HEA 3071 Module 4 Heart Failure Case Study: Neurohormones, Remodeling and the Drugs That Reverse Them Example

When Help Becomes Harm: Neurohormones and a Failing Heart in Bridgeton

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B.S. in Health Studies, Thomas Edison State University

HEA-3071: Pathophysiology for Health Professionals

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Month Day, Year

When Help Becomes Harm: Neurohormones and a Failing Heart in Bridgeton

The Patient

Mrs. Ortiz is invented for this case. She is 68, a retired seamstress who lives with her husband in Bridgeton. She had a heart attack six years ago. Over the past month she has become breathless climbing the stairs, needs three pillows to sleep and wakes at night gasping. Her ankles swell by evening, and she has gained nine pounds in two weeks. On examination she has crackles at both lung bases, raised neck veins and pitting edema to her shins. Her echocardiogram finds an enlarged left ventricle with an ejection fraction measured at 30 percent, and her natriuretic peptide level is high.

The Normal Heart

The left ventricle fills during diastole and ejects blood during systole. In a healthy adult, it ejects more than half of its filling volume with each beat, an ejection fraction above about 50 percent. Multiply heart rate by stroke volume and the result is cardiac output; stroke volume itself depends on how much the ventricle fills, how forcefully it contracts and the resistance it pumps against.

How the Heart Fails

Mrs. Ortiz's earlier heart attack killed part of her left ventricle. The remaining muscle cannot pump as forcefully, so stroke volume falls. The body senses lower output and lower pressure and responds in two ways. The sympathetic nervous system releases norepinephrine, which speeds the heart and strengthens contraction, and constricts arterioles so pressure does not fall. The kidneys, sensing reduced flow, release renin, setting off the renin-angiotensin-aldosterone cascade, in which angiotensin II tightens vessels and stimulates aldosterone, which signals the kidneys to hold on to sodium and water, expanding blood volume.

In the short term these responses keep blood flowing. Over months they cause harm. Constant sympathetic stimulation is toxic to heart cells and raises the heart's oxygen demand. Narrowed vessels add to the load on the weak ventricle. Extra fluid raises filling pressures. Angiotensin II and aldosterone promote fibrosis and enlargement of the ventricle, a process called remodeling, in which the ventricle becomes larger, rounder and weaker. Each step lowers output further and drives more activation, a vicious cycle. The heart's natriuretic peptides, released when the walls are stretched, oppose this cycle by promoting sodium loss and vessel relaxation, but they are overwhelmed.

Explaining Her Signs

High left ventricular pressure is transmitted back to the lungs, and fluid seeps out of lung capillaries into tissue and air spaces, causing breathlessness and crackles. Lying flat returns more blood to the heart and the lungs, so she needs pillows and wakes at night gasping. Raised pressure on the right side of the heart backs up into the veins, distending the neck veins and pushing fluid into the legs. Her weight gain is retained fluid. Her high natriuretic peptide level reflects stretched heart walls.

Blocking the Sympathetic System

Beta blockers were once thought dangerous in heart failure because they reduce contraction. In CIBIS-II, more than 2,600 patients with moderate to severe heart failure and an ejection fraction of 35 percent or less were randomly assigned to bisoprolol or placebo on top of standard therapy (CIBIS-II Investigators and Committees, 1999). The trial was stopped early because all-cause mortality was about a third lower with bisoprolol, 11.8 percent compared with 17.3 percent, and sudden deaths and hospital admissions also fell. Blocking long-term sympathetic stimulation allows the heart to recover some function over time.

Blocking Angiotensin and Boosting Natriuretic Peptides

McMurray et al. (2014) compared sacubitril-valsartan, which combines an angiotensin receptor blocker with a blocker of neprilysin, which normally degrades the natriuretic peptides, against enalapril, an angiotensin-converting enzyme inhibitor, in more than 8,400 patients with reduced ejection fraction. The trial was stopped early because cardiovascular death or hospitalization for heart failure struck 21.8 percent of patients on the combination drug and 26.5 percent of those on enalapril. The drug blocks the harmful angiotensin pathway while enhancing the protective peptides.

The Guideline

For reduced ejection fraction, Heidenreich et al. (2022) recommended four drug classes together: a combined angiotensin receptor and neprilysin blocker, with an ACE inhibitor or angiotensin receptor blocker as the fallback; a beta blocker proven in trials; a mineralocorticoid receptor antagonist to block aldosterone; and an SGLT2 inhibitor. Diuretics relieve congestion but do not change the disease course.

Matching Treatment to Mechanism

Mrs. Ortiz received an intravenous diuretic to remove fluid, and over the following weeks her clinicians started and adjusted the four drug classes. She learned to weigh herself daily, limit sodium and call the clinic after a quick gain, which her team set as any rise on the scale beyond two pounds since yesterday or beyond five since last week.

Lifespan and Social Factors

Heart failure grows more common with each decade and fills many hospital beds among people over 65. Living with her husband helps, but cost of medicines and the complexity of four new drugs may challenge adherence.

Why the Right Side Fails Too

Mrs. Ortiz's swollen legs and raised neck veins show that her right ventricle is also struggling. High pressure in the lungs, caused by the failing left ventricle, forces the thinner right ventricle to pump against more resistance. Over time it enlarges and weakens, and pressure backs up into the body's veins. This is why left-sided failure is the most common cause of right-sided failure.

Limits

The trials enrolled selected patients, and few were very old or frail. Mrs. Ortiz is invented, and her care illustrates principles rather than advice.

Conclusion

Mrs. Ortiz's breathlessness and swelling are the visible results of a cycle in which the body's responses to a weak heart become harmful. Sympathetic and renin-angiotensin-aldosterone activation retain fluid and remodel the ventricle. CIBIS-II showed that blocking the sympathetic system saves lives, PARADIGM-HF showed that combining angiotensin blockade with neprilysin inhibition does better still and the guideline brings these and other pathway-blocking drugs together.

References

CIBIS-II Investigators and Committees. (1999). The Cardiac Insufficiency Bisoprolol Study II (CIBIS-II): A randomised trial. The Lancet, 353(9146), 9-13. https://doi.org/10.1016/S0140-6736(98)11181-9

Heidenreich, P. A., Bozkurt, B., Aguilar, D., Allen, L. A., Byun, J. J., Colvin, M. M., Deswal, A., Drazner, M. H., Dunlay, S. M., Evers, L. R., Fang, J. C., Fedson, S. E., Fonarow, G. C., Hayek, S. S., Hernandez, A. F., Khazanie, P., Kittleson, M. M., Lee, C. S., Link, M. S., . . . Yancy, C. W. (2022). 2022 AHA/ACC/HFSA guideline for the management of heart failure: A report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. Circulation, 145(18), e895-e1032. https://doi.org/10.1161/CIR.0000000000001063

McMurray, J. J. V., Packer, M., Desai, A. S., Gong, J., Lefkowitz, M. P., Rizkala, A. R., Rouleau, J. L., Shi, V. C., Solomon, S. D., Swedberg, K., & Zile, M. R. (2014). Angiotensin-neprilysin inhibition versus enalapril in heart failure. New England Journal of Medicine, 371(11), 993-1004. https://doi.org/10.1056/NEJMoa1409077