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< PreviousValvular heart disease as part of the current burden of cardiovascular disease CHAPTER ONE OUR HIDDEN AGEING: TIME TO LISTEN TO THE HEART 8Heart valves – What they are and why they’re there The circulation takes oxygenated blood from the lungs, distributes it to every organ of the body and returns it to the lungs for re-oxygenation. The contraction of pumping chambers (ventricles) powers this process. Each ventricle has a valve at the inlet and the outlet, to stop the blood going backwards; on the left side of the heart, these are the aortic and mitral valves, with the pulmonary and tricuspid valve on the right side (Figure 1). During ventricular filling, the aortic and pulmonary valves are closed, so that blood can enter from the atrium without being mixed with arterial blood from the previous contraction. During contraction, the mitral and tricuspid valves close so that blood only goes forwards into the arteries and not backward into the atria and veins. These heart valves are made from similar tissues to the blood vessels - fibrous tissue which is covered by the endothelium. A number of processes may damage these valves, leading them to become narrowed, limiting the progression of blood, or leaky, causing blood to go backwards. In Australia, the most common causes of heart disease are age-related, and there is evidence of a growing age-related burden of heart valve disease in Australia. Recent modelling by the 2017 Global Burden of Disease study investigators demonstrated 50-170% increases in the numbers of people, deaths and disability adjusted life years from non-rheumatic valve disease between 1990 and 2017 in Australia (1). FIGURE 1. Location of the left- and right-sided heart valves. Figure 1. Location of the left- and right-sided heart valves. Figure 2. Heart valve structure. [E] endothelium, [F] lamina fibrosa, [S] fibro- elastic supporting layer, [M] myocardium. 9Types and causes of heart valve disease There are three potential problems with heart valves – narrowing, leaking, or less commonly, absence (atresia). Narrowing (stenosis) may occur because the valve is structurally abnormal from birth, the most frequent manifestation being the bicuspid aortic valve. The other major driver of valve narrowing is degenerative, largely age-related damage to the valve leaflets which produces scarring and calcification. This is most common in the aortic valve, where it is identified in 3% of people >65 years (2). Stenosis may less commonly occur because of an inflammatory process such as rheumatic fever or connective tissue diseases. The narrowed or stiffened valve produces an increased workload on the relevant pumping chamber of the heart, leading to thickening of the muscle, scarring, enlargement, and eventually failure. At some stage, this narrowing process exhausts the ability of the heart to compensate, at which stage the amount of blood flow through the valve is reduced. The most common causes of heart valve narrowing are bicuspid aortic valve (BAV) and degenerative aortic valve disease (calcific aortic stenosis). Leakage (regurgitation) may occur because the valve leaflets have stretched or ruptured, or are too small to close the orifice. When regurgitation occurs due to a valve leaflet problem, it is described as primary regurgitation. The most common manifestation is the stretching of the valve leaflets or supporting structures, which most frequently occurs in mitral valve prolapse, a degenerative disease representing a weakness in the fibrous tissue of the valve. Leaflets can be too small to close the valve orifice if they have shrunk due to scarring, or if the valve annulus has been stretched, usually because of enlargement of a connected chamber, typically the ventricle but also the atria. This mechanism is known as secondary regurgitation. The most common sites of valvular disease are on the aortic and mitral valves, respectively presenting as stenosis and regurgitation (Table 1). The most common causes of heart valve disease in affluent societies are congenital and degenerative. The most common congenital heart disease is bicuspid aortic valve, present in 1-2% of the population. The two major causes of degeneration are age-related changes (often described as “calcific”, even though calcium is a consequence of scarring rather than the primary cause) and myxomatous degeneration (a weakening of connective tissue in the mitral valve that affects 2% to 3%). Secondary mitral regurgitation occurs due to left ventricular damage from coronary artery disease or other causes of heart failure, including hypertension. Secondary tricuspid regurgitation is due to increased pressure in the pulmonary circulation, or right heart failure, most commonly caused by left heart failure. Less common causes of both stenosis and regurgitation are inflammatory diseases that cause damage the heart valve such as infectious endocarditis or the effects of radiation therapy, or damage of the annulus including connective tissue diseases and aortic aneurysms. TABLE 1. Causes of stenosis and regurgitation at each heart valve. Common causes are shown in bold. AorticMitralPulmonaryTricuspid StenosisBicuspid (BAV) Degenerative AS RheumaticCongenitalRare RegurgitationBicuspid (BAV) Degenerative AR MVP Degenerative MVD Secondary CongenitalSecondary OUR HIDDEN AGEING: TIME TO LISTEN TO THE HEART 10The current burden of cardiovascular disease in Australia Cardiovascular disease (CVD) is the leading cause of death in Australia and worldwide. In Australia, CVD accounts for 30% of all deaths, causing one death every 12 minutes (3). In 2017-18, it was estimated that 1.2 million (or 5.6%) Australian adults aged 18 years or over had one or more conditions related to CVD (4). CVD is Australia’s second largest direct health care cost, amounting to $10.4 billion annually (5). The major causes of death and disability due to CVD include coronary artery disease, stroke and heart failure. The Australian Burden of Disease Study (6) found that in 2015 coronary heart disease was the leading disease in males and females, accounting for 7% of the total burden (9% for males and 5% for females). Stroke was the ninth leading disease, accounting for 3% of total disease burden. In 2017-18, there were 1.2 million hospitalisations (or 11%) in Australia where CVD was recorded as the principal or additional diagnosis (7). Important risk factors for CVD, including high blood pressure, obesity and type 2 diabetes, are highly prevalent in the Australian population, but modifiable risk factors remain poorly managed (8). In general, CVD has a greater impact on males, the elderly, Indigenous Australians and people living in remote or socioeconomically disadvantaged areas. In 2017-18, the prevalence of CVD was higher among men (7%) than women (5%) and increased with age – 26% of those aged 75 years had CVD. 7% of those living in the most socioeconomically disadvantaged areas had CVD compared to 5% in least disadvantaged areas. Furthermore, 5% of Indigenous Australians had CVD in 2017-18, compared to 4% of non-Indigenous Australians (9). Heart valve disease is much less common than other types of cardiovascular disease – it only reaches the “top ten” for disease burden and mortality in elderly women (6). However, although heart valve conditions are serious, they are eminently and increasingly treatable. Burden of heart valve disease - 2021, 2031 and beyond Diseases of the aortic valve are most prevalent, followed by those of the mitral and tricuspid valves (10). Of note, it is common for people to have disease of more than one heart valve. Sometimes this is a consequence of the primary culprit - for example, secondary mitral regurgitation is a common consequence of the remodelling of the cardiac chambers due to aortic valve disease. Likewise, tricuspid valve problems are present in 10-20% of people with mitral or aortic disease undergoing valve repair or replacement (11). It is estimated that there are currently between 500,000 and 600,000 people in Australia with heart valve disease including narrowing (stenosis) or leakage (regurgitation) (Figure 2) (12). Increases in the burden of heart valve disease are strongly driven by the ageing of our population. Studies from the US and Europe demonstrate large increases in the incidence and prevalence of aortic and mitral valve disease with increasing age (10, 13). The increase in the burden of these diseases with age likely reflects accumulation of exposure to risk factors that cause stenosis and regurgitation of the heart valves (14). It is important to recognise that many people have undiagnosed heart valve disease. In the UK-based OxVALVE study, investigators imaged the hearts of a representative sample of the older population to find new heart valve disease (16). They found that the number of people with undiagnosed moderate to severe heart valve disease - the group that may be candidates for heart valve repair or replacement - overwhelmingly outnumbered those with diagnosed disease. It is estimated that there are 254,000 Australians with undiagnosed heart valve disease in 2021. It is projected that this number will grow substantially in 2031 to 336,000 and in 2051 to 435,000 (Figure 3). As Australians increasingly have greater access to heart imaging that can diagnose heart valve disease, there will be a large increase in the numbers of people eligible for intervention. 11Newly diagnosed HVD FIGURE 2. Total number of Australians with any form of heart valve disease (15) TIME AGE GROUP (YEARS) 2021 2031 2041 2051 65-6970-7475-7980-8485+65-6970-7475-7980-8485+65-6970-7475-7980-8485+ 202120312051 600 0 25000 50000 75000 75000 125000 800 1000 1200 TOTAL PROJECTED NUMBER AUSTRALIANS WITH ANY HVD (1000 s ) PROJECTED NUMBER OF AUSTRALIANS WITH HEART VALVE DISEASE (1000 s ) FIGURE 3. Projected number of people with newly and previously diagnosed heart valve disease in Australia using the OXValve prevalence data. Footnote: The 85+ age group has been truncated at 95 years of age.(17) New diagnosed moderate or severe HVD Previously diagnosed HVD OUR HIDDEN AGEING: TIME TO LISTEN TO THE HEART 12AORTIC VALVE DISEASE Aortic valve disease (encompassing both stenosis and regurgitation) is the most common cause of severe valve disease. There is arguably a greater understanding of its risk factors, epidemiology and management compared to mitral or tricuspid valve disease. The burden of aortic valve disease has increased in Australia - the Global Burden of Disease (GBD) investigators showed increases in the age-standardised prevalence of aortic stenosis or regurgitation in Australian men and women from 1990 to 2017 (men – 169 to 203 per 100,000 people; women – 118 to 148 per 100,000 people) (1). There were also large increases in the numbers of years lived with disability due to aortic valve disease in Australia over that period (men – 4215 to 7542; women – 2991 to 6115). AORTIC STENOSIS Aortic stenosis is strongly associated with ageing and cardiovascular risk factors (10). The prevalence of aortic stenosis increases with age from <0.1% of people aged under 55 years increasing to around 2% in those aged >75 years (4). In 2021, it has been estimated that there are 150,000 people in Australia with moderate to severe aortic stenosis (Figure 4), with even larger numbers reported internationally (18). As the prevalence of aortic stenosis increases rapidly with age, there is predicted to be a large increase in the number of people with aortic stenosis in Australia over the next 30 years, particularly among those aged >75 years (Figure 5). With an ageing population, the numbers of people with moderate to severe aortic stenosis will continue to climb to 200,000 in 2031 and 266,000 in 2051. The numbers of patients requiring intervention will depend on co-morbidities, symptom status, cardiac function and the progression from moderate to severe stenosis – but it seems likely that at least half will require intervention. These projected increases are due to the ageing of the Australian population but there is also some evidence of an increase in the incidence of aortic stenosis over time – due to better recognition, more disease or both. In Denmark, there was doubling in the incidence of aortic stenosis over a 15-year period using data on hospitalisations (20), with similar increases cited in France (21). Smaller increases in incidence, also based on hospitalisations, for aortic stenosis were noted in the United States of America (22) and Canada (21). In contrast, in Sweden, the incidence of aortic stenosis based on hospital admissions remained stable over a 20-year period, which was attributed to good risk factor control with similar trends in the incidence of other cardiovascular diseases also found (23). In addition to changes in the incidence or hospitalisation for aortic stenosis, changes in the distribution of disease severity have been noted. In a single hospital study in the United States over a 17-year period, records from over 130,000 people referred for echocardiography were examined for aortic stenosis. The investigators found that while prevalence of aortic stenosis was similar over time (6.4% in 1995 to 5.5% in 2012), the proportion of people with severe aortic stenosis increased from 19.3% to 35.2% (24).These data suggest that our projections of the numbers of people in Australia eligible for valve replacement are an underestimate, with a potential shift towards a greater proportion of people with severe disease in years to come. Fortunately, deaths due to aortic stenosis at the population-level or among those with diagnosed disease have decreased in recent years. In the United States, (17) from 2008 to 2018, there was an estimated 1% reduction in the age-adjusted mortality rate from aortic stenosis per year, which accelerated in more recent years. There have been similar reductions in in-hospital deaths of patients hospitalised for aortic valve diseases from 4.5% in 2000 to 3.5% in 2012 (18). The reduction in deaths from aortic stenosis are largely attributed to the increased availability of aortic valve replacements – especially transcatheter replacements. However, it is important to realise that unrecognised and/or untreated severe aortic stenosis is a malignant disease, with an outcome worse than many metastatic cancers. Indeed, the outcomes of patients unable to undergo surgery have been unchanged for five decades, with recent studies reporting a two-year mortality of 50% (25). 13While we predict that the numbers of people with aortic stenosis in Australia that are eligible for valve replacement will increase, with adequate resourcing of our hospital system to provide these services we should be able to maintain the trajectory of reduced deaths from aortic stenosis. AORTIC REGURGITATION Aortic regurgitation is mostly caused by cardiovascular risk factors and ageing, as well as congenital defects (10). As with aortic stenosis it is strongly associated with age. It has a low prevalence in younger age groups (e.g. <0.1% in those aged under 55 years) that rapidly increases with age to between 2-3% of people aged >70 years (12, 13). It is more prevalent in men than women (12). It is estimated that there are approximately 100,000 Australians with aortic regurgitation in 2021 (Figure 6). The number of people in Australia with aortic regurgitation will increase due to population ageing alone (Figure 7). The numbers will increase to 131,000 in 2031 and 160,000 by 2051. These projections are likely to be an underestimate of the future burden of aortic regurgitation because there is evidence of increasing incidence in other countries. For example, in Denmark, using national administrative data, the incidence of aortic regurgitation increased from 22 per 100,000 per year in 2000-2002 to 41 per 100,000 per year in 2015-2017 (12). Aortic regurgitation may occur as a complication after valve replacement for aortic stenosis, which could account for some of the increase in incidence over time (10). Treatment guidelines recommend surgical replacement in eligible people with aortic TIME 2021 2031 2041 2051 150 200 250 300 TOTAL PROJECTED NUMBER AUSTRALIANS WITH MODERATE AORTIC STENOSIS (1000 s ) AGE GROUP (YEARS) 18-4445-5455-6465-7475+18-4445-5455-6465-7475+ 202120312051 0 50 100 150 TOTAL PROJECTED NUMBER AUSTRALIANS WITH MODERATE AORTIC STENOSIS (1000 s ) 18-4445-5455-6465-7475+ FIGURE 5. Projected number of Australians with moderate to severe aortic stenosis FIGURE 4. Total projected number of Australians with moderate to severe aortic stenosis (19) OUR HIDDEN AGEING: TIME TO LISTEN TO THE HEART 14regurgitation (10). However, valve replacement using transcatheter approaches is feasible and has been increasing (27). As the field evolves, more people with aortic regurgitation may be eligible for interventions using transcatheter approaches. MITRAL VALVE DISEASE Mitral valve diseases (including stenosis and regurgitation) are also increasing. The GBD study investigators showed increases in age-standardised prevalence of moderate to severe mitral regurgitation in Australia from 1990 to 2017, but decreases in age-standardised death rates and loss of disability adjusted life years (28). The GBD study considered degenerative mitral regurgitation, but may not have captured ischaemic causes, so this likely underestimates the total burden of this disease. MITRAL REGURGITATION Mitral regurgitation (MR) is the most common specific type of heart valve disease across the entire population, with a prevalence estimated at around 2% (12). It is associated with cardiovascular risk factors (29) with a higher prevalence in men than women (30). As with other forms of heart valve disease, it increases in prevalence with age from 1-2% in those aged <60 years up to 9-11% in those aged >70 years (12, 31). There are over 400,000 people in Australia with MR, including mild, moderate and severe disease (Figure 11). The prevalence of moderate to severe MR is highly dependent on age – data from the Framingham study showed that this is <1% below the age of 50 years, 2-3% between 50 and 69, and >10% over the age of 70 years (13).Due to its strong association with age, the numbers of Australians with mitral regurgitation will increase overtime (Figure 9). TIME 2021 2031 2041 2051 120 150 180 TOTAL PROJECTED NUMBER AUSTRALIANS WITH AORTIC REGURGITATION (1000 s ) AGE GROUP (YEARS) 18-4445-5455-6465-7475+18-4445-5455-6465-7475+ 202120312051 0 20 40 60 TOTAL PROJECTED NUMBER AUSTRALIANS WITH AORTIC REGURGITATION (1000 s ) 18-4445-5455-6465-7475+ FIGURE 6. Projected numbers of Australians with aortic regurgitation (26) FIGURE 7. Projected numbers of Australians with aortic regurgitation in 2021, 2031 and 2051 (26) 15It is estimated that there will be 520,000 Australians with mitral regurgitation in 2021, increasing to 670,000 in 2051, with 30% having moderate to severe forms of disease (32) – and many of the latter group will require valvular intervention. Unlike other forms of heart valve disease, the incidence of mitral regurgitation appears to be stable over time. For example, in Denmark, the incidence remained at 38 per 100,000 people per year over a 15 year period (20). The outcomes of mitral regurgitation are poor (21) – severe secondary MR has a 50% mortality rate over 5 years, although much of this is attributable to cardiac dysfunction and co-morbidities. In the past, few patients with secondary MR received surgical interventions and two-thirds had hospital readmissions within 12 months of diagnosis (26). MITRAL STENOSIS Mitral stenosis is rare with sparse data on its prevalence or outcomes. Unlike other forms of heart valve disease, the most common cause of mitral stenosis is rheumatic fever and it is therefore more common in low and middle income countries than high income countries. Clinical samples suggest that, compared to other forms of heart valve disease, mitral stenosis is more common in women than men (10, 33, 34). It has similar survival after 6 months of follow-up (>95%) to other forms of heart valve disease (10). There is evidence that in higher income countries, such as Korea, the incidence of mitral stenosis has decreased from around 10 per 100,000 people per year in 2007 to 3.6 per 100,000 people per year in 2016 (23). This decrease in prevalence is likely due to reductions in rheumatic fever. Given the association with rheumatic fever, the burden of mitral stenosis among Indigenous Australians reflects the high incidence of rheumatic fever and rheumatic heart disease that has not decreased over time (35, 36). AGE GROUP (YEARS) 18-4445-5455-6465-7475+18-4445-5455-6465-7475+ 202120312051 0 100 200 300 TOTAL PROJECTED NUMBER AUSTRALIANS WITH MITRAL REGURGITATION (1000 s ) 18-4445-5455-6465-7475+ FIGURE 9. Projected numbers of Australians with mitral regurgitation by age in 2021, 2031 and 2051 FIGURE 8. Number of Australians with mitral regurgitation (12) TIME 2021 2031 2041 2051 400 500 600 700 800 TOTAL PROJECTED NUMBER AUSTRALIANS WITH MITRAL REGURGITATION (1000 s ) OUR HIDDEN AGEING: TIME TO LISTEN TO THE HEART 16TRICUSPID VALVE DISEASE Primary disease of the tricuspid valve is uncommon, although tricuspid regurgitation secondary to other illnesses (eg heart failure, mitral valve disease) is increasing. In the Framingham Heart Study, the prevalence of mild tricuspid regurgitation identified on echocardiography increased with age from 13% in those aged 26 to 39 years up to 26% in those aged 70 to 83 years. Moderate to severe TR may affect 3-5% of adults over the age of 75 years. Women appear more affected than men, particularly in terms of moderate or severe tricuspid disease (13). It is estimated that in Australia there are around 6,000 people with tricuspid disease in 2021 (Figure 10) – the increment of this over time will occur mostly in women (due to the increasing prevalence of tricuspid regurgitation with age and the greater life expectancy of women). Significant tricuspid regurgitation is associated with adverse outcomes, independent of the causative pathology, but how best to treat this at acceptable levels of risk is still being defined. Deaths from tricuspid valve disease also give some indication of the burden of this disease, although these are likely to represent severe disease and therefore underestimate its true burden. In the United States, the age adjusted mortality rate per 100,000 people was relatively stable from 2008 (0.08 per 100,000 people per year) to 2013 (0.08 per 100,000 people per year), but then experienced a 25% increase from 2013 to 2018 (26). The very low prevalence may make estimates of change unreliable, and may reflect increasing recognition. The 5-year survival of people with patients with functional tricuspid regurgitation (secondary to other cardiac or valvular diseases) is 79% (37). The risk of death among people with tricuspid valve disease is greater among older people, African Americans, those with co- morbidities (e.g. diabetes, kidney disease, heart and lung disease) (37). In the United States, there has been an increase in the number of repairs and replacements of the tricuspid valve over time (38). PULMONARY VALVE DISEASE Although important in children, pulmonary stenosis is uncommon in adults. Pulmonary regurgitation is also uncommon on a population-wide basis, although it is an important consequence of some surgery for some congenital valve disease, especially Tetralogy of Fallot. CONCLUSION There is a considerable burden of heart valve diseases in Australia with this projected to grow over the next three decades. Females Males TIME 2021 2031 2041 2051 1.25 1.50 1.75 2.25 2.0 PROJECTED NUMBER OF AUSTRALIANS WITH MILD AND MODERATE TO SEVERE TRICUSPID REGURGITATION (1000 s ) FIGURE 10. Projected numbers of Australians with tricuspid valve regurgitation to 2051(31) 17Next >