A History of Heart Failure: From the Valley of Queens to Valsartan

The clinical description of congestive heart failure has been recorded in the works of the ancient Greeks and Romans. Pathological analysis of an Egyptian dignitary who lived around 1479 BC and recovered from a plundered tomb in the Valley of the Queens revealed evidence of pulmonary edema—“likely due to heart failure,” according to Italian Egyptologist Ernesto Schiaparelli.

Hippocrates himself recognized some of the signs of congestive heart failure by putting his ear to the chest of the afflicted patients and hearing sounds akin to “boiling vinegar.” He described a modern treatment of draining the fluid through a hole drilled in the ribcage.

Early Egyptian physicians, as well as the Greek physician Galen, performed dissection on patients and recognized that the heart contracts. But they also believed the arteries were filled with air, and the veins with blood. It was believed for several centuries that the purpose of the heart was to distribute heat throughout the body by pumping air, and failed to see any connection to edema, dyspnea, or anasarca.

In the 17^th century, William Harvey was able to accurately describe the role of the heart in circulation, which provided early insight into the etiology of congestive heart failure. He observed that a dilated ventricle was associated with heart failure.

The significance of cardiac muscle dilation wasn’t appreciated until the breakthrough work of EH Starling who published his treatise “Law of the Heart” in the 1910s. Every first-year medical student learns about Starling’s law of the heart, a principal that still endures. His notion that as end diastolic volume increases, cardiac performance increases to a point.

Actually, Starling predicted that dilation to a point increased cardiac function—but after a certain point, it would weaken the heart. The concept is taught to students by imagining a rubber band continuously stretched. The more its stretched, the more force it generates on recoil. After a point, the band will overstretch and not recoil at all. This however doesn’t explain how patients can have heart failure without dilation of the ventricle, a condition we today call normal ejection fraction heart failure, or diastolic dysfunction.

Much about cardiac function in rheumatic and congenital conditions was learned with the introduction of cardiac catherization and surgery between 1940-1960. A good deal about heart failure was also learned, but did not solve the clinical challenges of heart failure as it didn’t address heart failure caused by coronary artery disease, hypertensive heart disease, and dilated cardiomyopathies.

In the 1980s, the treatment of heart failure was a combination of bed rest, digitalis, and diuretics, which relieved acute symptoms but failed to alter the course of the disease. Doctors were skilled with treating acute heart failure, but failed to alter the long term survival of patients once released from the hospital.

In the mid-1980s, the idea that increasing the ability of the heart muscle to contract more forcefully could improve heart failure became popular. Despite the inability to really measure contractility, most physicians believed that decreased contractility led to heart failure, and increasing contractility would improve cardiac function. It was a logical conclusion, and several drugs were developed that significantly increased cardiac contractility (as does digitalis). All trials were halted prematurely when it was found that these agents made patients worse not better.

A few years later, digitalis was no longer recommended to treat patients with heart failure in normal sinus rhythm. This was one of the first modern absolute truths that I had to unlearn as a young physician.

In the late 1980s, scientists began to view heart failure as a syndrome, or constellation of symptoms due to dysfunction of several organ systems, rather than a disease confined to the heart. In this model, dysfunction in the heart spreads outward to the periphery, involving the neuroendocrine neurohormonal systems via cytokines, as well as peripheral muscles, the kidneys, and even the gut—leading to the typical symptoms of fatigue, shortness of breath edema, and anasarca.

As an adaptive mechanism, the neuroendocrine system becomes overactive, with increased sympathomimetic activity. This is useful in patients with normal cardiac function who undergo transient stress, because it temporarily increases heart rate, cardiac output, and reduced vasodilation. In heart failure patients, this response is exaggerated and prolonged, and ultimately makes things worse because a rapid heart rate will decrease cardiac output in a patient with a dilated or damaged heart muscle.

Physicians began to think that inhibiting the sympathetic nervous system could improve the exaggerated response seen in chronic heart failure. When beta blockers were tried, they actually increased cardiac output in severe HF patients. Had a physician prescribed beta blockers in 1975 for heart failure, it would have been considered malpractice. The package insert even listed heart failure as a contraindication.

Paradoxically, beta blockers could increase cardiac output in certain patients. It was also discovered that drugs that lowered aldosterone, mineral coracoid receptor agonists, like spironolactone, had a very favorable effect on heart failure, not only for their weak diuretic effect, but primarily because of inhibition of the renin angiotensin system.

Likewise, when ACE inhibitors were developed, they too had a beneficial effect on heart failure because they blocked the renin angiotensin system. Improvements were seen in prognosis in patients with low ejection fraction heart failure. The angiotensin 2 receptor blockers, on the other hand, offer little advantage over ACE inhibitors, and none when used with them, and increased mortality and morbidity when used with beta blockers.

Despite improvements in pharmacologic therapies, the death rate in heart failure patients didn’t change much. The recognition that cardiac arrhythmias were responsible for a good number of sudden deaths in heart failure patients led to the recommendation that patients with severe heart failure have implantable defibrillators placed. These devices were later upgraded to include devices to resynchronize ventricular contractions.

As we move forward, we are looking for solutions in molecular biology, genetics, and stem cells. Someday, recognition of genetic defects leading to abnormal cardiac muscle will be corrected by gene editing.

The latest success we have had is the introduction of the combination medication with duel angiotensin antagonism, and neprilysin inhibition. The PARADIGM-HF trial proved that the of combination valsartan and sacubitril was more effective at improving heart failure prognosis in patients with reduced ejection fractions than any previous agent. This was not simply 2 drugs mixed together; they were engineered into a new molecule, which has opened the door to create new drugs in the same way.

In patients with heart failure and preserved ejection fraction, the treatment options are limited. In patients with acute heart failure, the main treatments remain oxygen, diuretics, vasodilators, and inotropic agents which improve symptoms and stabilization. We are fairly successful at this acute treatment, but the long-term prognosis remains poor. A patient with acute HF has about a one-third of a chance being readmitted or dying within 90 days of admission.

As such, we are looking for ways to improve long-term prognosis in patients who develop acute heart failure. Trials with serelaxin—a recombinant peptide of the human relazin 2 hormone that occurs normally in humans—has shown promising results in extending survival in patients who present initially with acute heart failure. But more work needs to be done.

The incidence of heart failure will increase as our population ages, and as our ability to stabilize patients with coronary syndromes improves and will put great strains on the medical system. While great advances have been made in patients with reduced ejection fraction heart failure, much work needs to be done to treat normal ejection fraction and acute heart failure.