stopped before its planned end.

21. A patient on sacubitril/valsartan who is clinically improving shows a rising BNP and a falling NT-proBNP. Explain why, in molecular terms, and state which measurement should be used to track this patient.

22. In one paragraph, state the chapter's central generalizable lesson about what it means to "target a system," using measure / supply / preserve as your evidence.

Answer key **1. B — atrial myocardium.** Extract of atrial tissue injected into recipient rats produced rapid sodium and water excretion and a fall in blood pressure. **2. B.** Ventricular tissue extract did *not* produce the effect. That contrast is what made the finding a discovery about the atria rather than a nonspecific response to injecting ground-up tissue. Saline controls matter too, but the tissue-specific control is what localized the source. **3. False.** The peptide was first isolated from porcine brain tissue, which is where the name came from, but it is overwhelmingly a product of ventricular myocardium. The name was subsequently reinterpreted as "B-type." It causes real confusion among patients who are told a heart test is measuring a brain hormone. **4.** ANP → atrial myocardium. BNP → ventricular myocardium. CNP → endothelium and chondrocytes. **5. B.** The intracellular portion of NPR-A and NPR-B *is* a guanylyl cyclase. Binding the peptide switches on the enzyme directly — no G protein required. **6. C — cGMP.** Cyclic GMP, which activates protein kinase G. Remembering this is what allows vericiguat (§28.8) into the chapter: it reaches the same second messenger through a different enzyme. **7. C.** NPR-C binds all three peptides and does not signal. It internalizes and degrades them — a clearance receptor. It contributes to the increased clearance seen in natriuretic peptide resistance. **8.** (i) Natriuresis and diuresis — opposes RAAS-driven sodium and water retention. (ii) Vasodilation — opposes angiotensin II–driven vasoconstriction. (iii) Suppression of renin and aldosterone release — opposes RAAS directly, at two points. (iv) Restraint of hypertrophy and fibrosis — opposes RAAS-driven remodeling. All four oppose the renin-angiotensin-aldosterone system. **9. B.** BNP (32 residues, C-terminal) is biologically active, binds NPR-A, and has a half-life around 20 minutes. NT-proBNP (76 residues, N-terminal) is inactive, longer-lived, and more stable in the specimen — which is why the useless half is the more useful measurement. **10. False.** The reference ranges differ by roughly an order of magnitude. A result is uninterpretable until you know which assay produced it. This is the single most practical fact in §28.3. **11. B — ruling out.** High sensitivity means few false negatives, so a low result meaningfully lowers the probability of the condition. Moderate specificity means a high result is compatible with several other things and does not settle the question. **12.** (a) age — raises. (b) chronic kidney disease — raises, more so for NT-proBNP. (c) obesity — **lowers**. (d) atrial fibrillation — raises, sometimes markedly. **13. Obesity**, because it is the only one of the four that pushes the number *down*. A confounder that raises the level costs you specificity, which the clinician is already primed to interpret cautiously. A confounder that lowers it undermines the test's rule-out function — the very thing the test is best at — and produces a falsely reassuring result in someone who may well have heart failure. **14. B.** Recombinant human BNP, identical in sequence. No analog engineering, which is worth noting: the failure had nothing to do with the molecule being wrong. **15. C.** Hemodynamic surrogate (pulmonary capillary wedge pressure) and a short-term symptom score (dyspnea at a few hours). Chapter 5 §5.6 is the framework. **16. C.** No meaningful effect on the 30-day composite of death or rehospitalization; the dyspnea difference was small and did not meet the prespecified threshold; more hypotension. The trial did **not** confirm the mortality or renal signals raised by earlier pooled analyses — the finding was absence of benefit, not presence of harm. **17.** Neprilysin degrades **angiotensin II** along with the natriuretic peptides. Inhibiting the enzyme alone would therefore raise angiotensin II — the peptide driving vasoconstriction, aldosterone release, and sodium retention — at the same time as it raised the peptides opposing those effects. You would be releasing the brake and the accelerator together in a disease where the accelerator is already the problem. **18. B.** Both neprilysin and ACE degrade bradykinin. Blocking both compounds bradykinin accumulation and raises angioedema risk. An earlier combined neprilysin–ACE inhibitor drug produced angioedema substantially more often than an ACE inhibitor comparator and was not approved; that history is why the successful drug pairs neprilysin inhibition with an **angiotensin receptor blocker** and why the label requires a washout. **19. B — enalapril.** An active comparator with an established mortality benefit. Beating it is a higher bar than beating placebo, and it is why the result carried the weight it did. **20.** Primary composite: cardiovascular death or heart failure hospitalization. Hazard ratio 0.80 (95% CI 0.73–0.87); event rates 21.8 percent versus 26.5 percent. It was stopped early, at a median follow-up of about 27 months, on the recommendation of the data monitoring committee, because the prespecified boundary for overwhelming benefit on cardiovascular mortality had been crossed. Note for full credit: trials stopped early for benefit tend as a class to overestimate effect size. **21.** Neprilysin degrades **BNP**, so inhibiting neprilysin raises measured BNP by reducing its clearance — not because the heart is deteriorating. **NT-proBNP is not a neprilysin substrate**, so it continues to reflect cardiac wall stress and falls as the patient improves. **NT-proBNP is the measurement to use in a patient on this drug.** A clinician who orders BNP instead may read a rising number as worsening disease and escalate treatment in a patient who is responding. **22.** Three interventions were made on one peptide system. **Measuring** it produced a diagnostic test that reorganized the evaluation of breathlessness — ✅. **Supplying** it, as an infusion of the identical human peptide, improved every physiological measurement available and changed no outcome that mattered — ❌, with a second peptide failing the same way independently. **Preserving** it, by inhibiting the enzyme that degrades it and pairing that with an angiotensin receptor blocker, reduced cardiovascular death and heart failure hospitalization against an active comparator — ✅. The biology was the same in all three. The strategy was not. Therefore: *targeting a system is not a strategy; it is a category containing several strategies with very different odds, and which one you choose matters more than which system you picked.* Any single verdict on "natriuretic peptides" would have to be wrong about at least two of the three.