Recent studies on valvular heart diseases have shown an evolutionary process of change due to the unexpected lengthening of life expectancy, especially in the population of developed countries. Mitral stenosis is a haemodynamic obstruction at the level of the mitral valve which involves an increased resistance to the transmitral flow. This obstruction is due to a modification in the physiological shape, thickness and mobility of the mitral leaflets. Generally, it is almost entirely associated with rheumatic disease but other aetiologies are increasingly relevant in the elderly population.
Nowadays, in this increasingly large section of the population, mitral valve stenosis is mainly due to sequelae of chronic rheumatic valvular disease and to calcific degeneration. The latter is supported by comorbidity and cardiovascular risk factors, which are often concomitant in frail patients. Finally, a small proportion is related to oncological therapies (as a long-term consequence), and an even smaller proportion to infiltrative diseases. Since mitral stenosis has a slow chronic progression, it is usually found in elderly patients when symptoms occur (or earlier as evidence of other clinical investigations).
A review of the evolving causes and the consequent characteristics of mitral valve disease is the key to optimising treatment times and methods.
Incidence and prevalence
In the last Euro Heart Survey, in patients referred to hospital, mitral stenosis represented 12% of valvular diseases . Rheumatic disease and degenerative calcific aetiology are the main causes contributing to the prevalence of mitral stenosis. Rheumatic disease accounts for about 85% and degenerative causes for about 12%; in all other valvular diseases this relationship is reversed. In the survey, the elderly population was about 40%, and mitral annular calcification determined 10%, 30% and 60% of the mitral stenosis for groups with increasingly advanced age, respectively from 60 to 70 years, from 70 to 80 years, and over 80 years .
In another study, mitral stenosis due to severe mitral annular calcification accounted for about 0.5% of unselected outpatient echocardiograms, and in another one it ranged from 0.2% up to 2.5% in patients over 90 years .
Finally, in a study focused on the elderly, with a mean age of 83±8 years, the assessment of echocardiographic Doppler recorded a 6% rate of mitral annular calcification that produced haemodynamically significant obstruction . These different prevalence values on stenotic calcifications, with higher values in the elderly, converge to indicate a tendency towards a calcific degenerative aetiology in this age-specific group .
Indeed, the prevalence and severity of mitral annular calcification is directly proportional to age. We do not yet have reliable data on the prevalence of the disease in one sex as compared to the other.
Chronic kidney disease
Among the various comorbidities of elderly patients, there is the subgroup of those affected by renal disease which is particularly significant. Chronic kidney disease is a very common clinical condition in elderly patients. It is related to an increase in morbidity and mortality and it acts as a catalyst for the progression of calcific degeneration. In the large MESA study, annular mitral calcification was present in 20% of subjects with renal insufficiency and mean age 70 years and only in 8% of younger subjects with normal renal function. Diabetes is also associated with the presence of mitral annular calcification but, if the cardiovascular risk factors are statistically erased, renal failure alone still determines a 60% probability of calcific degeneration [6,7].
Causes and prognosis
A history of rheumatic fever is present in between 50% and 70% of patients with mitral stenosis . In developed countries, consequent to a drop in the incidence of rheumatic disease, there is a reduction in cardiac sequelae. In contrast, rheumatic fever still represents a considerable problem in developing countries; the transient epidemics in Western communities correspond to migration streams or to the boost of streptococcal virulence . Mitral stenosis is often not identified at the time of cardiac rheumatic attack and is diagnosed only in advanced age as a chronic progressive disease .
The second cause of mitral stenosis in the elderly is mitral annular calcification. Currently, this anatomopathological condition is rarely considered a cause of left ventricular inflow obstruction and is underestimated. Mitral annular calcification consists in the progressive deposition of calcium above and below the valvular fibrous ring causing a reduction of leaflet mobility and therefore a hindrance to physiological diastolic annular dilation . This degenerative process increases with age and is related to inflammatory markers and chronic inflammatory diseases, renal failure and disorders of tissue mineralisation, systemic hypertension and other cardiovascular risk factors .
Another possible cause of valvular disease, and consequently also of stenosis, is exposure to cancer therapies. The cardiotoxicity of chemotherapy and radiation therapy is a complication of oncological treatments administered 10 to 20 years earlier .
Finally, there are other pathological conditions that can lead to haemodynamic obstruction mimicking mitral stenosis, such as atrial myxoma, extensive infectious vegetation, infiltrative pathologies, thrombus formation and prosthesis deterioration.
Rheumatic heart disease
Mitral stenosis is recognised as a chronic rheumatic heart disease and therefore as a consequence of acute rheumatic fever even when the patient has no history of rheumatic fever, probably as a result of a missed diagnosis. In fact, this is possible by finding the typical ultrasound characteristics of thickening and fusion of the leaflet commissures.
In developed countries this valvular disease is usually diagnosed in the age group around 50 when it becomes symptomatic, compared to developing countries where this occurs at a young age. The disease has a different rate of progression depending on the geographical area, which reflects the quality of care and the epidemiology of the country. For asymptomatic or almost asymptomatic patients, 10-year survival is above 80%, probably due to the absence of a worsening of the disease.
From the onset of symptoms, the valve narrowing is slow and progressive, of about 0.1 cm²/year, with a remarkable variability among patients and a 10-year survival of between 0% and 15% .
The first percutaneous or surgical treatment is performed at about 70 years. Because surgical replacement is disadvantageous in elderly patients due to age-related comorbidity and degenerated valve characteristics, the procedure of choice is percutaneous balloon valvotomy. The four- and five-year survival in two different studies on patients over the age of 70 is 59% and 36%, respectively [15,16].
Mitral annular calcification
Calcification at the level of the mitral annulus can determine haemodynamically significant obstruction due to the impairment of physiological diastolic annular dilatation and the reduction of leaflet motion. There are several risk factors which support calcific degeneration such as ageing, hypertension and mechanical stress, diabetes, atherosclerosis and systemic inflammation, kidney disease and mineral disorder .
Furthermore, studies show an association between mitral annular calcification and stroke, atrial fibrillation and other arrhythmias, atrioventricular block and mortality. Mitral annular calcification is due to progressive calcium deposition and is similar to atherosclerosis and aortic valve calcification. An aggregation of oxidised lipids forms an initial site of chronic inflammation, first at the annular C shape, with infiltration of white blood cells and tissue remodelling. The starting microinjuries converge in fibrocalcific plaques of ever larger size .
Because this process has a common basis with aortic calcifications and atherosclerosis, it also shares the inflammatory component in addition to cardiovascular risk factors. Studies have identified some actors of this mechanism in the low levels of the multifunctional fetuin-A glycoprotein, which deals with the inhibition of calcific degeneration, in the fibroblast growth factor, and in the presence of high values of inflammation markers .
Among the promoters of the development of mitral annular calcification, disorders of tissue mineralisation play a key role that is particularly evident in elderly patients with chronic kidney disease and even more in those on dialysis. In this context, the calcification degeneration is supported by an increase in phosphorus-calcium product, hypercalcaemia, hyperphosphataemia and then secondary hyperparathyroidism. This list also includes the phenomena of renal osteodystrophy such as uraemic osteopathy and adynamic bone disease, which are typical complications of patients undergoing dialysis for a long time .
Calcification of the mitral ring affects prognosis and is associated with adverse cardiovascular events, stroke and mortality. Calcium thickness is a strong predictor of risk for myocardial infarction and vascular death and increases in significance progressively with advancing age and gravity of calcification .
Unfortunately, the data available on prognosis and progression of the disease are limited. In a small study of 254 patients, an increase of the transmitral gradient of 0.8±2.4 mmHg per year was calculated . A large single-centre study showed a survival rate of 78% and 47% at one and five years, respectively, in patients with severe mitral annular calcification and a diastolic gradient >2 mmHg .
Long-term side effects of cancer treatment
The increase in the average age of the population with the majority represented by the elderly is also due to the improvement in the quality and possibility of treatment. This is particularly true in the cardiovascular and oncological fields, which are the main areas of disease prevalence in the elderly population. Therefore, there is an increase in the prevalence of cancer survivors and, at the same time, of long-term complications of cancer treatment. One of these is the development of cardiotoxicity with possible damage to all the components of the heart from the pericardium to the conduction system passing through the myocardium and the valvular apparatus .
Mediastinal irradiation leads to valvular degeneration resulting in stenosis and/or regurgitation. In particular, mitral stenosis is the third most prevalent valvulopathy after aortic stenosis and mitral regurgitation. Tissue damage determines a fibrotic degenerative process of the valvular elements with possible formation of calcification. The development of a significant valvular disease occurs at a mean time of 15 years from the radiation therapy with an incidence of 0.5% at five years and 8.7% at 25 years, especially in subjects receiving high radiation doses .
Finally, in a fragile population such as the elderly, cancer therapies, either in the case of chemotherapy alone or radiotherapy alone or their combination, act as a stimulus for the progression of pre-existing heart disease .
An active understanding of changes in population characteristics and their consequences on the aetiological evolution allows us to continue to improve and personalise the currently available therapies for complex pathologies. Likewise, at the end of the transition we are currently observing, mitral stenosis will have a higher prevalence in the elderly population with a predominantly degenerative and calcific aetiology.
In older patients, because of their inherent fragility and multi-comorbid characteristics, the diagnosis of mitral stenosis and the indications for treatment should always be associated with appropriate risk stratification. In order to propose the best therapeutic approach by reducing the risks and considering the expected natural history of the valvular disease, life expectancy and quality of life, the patient must be evaluated and discussed by the Heart Team, as indicated by international guidelines.