Cardiovascular Disease: Past, Present, and Future

Early Stirrings

In 1733, Steven Hales measured arterial and venous pressures in horses and other mammals. “Direct” auscultation (placing the ear on the precordium) to hear the heartbeat was used later in the 18th century. Cardiac examination accelerated after 1823, when René Laennec, a French physician, described the stethoscope. In his 1775 monograph on foxglove (digitalis), William Withering described its effectiveness in the treatment of patients with “dropsy,” that is, edema, presumably due to heart failure (HF). William Heberden described angina in 1772 and 40 years later the first paper in the first issue of the New England Journal of Medicine by John Warren, a Boston physician, discussed this symptom. However, angina does not appear to have been recognized frequently. In 1879, F.A. Mahomed described hypertension not associated with renal disease, the forerunner of what is now referred to as primary or essential hypertension. Several important arrhythmias were described in the mid-to-late 19th century. These included severe bradycardia by Stokes in 1854 and ventricular fibrillation (VF) by MacWilliams in 1887.

By the end of the 19th century, physiologists and clinicians were aware of electrical depolarization and repolarization of the heart and could recognize some cardiac arrhythmias by cardiac auscultation and palpation of the pulse. They also knew that hypertension could occur both in the presence and absence of advanced renal disease and could be associated with ventricular hypertrophy. They recognized congenital and valvular heart disease, angina pectoris, and HF. However, cardiovascular disease was not considered to be very common; it was treated with bed rest, digitalis, nitrates, and sometimes morphine.

Emergence of a Specialty

The decade from 1895 to 1905, bridging the 19th and 20th centuries, was probably the most important in the history of cardiology because of the discovery of three critically important technologies. In 1895, Wilhelm Roentgen, ^{, ∗}

∗ Names followed by an asterisk were awarded a Nobel Prize.

a German physicist, discovered the use of x-ray, the first technique for imaging body parts in intact humans, allowing estimation of the heart’s size and shape. The noninvasive measurement of blood pressure (BP) was developed by Riva Rocci, an Italian physician, in 1896 and Korotkoff in Russia in 1905. The first recording of the electrocardiogram using a string galvanometer by Willem Einthoven, ^∗ a Dutch clinical physiologist, was reported in 1903. When added to the clinical examination, these three new technologies permitted clinical assessment of key elements of the cardiovascular system. It soon became apparent that heart disease was far more common than had been suspected. Physicians who became expert in using and interpreting these new technical wonders were dubbed “heart specialists” or “cardiologists.”

Advances came rapidly in this new specialty, and it soon became necessary to develop medical journals to record them. The earliest were the Zentrallblatt für Herz Krankenheiten in Germany and the Archives des Maladies du Coeur in France, both in 1908. Subsequently, an enormous expansion of cardiac journals occurred. As of 2020, 138 cardiovascular journals are published on a regular basis.

National cardiac societies were created to bring cardiologists and their trainees from each country together to share experiences and describe advances in cardiovascular science and clinical cardiology. The first of these, the British Cardiac Club, was organized in 1922, and in 1937 it morphed into the British Cardiac Society. In addition to organizing annual meetings, these societies also publish national cardiology journals. Beginning in the last third of the 20th century, the societies have developed and promulgated clinical practice guidelines that have improved the accuracy of cardiovascular diagnosis and the quality of care. National cardiac societies have joined with their continental neighbors to form regional societies, such as the European Society of Cardiology. The development of the World Heart Federation reflects the globalization of clinical cardiology and cardiovascular research.

The Past

After the development of roentgenography, venous angiography was begun in the 1920s. Selective angiography, in which radiocontrast material is injected through an intracardiac or intravascular catheter, allowed enhanced visualization of specific sites in the heart and great vessels. In 1948, Mason Sones, a cardiologist in Cleveland, described and perfected coronary arteriography, which provided accurate anatomic assessment of the coronary arterial bed.

In 1952, Edler and Herz, a Swedish cardiologist/physicist team, developed echocardiography. This technique assumed growing importance for assessing cardiac structure and function, becoming the “work horse” of cardiac imaging. The devices became smaller, more portable, and even handheld. By the end of the 20th century, three-dimensional echocardiography had become a valuable clinical tool.

The development of computed tomography (CT) by Hounsfield ^∗ and Cormack ^∗ in 1973 and of cardiovascular magnetic resonance imaging (CMR) by Lauterbur ^∗ and Mansfield ^∗ in the same year have revolutionized cardiac diagnosis. Both technologies provide precise three-dimensional displays of the cardiac chambers and great vessels. CMR is especially useful in assessing regional myocardial perfusion, tissue characteristics, systolic and diastolic function, inflammation, and scar. Although coronary calcium had been detected occasionally by fluoroscopy, the field leaped forward in 1990 when Agatston introduced calcium scoring by CT. Larger and more extensive calcium deposits in the coronary arteries were associated with a higher incidence of subsequent coronary events, thereby enhancing risk assessment (see later).

The Present

Nuclear cardiology, developed in the 1930s, is now used largely to detect the presence and assess the severity of myocardial ischemia. CMR imaging is now used routinely in the diagnosis and assessment of cardiomyopathies and myocarditis and in the assessment of cardiac fibrosis and masses. CT has been shown to be particularly effective in the assessment of aortic stenosis (AS). Dobutamine stress CMR is a sensitive, accurate method of detecting and quantifying myocardial ischemia. Because CMR does not require ionizing radiation, it is used repeatedly to track the progression of disease and the effects of therapeutic interventions. For CMR spectroscopy, the new 7-Tesla magnets provide higher signal-to-noise ratios and more precise quantification of myocardial high-energy phosphates.

Improvements in coronary computed tomographic angiography (CCTA) with intravenous injection of contrast material provide accurate, high-quality, noninvasive visualization of the epicardial coronary arteries. This technique is now widely employed in patients with chest pain of possible cardiac ischemic origin, in whom it has reduced the need for invasive coronary arteriography. Quantitative positron emission tomography has become useful in the assessment of myocardial ischemia and viability and in the evaluation of inflammatory cardiomyopathies and infective endocarditis.

Cardiac Catheterization

The first human catheterization was carried out (on himself!) by Werner Forssmann, ^∗ a German surgical resident who was forbidden to repeat the procedure, but who wisely published his experience ( Fig. 1.2 ). In the late 1940s, the technique was applied to a variety of congenital and acquired cardiac disorders by Andre Cournand ^{∗ ,} and Dickinson Richards ^{∗ ,} in New York. In addition to measuring pressures in the chambers of the right heart and pulmonary arteries, they also determined cardiac output at rest and during exercise. By the third quarter of the century, cardiac catheterization had become extremely important in the diagnosis of congenital and valvular heart disease.

Percutaneous Coronary Intervention

The field of invasive interventions virtually exploded in 1977 when Andreas Grüntzig, a Swiss cardiologist, described a new technique—percutaneous transluminal coronary angioplasty (PTCA), thereby ushering in a new subspecialty, interventional cardiology. PTCA began with the treatment of patients with poorly controlled angina and an obstructive plaque in a proximal coronary artery. It was applied to progressively more complex lesions, and then on an emergent basis to patients with acute myocardial infarction (AMI) (see later). In the late 1980s, coronary arterial stents were introduced to prevent restenosis. Percutaneous coronary interventions (PCIs) expanded rapidly and began to compete with coronary artery bypass grafting (CABG). In properly selected patients it was of equivalent safety and efficacy and greatly preferred by patients who recovered in a day or two, compared with the weeks or months required after surgery.

Cardiovascular Surgery

After a number of early sporadic failures, cardiovascular surgery began in earnest in 1938 when Robert Gross of Boston successfully closed a patent ductus arteriosus. Operative correction of coarctation of the aorta and of a variety of other congenital cardiac malformations soon followed. Mitral valvulotomy for stenosis was begun in 1946. A major step forward was taken by John Gibbon of Philadelphia, who developed a “heart-lung” machine in 1953, which was used for cardiopulmonary bypass and led to the era of open heart surgery. This allowed repair of a large number of congenital and acquired disorders. In 1961, Albert Starr reported mitral valve replacement with a prosthetic ball valve.

Beginning in the 1940s, attempts were made to treat patients with coronary artery disease (CAD) and severe angina by surgery; most were unsuccessful. In 1968, René Favaloro, a cardiac surgeon in Cleveland, Ohio described coronary artery bypass grafting, which proved to be very effective in the management of severe angina pectoris and was shown in randomized clinical trials to prolong survival in patients with severe, multivessel CAD.

Comments

During the last third of the 20th century, cardiology went through a major change. Before about 1970, the diagnosis of many congenital and acquired cardiac lesions were established by cardiac catheterization, often aided by selective angiography. If a mechanical therapeutic intervention was required, it was usually surgical. By the end of the century, as a consequence of the important advances in cardiac imaging, the need for diagnostic cardiac catheterization had declined. Simultaneously, catheter-based therapy advanced rapidly and expanded widely to patients with congenital and valvular heart disease. PCI became the most frequent therapy for improving coronary perfusion in ischemic heart disease and in acute myocardial infarction (AMI) (see later). Surgical therapy was reserved for patients in whom catheter-based therapy was not possible or in whom it had failed.

The Past

The recognition of hypertension as a critically important clinical entity was made possible by the simple noninvasive measurement of BP (see earlier) leading to the recognition of the high prevalence of the condition. The close relation between renal disease and hypertension goes back to Richard Bright, an English physician, who suggested in 1827 that patients with chronic renal disease were hypertensive. In 1897, Robert Tigerstedt, a Swedish physiologist, injected an extract of rabbit kidney into a normal rabbit. He observed a prolonged elevation of arterial pressure and named the pressure-raising substance “renin.” In 1934, Harry Goldblatt, a Cleveland pathologist, demonstrated a rise in arterial pressure in dogs in which renal ischemia had been induced. In 1940, Braun-Menendez, a physiologist in Buenos Aires, Argentina, reported that renin is an enzyme that acts on a globulin (now known as angiotensinogen ) to produce a polypeptide with pressor properties, which he named hypertensin (now known as angiotensin ), presumably produced by the ischemic kidney that had been described by Goldblatt. In the first quarter of the 20th century, it became clear that in addition to renal disease, coarctation of the aorta, pheochromocytoma, and other endocrinopathies were causes of secondary hypertension. A large majority of patients with hypertension have no discernable cause; these are referred to as primary (essential) hypertension.

The clinical importance of hypertension was recognized and explicitly summarized by Soma Weiss, a Boston physician (who was a predecessor of the present author at Harvard and at the Brigham). In 1930, Weiss wrote:

Persistently elevated arterial pressure is probably responsible for more disability and death than any other single pathological condition, including cancer and tuberculosis. Persistent hypertension combined with vascular pathology is the etiological factor in the bulk of instances of cerebral accident, myocardial failure and chronic insufficiency of the kidneys.

Weiss was prescient, and today, almost a century after his paper, hypertension remains a major risk factor for stroke, AMI, HF, and renal failure. It plays a central role in cardiology and in internal medicine, neurology, and nephrology as well. However, Weiss’ view was accepted very slowly until the 1950s, when systems for grading the severity of hypertension were developed, and followed by the realization of the wide spread and breadth of its serious complications.

Walter Kempner, an internist at Duke University, emphasized the use of an extremely low-salt diet (<200 mg Na ⁺ daily) based on rice, fruit, and juice. Although this strict regimen reduced elevated BP, the diet was difficult to sustain. The most widely used antihypertensive drug in the mid-20th century was reserpine, an extract of the Indian root— Rauwolfia serpentina —which depresses cerebral sympathetic centers. Other early hypotensive agents included veratrum alkaloids, thought to act on the parasympathetic system, and hexamethonium derivatives, which block transmission through autonomic ganglia. The latter, while powerful, were associated with severe side effects. In patients with malignant hypertension who were not responsive to or could not tolerate potent hypotensive drugs, a splanchnic sympathectomy, championed by Reginald Smithwick, a Boston surgeon, could be considered. Although it usually reduced BP, the adverse effects of this difficult operation were substantial.

Two well-designed, well-executed placebo-controlled trials in U.S. Veterans Hospitals, led by Edward D. Freis, a cardiologist in Washington, D.C., provided the first definitive evidence of the benefit of antihypertensive therapy. The first, conducted on patients with severe hypertension (diastolic pressures 115 to 129 mm Hg) compared treatment using the combination of hydrochlorothiazide, reserpine, and hydralazine, with placebo. The second trial had a similar design and studied patients with diastolic pressures between 90 and 114 mm Hg. The risks of severe vascular events, especially HF and stroke, were markedly reduced in the treated group in both trials.

The Present

By the end of the 20th century, treatment of essential hypertension had made many advances. They emphasize lifestyle changes, focusing on weight reduction, dietary salt restriction, and smoking. Of the large number of approved antihypertensive drugs, the primary agents include (1) thiazide or thiazide-like diuretics; (2) blockers of the renin-angiotensin system; and (3) calcium channel blockers. Compliance with the regimen is an important first step. Patients whose BP is not controlled with the combination of these drugs are considered to have resistant hypertension ^, and may require intensification of their lifestyle changes, the maximally tolerated doses of the primary agents, and/or the addition of a drug from another class, such as a mineralocorticoid receptor blocker, beta blocker, or vasodilator. The drugs for the treatment of hypertension are readily available, usually well tolerated, and inexpensive. One explanation for the inadequate control is that hypertension per se causes few if any symptoms and has been termed “the silent killer,” leading to a combination of physician and patient inertia.

In the 20th century there were dozens of clinical trials, observational studies, and meta-analyses on drugs for the treatment of hypertension. The extent of clinical benefit appears to be related to five features: (1) the level of the baseline BP, (2) the event rate in the control group; (3) the extent of BP lowering by the intervention; (4) the tolerance to side effects; and (5) the duration of the trial. The higher each of these features, the greater is the clinical benefit.

The Future

Recent studies have shown a previously unrecognized primary aldosteronism in many patients with “essential” hypertension. Such patients could be managed with a new nonsteroidal mineralocorticoid receptor antagonist.

There have been multiple efforts to understand the genetic basis of essential hypertension, now recognized as a polygenic condition. In a genome-wide association study (GWAS) in 475,000 persons, Kraja et al. identified 21 single-nucleotide polymorphisms (SNPs) and four novel loci associated with hypertension. These include several candidate genes that may identify specific subgroups, with differing BP regulation and optimal therapies.

In a mendelian randomization study involving more than 600,000 subjects, triglyceride concentration, type 2 diabetes mellitus (T2DM), body mass index, alcohol dependence, insomnia, and smoking were each associated with an increased risk of hypertension, and longer sleep duration, higher high-density cholesterol concentrations, and higher education levels were each associated with a lower risk. Several of these characteristics appear to be causally related, and their modification could prove to be useful in primary and/or primordial (see later) prevention. The combination of a low polygenic risk score for hypertension and adherence to a dietary approach was associated with a low BP in children.

Going forward, more research on the combination of genomic and phenotypic features of hypertension is likely to provide clinically useful, actionable findings. An important goal is to identify the responders and nonresponders before the onset of therapy. In addition, there have been several observational studies suggesting that gut microbiota can influence BP. Their mechanisms are not clear but may involve levels of activation of G protein–coupled receptors. Possible treatment with prebiotics, probiotics, and postbiotics to modify such microbiota may become a fertile field for future research on hypertension.

The Past

Cardiac involvement in rheumatic fever was described by Wells in 1812. Acute rheumatic fever and its sequel, rheumatic valvular disease, were common in Europe and North America until the mid-20th century and then declined with the introduction of penicillin and some relief of extreme poverty and overcrowding. However, almost simultaneously, a reciprocal increase in degenerative calcific disease of the aortic and mitral valves occurred in the rapidly growing elderly population. Acute rheumatic fever is still observed frequently in developing nations in tropical and subtropical latitudes.

The Present