Emergence of the concept of cardiovascular disease

The heart 

To be sure, many historians commence the story of our knowledge of the heart and its diseases with the work of Harvey (Fig 1). However, Harvey’s discovery was slow to be accepted and knowledge of the heart and its diseases even slower to accrue, while awaiting growth of the basic sciences, technical innovations, and institutional developments. Not until the nineteenth century was the heart taken as a specific object of study by an increasing number of investigators, primarily experimental physiologists, who demonstrated that instead of being a simple muscular pump, the heart was a complex muscle with properties of excitability, contractility, tonicity, conductivity, and rhythmicity. Parallel clinical studies, using various instruments of precision (stethoscope, catheterization, electrocardiogram, and radiographs) described and identified the ontological concepts of diseases of the heart as we know them now.3, 6

View Large Image Download to PowerPoint

Figure 1. William Harvey. Engraving by J. Houbraken, 1739.

However, much had happened before Harvey, including the pathological descriptions of cardiovascular lesions and the publication of several treatises on the pulse and dropsy, both of which have an ancient history and had been related to the heart.7, 8, 9 Actually, the deciphering of dropsy distinguished and established the link between diseases of the kidneys, heart, and vasculature. Dropsy, or the accumulation of fluid, was regarded as a separate disease until the end of the eighteenth century. Its association with cirrhosis of the liver was well known in antiquity. Its association with kidney disease was also described, particularly in patients with oliguria, but its association with diseases of the heart was indirect and generally ascribed to the broader concept of diseases of the chest, when fluid was detected in the lungs or pleural space of some dropsical patients. Two landmark publications laid the foundations that were to clarify the role of the kidneys and the heart in dropsy, their interrelationships in health and disease, and ultimately the identification of edema as a symptom of underlying diseases rather than a disease itself.

First was the publication in 1785 of An Account of the Foxglove and Some of Its Medical Uses” by William Withering (1741–1799), who showed that the administration of an infusion of the leaves of foxglove (digitalis purpurea) produced a diuresis and an amelioration of dropsical symptoms. From the outset, however, not all dropsical patients responded to foxglove therapy, and some of the nonresponders who died while taking the infusion were seen to be suffering from cirrhosis of the liver with ascites. The distinction of the 2 other principal causes of dropsy (kidney and heart) had to await the second landmark publication in 1827 of Reports of Medical Cases by Richard Bright (1789–1858), which contained his description of end-stage kidneys and distinguished dropsy caused by kidney disease from that of cardiac decompensation.1, 8, 9, 10

The vasculature 

Importantly, whereas Harvey’s work was instrumental in launching the study of diseases of the heart, Bright’s work launched the study of diseases of the vasculature.11 Bright noted the hard pulse of his patients and reported the association of cardiac hypertrophy with kidney disease. For this observation, T.C. Janeway (1872–1917) has called Bright “the first student of the hypertensive problem.” Although this is an overstatement of the case, the observations of Bright launched the subsequent series of investigations that were to determine the central role of studies on the diseased kidney in the recognition, conceptual evolution, and understanding of hypertension as detailed in the historical article in the previous issue of Advances in Chronic Kidney Disease.12 After the clinical application of the sphygmomanometer, the initial confusion surrounding hypertension and kidney disease was resolved by the landmark studies of T.C. Allbutt (1836–1925) in England, H. Huchard (1844–1910) in France, and Janeway in the United States, which demonstrated that hypertension was associated with arteriosclerosis and that a great number of hypertensive individuals did not have evidence of kidney disease. To quote Allbutt on the course of this newly recognized disease: “the overstrained vessels in the brain will bust, the laboring heart will suffer defeat, before the symptoms of uremia are likely to make their appearance.”1, 10, 11, 12, 13

As a result, by the end of the nineteenth century, the paradigm had shifted from the diseased kidney as the cause of vascular sclerosis to hypertensive vascular disease that may encroach on the kidneys (nephrosclerosis), but before the kidneys are affected to a degree incompatible with life (less than 10% of cases) 2 other vital organs (heart and brain) succumb and account for much of the mortality and morbidity of this newly identified disease. The driving force behind the full realization of hypertension as a risk factor, which occurred between the world wars, was financial rather than medical and was set in motion by the insurance industry based on the vital statistics data it had accrued. The subsequent evolution in the understanding and management of hypertension, after the Second World War, reflects much of the profound changes that have affected twentieth century medicine.13, 14

The kidney 

A detrimental consequence of this otherwise important paradigm shift was the neglect of 2 important features of the disease as it relates to the kidneys that are of considerable clinical significance. First was the forgotten part of Allbutt’s quote that although uremia may not occur, what is found in these patients “is a scarred but not corrupt kidney.” A pathological notion whose clinical counterpart was enunciated by Francis Delafield (1841–1915), an astute but forgotten authority of diseases of the kidney, that “simple persistent albuminuria” is not a “good risk” for insurance companies because “sooner or later disease of the kidneys, of the heart or of the arteries is apt to develop.”15 Indeed, insurance companies heeded this advice and continued to require a urinalysis as part of the evaluation of insurance applicants. By contrast, in its enthusiasm to treat the disease, the medical profession neglected the evaluation of albuminuria in these individuals at increased risk for kidney injury. Fortunately, this omission is finally being corrected, thanks to new guidelines and the exponential rise of articles identifying albuminuria as a risk factor for cardiovascular disease in otherwise healthy people. However, the prevalence of peripheral arterial disease and medial arterial calcification in patients with chronic kidney disease (CKD) is just beginning to be appreciated.

Second, was the reported incidence of kidney disease in mortality figures. Before 1925, “chronic heart disease” was certified jointly with “chronic nephritis,” and the death was certified under “cardiac disease.” This practice was reflected in a rise in the relative importance of cardiovascular disease and the simultaneous fall in nephritis. After 1925, the assignment was partially corrected with a reversal of statistical reports that raised the mortality from “chronic nephritis.”13 The effect of subsequent refinements in disease classification on the reported incidence of CKD as a cause of death is shown in Figure 2. Appropriately, diseases of the heart and cerebrovascular disease remain the leading causes of death, but diseases of the kidney are now ninth among the top leading causes of deaths.16 This ranking may still be an underestimate because all hypertensive deaths are reported together as those with or without kidney disease. The K/DOQI guidelines on Chronic Kidney Disease: Evaluation, Classification and Stratification provide a rational basis for the correction of this confusion (Table 1).17 Hopefully, future modifications of the International Classification of Disease (ICD) will further correct this error and abandon the use of archaic terms such as nephritis and nephrosis in the classification of CKD.

View Large Image Download to PowerPoint

Figure 2. Age-adjusted death rates for the leading causes of death: United States, 1958–2000. The numbers in circles indicate the rank order of the disease as a cause of death: 1, diseases of heart; 3, cerebrovascular diseases; 6, diabetes mellitus; 9, nephritis, nephritic syndrome and nephrosis; 13, hypertension with and without kidney disease. Data from the National Vital Statistics Report.16.

Table 1. Definition and Stages of CKD

	GFR (mL/min/1.73 m2)	With Kidney Damage		Without Kidney Damage
		With HBP	Without HBP	With HBP	Without HBP
	>90	1	1	↑ BP	Normal
	60–89	2	2	↑ BP + ↓ GFR	↓ GFR∗
	30–59	3	3	3	3
	15–29	4	4	4	4
	<15 or dialysis	5	5	5	5

NOTE. Numbers represent CKD stages. Markers of kidney damage include pathologic abnormalities or abnormalities in blood or urine tests or imaging studies. HBP is defined as ≥140/90 mm Hg in adults and >90th percentile for height and sex in children. Data from the National Kidney Foundation.17.

∗ May be normal for age.

The kidney, heart, and vasculature relationship 

Although Harvey’s descriptions undoubtedly accounts for the recognition of the functions and diseases of the heart, equally important was his discovery of the circulation, which threw light on its central role as a vector as well as a site of disease.18 In the initial focus on the heart, the circulation as a system of communication and the vasculature as a site of disease was neglected. Nowhere is the normal role of the circulation as a vector of communication more important than between the heart and the kidney in maintaining volume homeostasis, and, by extension, to the very function of the circulation in health and disease.19 Perhaps, Vesalius (1514–1564) had a foresight of things to come in his depiction of the arterial circulation (Fig 3) in the 6 plates intended for use by students (Tabulae Sex) published in 1538, 5 years before the publication of his masterpiece De Humani Corporis Fabrica (1543). The only 2 organs supplied by the arterial tree that are depicted in this figure are the kidney and the heart. Actually, the reason for the choice of the figure to illustrate William Harvey for this article (Fig 1), from the hundreds that are available, is that it has an insert of the vascular tree with only the heart and kidneys depicted. This engraving by J. Houbraken (1698–1780), known as the Dutch Hogarth, was done in 1739, almost exactly 200 years after that of Vesalius but well before the hidden message therein was deciphered. The functional significance of the interrelationship was elucidated by Ernest Starling (1866–1927) in his studies on microvascular permeability and fluid distribution between the blood and tissues, in which he identified the central role of the kidney in maintaining fluid balance.20

View Large Image Download to PowerPoint

Figure 3. The arterial tree. Third of six plates (Tabulae Sex) by Andreas Vesalius, 1538.

Another index of the importance of this connection is presented in Circulation of the Blood. Men and Ideas published by the American Physiological Society,21 which is aptly dedicated to Homer Smith (1895–1962), who established the very science that was to determine the relations between the functions of the kidneys and the heart in maintaining the circulation. Another feature of note in the illustration of Vesalius (Fig 3) is the arterial tree, itself a site of disease then unknown but which came to be termed arteriosclerosis in 1833 by J. F. G. Lobstein (1777–1835) and atherosclerosis by F.J. Marchand (1846–1928) in 1904,22, 23 thereby closing the circle of cardiovascular disease. The term cardiovascular itself had been introduced in 1879.24

Cardiovascular disease 

From being considered of modest significance, cardiovascular disease has become recognized as one of the leading causes of death in the Western world. Recognition of the disease was based on parallel studies of the kidneys and the heart. The present issue of Advances in Chronic Kidney Disease examines but the final stage of the problem, when both kidney and heart disease are at their end stage. However, cardiovascular diseases usually develop insidiously and over a considerable period of time, during which they go undetected. Part of the long course that precedes the end stage covered in this issue was the topic of the previous issue of Advances in Chronic Kidney Disease, but, more is to come in future issues.