Global, regional, and national prevalence and risk factors for peripheral artery disease in 2015: an updated systematic review and analysis

BACKGROUND:Peripheral artery disease is a major cardiovascular disease that affected 202 million people worldwide in 2010. In the past decade, new epidemiological data on peripheral artery disease have emerged, enabling us to provide updated estimates of the prevalence and risk factors for peripheral artery disease globally and regionally and, for the first time, nationally. METHODS:For this systematic review and analysis, we did a comprehensive literature search for studies reporting on the prevalence of peripheral artery disease in the general population that were published between Jan 1, 2011, and April 30, 2019, in PubMed, MEDLINE, Embase, the Global Health database, CINAHL, the Global Health Library, the Allied and Complementary Medicine Database, and ProQuest Dissertations and Theses Global. We also included the Global Peripheral Artery Disease Study of 2013 and the China Peripheral Artery Disease Study as sources. Peripheral artery disease had to be defined as an ankle-brachial index lower than or equal to 0·90. With a purpose-built data collection form, data on study characteristics, sample characteristics, prevalence, and risk factors were abstracted from all the included studies identified from the sources. Age-specific and sex-specific prevalence of peripheral artery disease was estimated in both high-income countries (HICs) and low-income and middle-income countries (LMICs). We also did random-effects meta-analyses to pool the odds ratios of 30 risk factors for peripheral artery disease in HICs and LMICs. UN population data were used to generate the number of people affected by the disease in 2015. Finally, we derived the regional and national numbers of people with peripheral artery disease on the basis of a risk factor-based model. FINDINGS:We included 118 articles for systematic review and analysis. The prevalence of peripheral artery disease increased consistently with age. At younger ages, prevalence was slightly higher in LMICs than HICs (4·32%, 95% CI 3·01-6·29, vs 3·54%, 1·17-10·24, at 40-44 years), but the increase with age was greater in HICs than LMICs, leading to a higher prevalence in HICs than LMICs at older ages (21·24%, 15·22-28·90, vs 12·04%, 8·67-16·60, at 80-84 years). In HICs, prevalence was slightly higher in women than in men up to age 75 years (eg, 7·81%, 3·97-14·77, vs 6·60%, 3·74-11·38, at 55-59 years), whereas in LMICs little difference was found between women and men (eg, 6·40%, 5·06-8·05, vs 6·37%, 4·74-8·49, at 55-59 years). Overall, the global prevalence of peripheral artery disease in people aged 25 years and older was 5·56%, 3·79-8·55, and the prevalence estimate was higher in HICs than that in LMICs (7·37%, 4·35-13·66, vs 5·09%, 3·64-7·24). Smoking, diabetes, hypertension, and hypercholesterolaemia were major risk factors for peripheral artery disease. Globally, a total of 236·62 million people aged 25 years and older were living with peripheral artery disease in 2015, among whom 72·91% were in LMICs. The Western Pacific Region had the most peripheral artery disease cases (74·08 million), whereas the Eastern Mediterranean Region had the least (14·67 million). More than two thirds of the global peripheral artery disease cases were concentrated in 15 individual countries in 2015. INTERPRETATION:Peripheral artery disease continues to become an increasingly serious public health problem, especially in LMICs. With the demographic trend towards ageing and projected rise in important risk factors, a larger burden of peripheral artery disease is to be expected in the foreseeable future. FUNDING:None

Increased Urinary Angiotensin-Converting Enzyme 2 in Renal Transplant Patients with Diabetes

Angiotensin-converting enzyme 2 (ACE2) is expressed in the kidney and may be a renoprotective enzyme, since it converts angiotensin (Ang) II to Ang-(1-7). ACE2 has been detected in urine from patients with chronic kidney disease. We measured urinary ACE2 activity and protein levels in renal transplant patients (age 54 yrs, 65% male, 38% diabetes, n = 100) and healthy controls (age 45 yrs, 26% male, n = 50), and determined factors associated with elevated urinary ACE2 in the patients. Urine from transplant subjects was also assayed for ACE mRNA and protein. No subjects were taking inhibitors of the renin-angiotensin system. Urinary ACE2 levels were significantly higher in transplant patients compared to controls (p = 0.003 for ACE2 activity, and p≤0.001 for ACE2 protein by ELISA or western analysis). Transplant patients with diabetes mellitus had significantly increased urinary ACE2 activity and protein levels compared to non-diabetics (p<0.001), while ACE2 mRNA levels did not differ. Urinary ACE activity and protein were significantly increased in diabetic transplant subjects, while ACE mRNA levels did not differ from non-diabetic subjects. After adjusting for confounding variables, diabetes was significantly associated with urinary ACE2 activity (p = 0.003) and protein levels (p<0.001), while female gender was associated with urinary mRNA levels for both ACE2 and ACE. These data indicate that urinary ACE2 is increased in renal transplant recipients with diabetes, possibly due to increased shedding from tubular cells. Urinary ACE2 could be a marker of renal renin-angiotensin system activation in these patients

Time domains of the hypoxic ventilatory response in ectothermic vertebrates

Over a decade has passed since Powell et al. (Respir Physiol 112:123–134, 1998) described and defined the time domains of the hypoxic ventilatory response (HVR) in adult mammals. These time domains, however, have yet to receive much attention in other vertebrate groups. The initial, acute HVR of fish, amphibians and reptiles serves to minimize the imbalance between oxygen supply and demand. If the hypoxia is sustained, a suite of secondary adjustments occur giving rise to a more long-term balance (acclimatization) that allows the behaviors of normal life. These secondary responses can change over time as a function of the nature of the stimulus (the pattern and intensity of the hypoxic exposure). To add to the complexity of this process, hypoxia can also lead to metabolic suppression (the hypoxic metabolic response) and the magnitude of this is also time dependent. Unlike the original review of Powell et al. (Respir Physiol 112:123–134, 1998) that only considered the HVR in adult animals, we also consider relevant developmental time points where information is available. Finally, in amphibians and reptiles with incompletely divided hearts the magnitude of the ventilatory response will be modulated by hypoxia-induced changes in intra-cardiac shunting that also improve the match between O2 supply and demand, and these too change in a time-dependent fashion. While the current literature on this topic is reviewed here, it is noted that this area has received little attention. We attempt to redefine time domains in a more ‘holistic’ fashion that better accommodates research on ectotherms. If we are to distinguish between the genetic, developmental and environmental influences underlying the various ventilatory responses to hypoxia, however, we must design future experiments with time domains in mind

The Role of Carbonic Anhydrase in the Modulation of Central Respiratory-related pH/CO2 Chemoreceptor-stimulated Breathing in the Leopard Frog (Rana pipiens) Following Chronic Hypoxia and Chronic Hypercapnia

The aim of this thesis was to elucidate the role of carbonic anhydrase (CA) in the modulation of central pH/CO2-sensitive fictive breathing (measured using in vitro brainstem-spinal cord preparations) in leopard frogs (Rana pipiens) following exposure to chronic hypercapnia (CHC) and chronic hypoxia (CH). CHC caused an augmentation in fictive breathing compared to the controls (normoxic normocapnic). Addition of acetazolamide (ACTZ), a cell-permeant CA inhibitor, to the superfusate reduced fictive breathing in the controls and abolished the CHC-induced augmentation of fictive breathing. ACTZ had no effect on preparations taken from frogs exposed to CH. Addition of bovine CA to the superfusate did not alter fictive breathing in any group, suggesting that the effects of ACTZ were due to inhibition of intracellular CA. Taken together, these results indicate that CA is involved in central pH/CO2 chemoreception and the CHC-induced increase in fictive breathing in the leopard frog.MAS

Urinary ACE2 activity and protein in control subjects and renal transplant (Tx) recipients.

<p>(A) Graph depicts box plots of urinary ACE2 activity in control subjects (n = 50) and Tx recipients (n = 100). For each box plot, median values are indicated by the line within the box, with value shown beside or above the line. The box represents 50% of the values (25^th and 75^th percentiles), with the upper bar representing the 90^th percentile and the lower bar representing the 10^th percentile. Open circles indicate outliers. * p = 0.003, Control vs Tx recipients. (B) Graph depicts box plots of urinary ACE2 protein by ELISA in control subjects and Tx recipients. ** p<0.001, Control vs Tx recipients. (C) Graph depicts box plots of urinary ACE2 protein by western analyses in control subjects and Tx recipients. Densitometry analysis was performed on both urinary ACE2 bands (120 kDa and 90 kDa), and the sum of the two bands was used for quantitative comparisons. **p = 0.001, Control vs Tx recipients.</p

Subject demographic data.

<p>Values are medians with interquartile range in parentheses. Abbreviations: eGFR: estimated glomerular filtration rate, ACR: urine albumin to Cr ratio, CNI: calcineurin inhibitor. ^a calcineurin inhibitor, mycophenolate mofetil or azathioprine, and corticosteroid. N/A: not applicable.</p

Urinary Ang II and Ang-(1-7).

<p>(A) Graph shows box plots of RIA for Ang II in urine specimens from transplant recipients without diabetes (no Diabetes) or with diabetes (Diabetes). For each box plot, median values are indicated by the line within the box, with value shown above the line. The box represents 50% of the values (25^th and 75^th percentiles), with the upper bar representing the 90^th percentile and the lower bar representing the 10^th percentile. Open circles indicate outliers. * p = 0.027, Diabetes vs. No Diabetes. (B) Graph shows box plots of EIA for Ang-(1-7) in urine specimens from transplant recipients without or with diabetes. There was no significant difference between the two groups (p = 0.126).</p

Urinary ACE2 activity and protein in renal transplant recipients: Effect of diabetes.

<p>(A) Graph depicts box plots of urinary ACE2 activity in transplant recipients without diabetes (No Diabetes), or with diabetes (Diabetes). For each box plot, median values are indicated by the line within the box, with value shown above the line. The box represents 50% of the values (25^th and 75^th percentiles), with the upper bar representing the 90^th percentile and the lower bar representing the 10^th percentile. Open circles indicate outliers. * p<0.001, Diabetes vs. No Diabetes; n = 62 (No Diabetes), n = 38 (Diabetes). (B) Graph depicts box plots of urinary ACE2 protein by ELISA in transplant recipients without diabetes (No Diabetes), or with diabetes (Diabetes). *p<0.001, Diabetes vs. No Diabetes. (C) Graph depicts box plots of urinary ACE2 protein by western analysis in transplant patients without diabetes (No Diabetes), or with diabetes (Diabetes). *p<0.001, Diabetes vs. No Diabetes. Above graph is representative immunoblot for ACE2 in urine, showing bands at 120 kDa and 90 kDa. Densitometry analysis was performed on both bands, and the sum of the two bands was used for quantitative comparisons. The protein bands for ACE2 in urine specimens were not observed when membranes were incubated with the secondary antibody alone, bypassing the primary antibody step. Lanes 1–3, No Diabetes. Lanes 4–6, Diabetes. Lane 7: recombinant human ACE2 protein (hACE2), used as a positive control. (D) Representative immunoblot for urinary ACE2 treated without (−) or with (+) the deglycosylase enzyme PNGase F. Lanes 1+, 2+, 3+, and 4+ show a reduction in the sizes of urinary ACE2 fragments to ∼85 kDa and ∼65 kDa in urine samples treated with PNGase F. Lanes 1 and 2, No Diabetes. Lanes 3 and 4, Diabetes. Lane 5: recombinant human ACE2 protein (hACE2).</p