The Local Burden of Disease for Non-Rheumatic-Acquired Valvular Heart disease in Iran, North Africa and Middle East from 1990 to 2017: Findings from a Sub-Analysis of the Global Burden of Disease Study 2017 CURRENT STATUS: POSTED

Background: Cardiovascular diseases (CVDs) are one of the main causes of mortality and a major barrier to sustainable development, being the main cause of “Disability-Adjusted Life Years” (DALYs), “Years of Life lost” (YLLs) and “Years Lived with Disability” (YLDs). Among CVDs, one of the most common and treatable CVD is non-rheumatic-acquired valvular heart disease (NRVD). However, in some countries such as Iran, the burden of NRVD is almost unknown because previous studies have focused mostly on the burden of ischemic heart disease, heart failure and other cardiovascular diseases. Method: Using data from the 2017 “Global Burden of Disease study”, we compared the number of deaths, DALYs, YLLs, YLDs, incidence and prevalence trends for NRVD in Iran, North Africa and Middle East since 1990 to 2017. Results: Our study yielded 3 major results: 1) a higher rate of death in Iran compared with North Africa, the Middle East and globally; 2) a higher increase in DALYs, YLLs, and YLDs in Iran in comparison with North Africa, the Middle East, and globally from 1990 to 2017; and 3) vast differences in increasing rates of prevalence and incidence of NRVD in Iran compared with the global trends from 1990 to 2017. The significant difference in the prevalence rate of NRVD in Iran versus global rate can be due to the higher growth rates of aging and the co-morbidities associated with NRVD, such as hypertension. Conclusion: Iranian health policy- and decision-makers should allocate significant resources for their diagnosis, treatment and management.


Introduction
According to the third goal of the Sustainable Development Goals (SDGs) settled by the United Nations, ensuring health, by promoting healthy lifestyles and well-being at all ages, is of paramount importance to achieve a sustainable human development (1). Cardiovascular diseases (CVDs) are one of the main causes of mortality and a major barrier to sustainable development (1,2). More in detail, in 2017, CVDs represented the main cause of "Years of Life lost" (YLLs) (3). Among CVDs, one of the most common and treatable CVD is non-rheumatic-acquired valvular heart disease (NRVD) (4,5): aortic and mitral valve disease affects up to 2.5% of the USA population (5,6).
The "Global Burden of Diseases, Injuries, and Risk Factors Study 2017" (GBD 2017) performed a comprehensive and systematic assessment of incidence and prevalence rates, "Disability-Adjusted Life Years" (DALYs), YLLs and "Years Lived with Disability" (YLDs), for 354 disorders, including NRVD, in 195 countries and territories from 1990 to 2017, with estimates broken down by age and sex (7,8,9). More in detail, according to the study, 1.5 million and 1.1 million DALYs were lost due to calcific aortic and degenerative mitral valve diseases across the world, respectively, representing 0.12% of the total health lost from all diseases in 2017 (4,8).
Nkomo and colleagues performed a population-based study in 2006, computing the burden of valvular heart diseases. Authors found that the prevalence rate of valvular heart diseases increased with age, from 0.7% in the 18-44 years to 13.3% in the 75 years and older age group (5).
Coffey and coworkers have performed a systematic review of the literature and meta-analysis to compute the prevalence, incidence, and progression rates, and risks of aortic valve sclerosis, finding that the prevalence of aortic valve sclerosis increased according to the age, ranging from 9% in the 54 years to 42% in the 81 years. In total, 1.8% to 1.9% of participants with aortic valve sclerosis is expected to progress to clinical aortic stenosis per year (10).
In some countries such as Iran, the burden of NRVD is almost unknown because previous studies have focused mostly on the burden of ischemic heart disease, heart failure and other cardiovascular diseases.
We hypothesized that NRVDs are highly prevalent and represent a public-health problem in developing countries. To the best of our knowledge, no study has ever been done to comprehensively compare the burden of NRVD in Iran, North Africa and the Middle East, stratifying incidence, prevalence, mortality rates, and overall burden of valvular heart disease by country. The present study can provide detailed information to policy-and decision-makers in making informed, evidencebased decisions to prioritize and allocate resources for NRVDs, taking into account trade-offs and opportunities.

Methods
Relevant data (number of deaths, DALYs, YLLs, YLDs, incidence and prevalence trends for NRVD) were extracted from the GBD 2017 report, for Iran, North Africa and the Middle East, stratified by age and sex, from 1990 to 2017.
DALYs were defined as the quantitative measurement of the overall span of years of healthy life lost due to disease (7,8,11). YLLs were defined as the amount of years lost due to premature mortality and were calculated by subtracting the age at death from the longest possible life expectancy (8,11).
YLDs were computed multiplying disease prevalence by disability weighted for that condition, which reflects the severity of different conditions as assessed by means of surveys administered to the general public (7,8).
Age-standardized rate was the rate computed per 100,000 population following the standardization procedure according to the global age structure irrespective of population size and age structure (7,12).
Calcified aortic valve disease (CAVD) was defined as a clinical diagnosis of aortic valve stenosis or regurgitation due to progressive calcification of the valve or annulus leading to hemodynamically moderate or severe stenosis or regurgitation.
Degenerated mitral valve disease (DMVD) was defined as a disorder caused by a myxomatous degeneration of the mitral valve leading to hemodynamically moderate or severe regurgitation.
Other NRVD is a residual category that captures non-rheumatic, non-congenital valve disorders of the tricuspid and pulmonary valves (5).
Finally, a category of total NRVD was defined as the aggregate of the three previously mentioned categories (CAVD, DMVD, other NRVD).
Moreover, it should be noted that the GBD 2017 study estimated causes of death incorporating sophisticated methods to adjust for incomplete or missing value, including vital registration (VR) and verbal autopsy (VA) data, general heterogeneity in data completeness and quality, and the redistribution of so-called garbage codes (that is to say, those insufficiently specific or implausible causes of death codes) (7).
Also the GBD 2017 study provided a standardized approach for estimating incidence, prevalence rates, DALYs, YLLs and YLDs by cause, age, sex, year, and location (13). The GBD used statistical modelling tools, including the "Cause of Death Ensemble model" (CODEm), to generate cause fractions and cause specific death rates for each location, year, age, and sex. The model computed 95% Uncertainty Interval (95% UI) for each epidemiological parameter. More in detail, the 95% UIs were derived from the 2.5 th and 97.5 th percentiles of 1,000 draws for each parameter. Uncertainty from all data sources imputed into the calculations of DALYs was propagated by means of Monte Carlo techniques (8,14). Table 1 shows the number of deaths and mortality rate for NRVDs in Iran (1990 -2017). The crude death number for men for all ages increased by 190% (160.9 to 466.7) from 1990 to 2017. A huge portion of this increase occurred in the 70+ age group (404%). The age-standardized death rate for NRVD increased for both sexes; 10% (1.28 to 1.41) in men and 24% (1.29 to 1.60) in women from   The number of crude deaths increased in all age groups for both sexes in Iran. The age-standardized rate of death increased by 10% for men and 24% for women, and this higher age-standardized rate in women can be attributed, at least partially, to the higher life expectancy of women compared with men (76.9 versus 74.4 for 2017).

Results
These results are not in line with the data from North Africa and the Middle East as well as the global data. The age-standardized rate of death for both sexes decreased by 19% in North Africa and the Middle East, and by 2.9% at the global level. There is a significant difference in rate of death in Iran versus North Africa and the Middle East and at a global level. This difference can be due to the higher rate of aging in Iran. The rate of aging in Iran has risen from 3.34% (population aged 65 and above % of total) to 5.44% between 1990 and 2017 with a growth rate of 62.8% (15). The aging growth rate in global and in North Africa and the Middle East was 39.8% (6.15% to 8.6%) and 37.4% (3.74% to 5.14%) respectively (16). According to the data, it can be concluded that the aging rate in Iran during this time period was 1.5 times more than the global rate as well as its rate in the EMRO region.
Age-standardized DALYs in Iran increased by 2% over 1990 to 2017; however, these results are not consistent with the findings from North African and Middle Eastern countries as well as the data at the global level. Over these years, age-standardized DALYs decreased by 20% in North Africa and Middle East and by 13% at the global level. Also, age-standardized YLLs increased by 1.3% in Iran, but it decreased by 16.2% at the global level over 1990 to 2017. Furthermore, age-standardized YLDs increased by 6.9% for both sexes in Iran; however, there was a 5% reduction in age-standardized YLDs at the global level and a 6% increase for North Africa and the Middle East over 1990 to 2017.
The percentage of total death attributed to NRVD increased by 150 % (0.1% to 0.25%) in Iran, by 69% Prevalence of NRVD in all ages and for both sexes increased by 211% (55,809 to 174,071) in Iran, by 175% in North Africa and Middle East, and by 105% at the global level in 1990 to 2017. Also, the agestandardized rate of prevalence of NRVD increased similarly in Iran and North Africa and Middle East by 14.9% and 12.5%, respectively; but this increase was so slow at the global level (1.8%).
The significant difference in the prevalence rate of NRVD in Iran versus its global rate can be due to the higher growth rates of aging and the co-morbidities associated with NRVD, such as hypertension.
For instance, in 2017, the age-standardized rate for prevalence of hypertension in Iran and at the global level was 420.38 (per 100,000) and 217.89 (per 100,000) respectively.
Age-standardized incidence rate for NRVD was very similar to its prevalence rate in all three age groups in both sex (Iran, North Africa and Middle East and at the global level).

Conclusion
NRVDs generate a high and relevant burden in Iran, especially among the elderly. An increase in the number of deaths and DALYs in Iran can be associated with the higher rate of aging (1.5 times) and increased prevalence of risk factors such as hypertension (1.9 times) compared with the world, North Africa and Middle East.
The results of the present study indicated that, due to incremental trend in rate of death, DALYs, prevalence and incidence of NRVD in Iran, health policy-and decision-makers should allocate   The percentage of total death, DALYs and YLLs attributed to VHD increased in Iran, North Africa, the Middle East, and globally