Highlights
-
•
The increase of arterial stiffness at younger ages has been considered a strong predictor of cardiovascular outcomes.
-
•
Elevated “pulsatile load”, which translates into elevated arterial stiffness, would lead to a cascade of phenomena (left atrium distension, neurohormonal activation and inflammatory response), that in their final common path would lead to the development of atrial fibrillation.
-
•
A genetic predisposition for a higher arterial stiffness index was unidirectionally associated with an increase in incidence risk and prevalence of atrial fibrillation. These results are consistent with a causality association between arterial stiffness and atrial fibrillation.
-
•
A knowledge gap to be clarified is whether a reduction in arterial stiffness could lead to a decrease in atrial arrhythmia burden, from frequent atrial ectopic beats to atrial fibrillation. Another knowledge gap is the possible rule of arterial stiffness in the so-called “pre-fibrillatory stage”.
Keywords: Atrial fibrillation, Arterial stiffness, Atrial arrhythmia
Abstract
Arterial stiffness has been investigated as part of the physiopathology of arterial hypertension since the 1970s. Its role in increasing the “pulsatile load” imposed over the Left Ventricle (LV) has been intensely studied recently and has helped in understanding the mechanisms of Atrial Fibrillation (AF) in hypertensive patients. This paper aims to review the main evidence on this issue and establish possible mechanisms involved in the development of AF in patients with arterial stiffness. A PubMed search was performed, and selected articles were searched for references focusing on this topic. In the long term, lower blood pressure levels allow for arterial wall remodeling, leading to a lower stiffness index. To this day, however, there are no available treatments that directly promote the lowering of arterial wall stiffness. Most classes of anti-hypertensive drugs ‒ with stronger evidence for beta-blockers and diuretics ‒ could be effective in reducing arterial stiffness. There is strong evidence demonstrating an association between arterial stiffness and AF. New studies focusing on arterial stiffness and pre-fibrillatory stages would strengthen this causality relation.
Introduction
Atrial Fibrillation (AF) is the most frequent sustained arrhythmia in clinical practice. Although its prevalence varies regionally [1,2], the estimated global burden of AF is around 1‒2% of the population of all ages [3,4]. Discrepancies appear to be explained by differences among study designs but also by racial differences and cultural variations [5].
Among developing countries, AF affects around 0.5% of the population, while its prevalence is estimated to be 3% in the USA, 1.6% in Asia, 4% in Australia and New Zealand, and in Europe, it has been reported to range between 1.9% and 3.3% of the population, depending on the country [1,3,6, 7, 8]. Hypertension and AF share an intimate relationship, since elevated Blood Pressure (BP) is an established risk factor, not only for newly-diagnosed AF, but also for its maintenance and progression 9, 10, 11, and that may be explained, for the most part, by the increase in arterial stiffness.
The role of arterial stiffness in the pathophysiology of hypertension became a focus for research and investigation in the 1970s in France 12, 13, 14, 15. At that time, a series of biochemical and hormonal factors, such as those involved in the renin-angiotensin-aldosterone system causing hypertension were understood, with very little exploration of the mechanisms related to arterial stiffness. The identification of arterial stiffness as a risk factor was an important milestone in the understanding of hypertension, as well as in the development of treatment strategies.
The aim of this paper is to review the role of arterial stiffness in AF development as one independent factor. The present study's objective was to explore the effects of arterial stiffness in left atrium physiology, providing a basis for the understanding of atrial arrhythmias related to hypertension, especially AF.
Methods
The authors performed a non-systematic comprehensive review of arterial stiffness in patients with AF. A literature search was conducted using the databases PubMed, applying the search terms “Arterial Stiffness and Atrial Arrhythmia” and “Arterial Stiffness and Atrial Fibrillation.” Additionally, reference lists from the available articles were further checked. The studies selected were, for the most part, clinical studies with an observational design. At the same time, articles that were not accessible or only available as an abstract or in a language other than German, English, French, or Spanish were excluded.
Arterial stiffness assessment
Arterial stiffness is estimated from the aortic or Carotid-Femoral Pulse Wave Velocity (CFPWV), considered the gold-standard method. It is recognized as an independent predictor for future cardiovascular events and all-cause mortality [16,17]. A 1 m/s increase in aortic Pulse Wave Velocity (PWV) leads to 14% and 15% increases in cardiovascular events and mortality, respectively, after adjusting for age, gender, and other risk factors [18], Since aortic PWV is a superior predictor of events to traditional cardiovascular risk factors, it has been proposed that it should be considered an intermediate cardiovascular outcome, not only a regular risk factor [18].
As patients age (the most commonly known risk factor for arterial stiffness), there is a loss of elasticity in the arteries, caused by the substitution of elastin fibers by collagen, which is less elastic, and these changes are associated with the reorganization of cell elements within the vascular wall. The result is a blood vessel less capable of expanding itself to transmit the wave created in the systole during the opening of the aortic valve [18].
PWV measurement is performed by the simultaneous positioning of two mechanographic sensors over the carotid and femoral arteries, located at a known distance. These sensors contain membranes that are successively deformed by the pulse wave shock, and this deformation is initially transformed into an electric signal which is then transmitted to a computer-based calculation program, as shown in Fig. 1.
Table 1 summarizes the main methods for assessing arterial stiffness.
Table 1.
Carotid-Femoral Pulse Wave Velocity (cfPWV) | Gold-standard method. |
Brachial-Ankle Pulse Wave Velocity (baPWV) | baPWV was calculated as: Distance (meters)/Δt (seconds). |
Augmentation Index (AI) | Assessed by Applanation Tonometry.The augmentation pressure (AG) is the measure of contribution that the wave reflection makes to the systolic arterial pressure, and it is obtained by measuring the reflected wave coming from the peripheral to the central arteries. |
Cardio-Ankle Vascular Index (CAVI) | CAVI is an index obtained by recording the distance from the level of the aortic valve (i.e., brachial level) to the measuring point (i.e., the ankle) and the time delay between the closing of the aortic valve to the detected change in arterial pressure wave at the set point. Information for CAVI computation, including PWV, systolic and diastolic blood pressure as well as arterial pulse waveforms, can then be acquired through the electrocardiogram, cardiac phonogram, and the pressure cuffs on the testing subject at the reference points.Thought to be or claimed to be blood pressure independent. |
QKDh | The QKd interval is the time (measured in milliseconds) between the onset of depolarization on electrocardiography (Q) and detection of the last Korotkoff sound (K) at the brachial artery during cuff deflation, corresponding to the diastolic blood pressure (d). This interval is inversely correlated with pulse wave velocity. |
β Index | Stiffness Index Beta is derived from PWV, PP, SBP, DBP and viscosity and was calculated by an equation.Thought to be or claimed to be blood pressure independent |
Ambulatory Arterial Stiffness Index (AASI) | The Ambulatory Arterial Stiffness Index (AASI) is an indirect arterial stiffness index, which can be simply calculated from 24-h Ambulatory Blood Pressure Monitoring (ABPM). |
Arterial stiffness: epidemiology
Early vascular aging, that is, the increase of arterial stiffness at younger ages, is a strong predictor of cardiovascular outcomes.
Collectively, most studies with ethnic analysis on arterial stiffness demonstrate that populations with African (and many times Hispanic) ancestry have higher arterial stiffness than Caucasian populations, and this has been seen in individuals as young as 6 and as old as 70 years old. Elevated blood pressure frequently accompanies arterial stiffness in Black populations [20,21].
Higher arterial stiffness in black individuals has also been seen in healthy, normotensive people, a phenomenon indicated in studies with normotensive children [20,23,24] and young adults [22]. When analyzing arterial stiffness and aging, it becomes clear that early vascular aging in the black population increases cardiovascular risk in the long term [25,26].
In spite of this, studies reveal only modest evidence of genetic influence over arterial stiffness, with no differences between ethnicities 27, 28, 29. There is also little evidence for maternal risk factors in predicting higher arterial stiffness in children. In contrast, psychosocial factors including racism, lower socioeconomic status, and inadequate health behaviors (such as obesity and sedentary lifestyle) have a significant impact on arterial stiffness 30, 31, 32 and may be the explanation for the ethnic disparities found in the literature.
Arterial stiffness: pathophysiology
Studies have demonstrated the vast interference of cardiovascular risk factors on the pathophysiology of arterial stiffness. The mechanisms by which these risk factors lead to stiffening of the great arteries were progressively deciphered [15].
For instance, in patients with primary hypertension, arterial stiffness elevates as a result of the increase in vascular wall collagen, caused by high levels of blood pressure in repeated pulses, leading to biomechanical fatigue. Furthermore, activation of the renin-angiotensin-aldosterone system also influences this process by stimulating the proliferation of smooth muscle cells in the vessels, promoting low-grade inflammation, increasing collagen production, and favoring the formation of advanced glycation end products [16].
In individuals with type 2 diabetes, the damage to the walls of great arteries may derive from the main characteristics of the disease: hyperglycemia and insulin resistance [17]. Both factors act on structural and functional levels by various mechanisms. Chronic exposure to hyperglycemia leads to smooth muscle cells proliferation and increased production of advanced glycation end products, as well as to the promotion of collagen reticulation and stiffening of the arterial wall [33]. There is also an increase in the expression of matrix metalloproteinases 2 and 9 and angiotensin II receptors in the vascular tissue [34]. Insulin resistance increases collagen synthesis and the expression of many genes involved in inflammatory processes [35]. Arterial stiffness is a possible consequence of these phenomena.
In Chronic Kidney Disease (CKD), the process occurs essentially through vascular calcifications [36]. This is caused by a sequence of molecular events, beginning with the reduced expression of constitutive inhibitory proteins in smooth muscle cells, and increased expression of proteins related to the calcification process [37].
The Matrix Gla Protein (MGP) signaling pathway, in particular, contributes to the process of calcification and arterial stiffness. MGP is a small secretory protein produced by chondrocytes and vascular smooth muscle cells [38]. Its inactive form (desphospho-uncarboxylated MGP or dpucMGP) is carboxylated and phosphorylated to form active MGP, a potent arterial calcification inhibitor. This carboxylation depends on the disponibility of vitamin K on the vascular wall [38]. Curiously, vitamin K deficiency, even in low levels, seems to interfere in with this process. DpucMGP is secreted in the circulation, making it an interesting biomarker reflecting the vascular disponibility of vitamin K [38].
An increase in dpucMGP circulation is independently associated with an increase in arterial stiffness in many populations, including the general population [39,40] and adults with diabetes [41], hypertension [42], CKD [43], and Heart Failure (HF) [44]. Warfarin, a vitamin K antagonist, inhibits MGP activation and potently promotes vascular calcification in animal models. Its use has been associated with arterial stiffness in individuals with HF[44] and aortic valve calcification. There is data suggesting that vitamin K2 supplementation could reduce or improve arterial stiffness [45].
This biological process does not affect every individual equally. Evidence in animal and human beings suggest that different segments of the aortic wall are affected heterogeneously [37,46]. Factors such as genetic susceptibility, epigenetic influence in intrauterine life, sociodemographic factors and health behaviors (including diet and exercise) all contribute to these differences, as illustrated in Fig. 2.
Increased arterial stiffness is frequently found in ethnic groups of lower socioeconomic status that have limited access to healthcare, inadequate diet, and unhealthy lifestyle [48], as stated in the previous section.
Atrial consequences of arterial stiffness
Elevated arterial stiffness makes the transmitted pulse wave return from the terminal organs earlier, before the systole ends, increasing the pressure load over the left ventricle. Given the fact that different organs have different degrees of arterial pressure, consistent with the distance from the aorta and the anatomy of the vascular tree, registers of these waveforms vary according to the analyzed site [49], which explains the amplification of pulse pressure towards the peripheral vessels.
A sub-analysis of the MESA Study demonstrated that Pulse Pressure (PP), but not median arterial pressure, was associated with a higher incidence of AF, even when adjusting for left atrium diameter and left ventricle mass index. An association between arterial stiffness and new AF episode has also been seen, even when adjusting for hypertension. Elevated “pulsatile load” ‒ that translates into elevated arterial stiffness ‒ would lead to left atrium distension and consequently neurohormonal activation leading to an inflammatory response, contributing to the development of AF [50], as illustrated in Fig. 3.
Chen et al. showed that patients with isolated AF (under 60 years of age and no history of diabetes, hypertension, coronary artery disease, HF, cardiomyopathy, hyperthyroidism or valvopathies), had a higher CFPWV, suggesting that early structural and functional changes in the arteries could be implicated in the pathogenesis of AF in these individuals [52].
In a population of 4264 Japanese individuals, Cui et al. identified an association between arterial stiffness (analyzed with the Augmentation Index) and new episodes of AF [53]. In the follow-up of a cohort of hypertensive patients in France, Cremer et al. demonstrated that arterial stiffness (analyzed by the QKD index) was associated with the occurrence of AF [54]. Also in France, Lantelme et al. showed PWV was associated with increased left atrium diameter and higher levels of NT-pro-BNP [55].
Yoshida et al. demonstrated for the first time, in a cohort of 1156 individuals, that arterial stiffness has a negative impact on left atrium function, assessed through transthoracic echocardiogram strain. The identified associations were independent of left ventricle volume and function, as well as BNP levels [56].
In echocardiography, left atrium peak systolic strain has been studied mainly in AF, where it was shown to be a factor for prognosis [57,58]. Shaik et al. found that it was significantly lower in AF patients when compared to healthy individuals [57]. Moreover, in AF patients submitted to electrical cardioversion, left atrium peak systolic strain was superior in patients that remained in sinus rhythm in comparison to those that had a recurrence of AF [57].
Additionally, a meta-analysis by Ma et al., with 686 total patients, showed that patients with recurrent AF after catheter ablation had higher values of left atrium peak systolic strain when compared to those that did not present recurrence. Finally, Parwani et al. demonstrated that reduced left atrium peak systolic strain (< 10%) was the most important factor associated with AF recurrence [59]. Therefore, it is possible to infer a strong association between atrial strain and atrial arrhythmia burden on follow-up.
More recently, in a Korean cross-sectional study with 8048 individuals, Chung et al. found that an increased arterial stiffness (assessed by the Cardiothoracic Vascular Index ‒ CAVI) is significantly associated with a higher prevalence of AF among those classified as being at intermediate and high risk by the Framingham Score [60].
Table 2 summarizes the main observational studies that studied the association between atrial fibrillation and arterial stiffness.
Table 2.
Roetker et al [42]. | |
Prospective | Higher levels of systolic BP and PP, but not MAP or diastolic BP, were each individually associated with increased risk of AF after adjustment for all AF risk factors. |
Chen et al.[44] | |
Retrospective | After full adjustment, the odds ratios of AF were significantly higher per quartile increase in CFPWV and β index. |
Cui et al [45]. | |
Cross-Sectional | The prevalence of atrial fibrillation and total arrhythmia were higher with larger AI (Augmentation Index) values. |
Cremer et al [46]. | |
Prospective | Arterial stiffness (Assessed by QKDh) is a strong predictor of future atrial fibrillation in hypertensive patients, independently of age, 24-h pulse pressure and LAD. |
Lantelme et al [47]. | |
Cross-Sectional | PWV was associated with increased left atrium diameter and higher levels of NT-pro-BNP. |
Yoshida et al [48]. | |
Prospective | Arterial stiffness was independently associated with LA phasic function, even in the absence of overt cardiovascular disease, which may explain the higher incidence of atrial fibrillation in individuals with increased arterial stiffness. |
Chung et al [68]. | |
Cross-Sectional | High arterial stiffness (assessed by CAVI) shows a significant association with AF in those with intermediate or high cardiovascular risk (Framingham) and can be used for further risk stratification of patients. |
Genetic aspects of arterial stiffness and atrial fibrillation
Regarding hypertensive individuals in general, a recent study by Hyman et al. demonstrated, through Mendelian randomization, that genetic variants related to increased arterial pressure were associated with a higher risk of AF, consistent with a causal relationship. These data support the concept that to lowering the blood pressure through pharmacological intervention could reduce the risk for AF. In the same study, interestingly, this last association was only significant for variants related to beta-blockers and calcium channel blockers target proteins [61].
The difference in effect size may also be due to the pleiotropic effects of these particular anti-hypertensive medications, as β-receptor signaling and calcium handling have both been implicated in AF initiation and arrhythmogenesis independent of blood pressure [61].
In another mendelian randomization study that assessed polymorphisms associated with increased arterial stiffness, it was shown that a genetic predisposition for a higher arterial stiffness index was unidirectionally associated with an increase in incidence risk and prevalence of AF. These results are consistent with a causality association between arterial stiffness and AF [62].
A similar study by Georgipoulos et al. presented the same causality relation between hypertension and atrial fibrillation, in which a 1 mm. Hg increase in systolic blood pressure increased the relative risk of AF development by 1.8%. For diastolic blood pressure and pulse pressure, this increase was 2.6% and 1.4%, respectively [63].
These data support the hypothesis of causality between arterial stiffness, hypertension, and atrial arrhythmias.
Treatment and future perspectives
At this moment, there are no available drugs that directly promote arterial stiffness lowering. Nonetheless, most classes of anti-hypertensive drugs ‒ with most evidence for beta-blockers and diuretics, may be effective in reducing arterial stiffness. Among many patients with hypertension, an immediate decline in arterial stiffness may occur with anti-hypertensive therapy due to the reduction of the circumferential stress in the vessel.
In the long term, lower pressure levels allow for arterial wall remodeling, leading to lower stiffness. However, it cannot be assumed that anti-hypertensive therapy always improves arterial stiffness. The first randomized clinical trial to determine whether normalization of aortic stiffness improves cardiovascular outcomes, the SPARTE Trial, was recently published, showing no benefit in reducing cardiovascular events when guiding the treatment of hypertension by PWV when compared to the standard strategy by current guidelines, although there was a greater reduction in PWV in the group that guided the treatment by this parameter. It is important to emphasize that the work did not reach statistical power [64].
Many therapeutic strategies have been successful in animal models, including allopurinol and nitric oxide stimulants ‒ like nitrates, renin-angiotensin-aldosterone blockers ‒ such as angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, and aldosterone receptor blockers (spironolactone). Although commonly prescribed in clinical practice for the treatment of hypertension and HF, they are not approved specifically for the reduction of arterial stiffness [65,66].
Exercise has also been demonstrated to have a positive modulator effect over arterial stiffness. A cross-sectional study showed an inverse relationship between exercise and stiffness, even with low-intensity physical activity. On the other hand, a sedentary lifestyle was associated with higher systolic blood pressure and PWV [65].
Other proposed therapies include the use of Dipeptidyl-Peptidase 4 (DPP4) inhibitors [66,67] and Sodium-Glucose Cotransporter 2 (SGLT2) inhibitors. One study found that switching from DPP4 inhibitors to tofogliflozin improved arterial stiffness in diabetic patients [68]. In another study with animal models, dapagliflozin improved vascular function in mice with type 2 diabetes [69].
A knowledge gap that is still to be clarified is whether a reduction in arterial stiffness leads to a decrease in the burden of atrial arrhythmias, from frequent atrial ectopies to AF. Another knowledge gap is whether there is an association between arterial stiffness and stages considered to be pre-fibrillatory that, once identified, would help in the understanding of this process.
Conclusion
There is much evidence in the literature from different designs of observational studies indicating an association between arterial stiffness and atrial fibrillation. New studies exploring the association between arterial stiffness and pre-fibrillatory stages, and therefore, early stages of AF, would help corroborate the causality relationship between these two conditions.
Although much has been discovered since the first studies that related arterial stiffness to the progression of cardiovascular disease, the ability to clinically interrupt or revert the stiffness demands a much deeper understanding of the molecular, cellular and matrix interactions involved in this process.
Authors’ contributions
Lage JGB - Conceptualization, - Data curation, - Formal analysis, Resources AND Writing - review & editing. Bortolotto LA - Conceptualization, - Data curation. Bortolotto AL - Data curation, Writing review and editing. Scanavacca MI - Supervision, - Validation, - Visualization Darrieux FCC - Supervision, - Validation, - Visualization Anyway.
Declaration of Competing Interest
The authors declare no conflicts of interest.
References
- 1.Zoni-Berisso M, Lercari F, Carazza T, Domenicucci S. Epidemiology of atrial fibrillation: European perspective. Clin Epidemiol. 2014;6:213–220. doi: 10.2147/CLEP.S47385. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2.Zhou Z, Hu D. An epidemiological study on the prevalence of atrial fibrillation in the Chinese population of mainland China. J Epidemiol. 2008;18(5):209–216. doi: 10.2188/jea.JE2008021. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3.Go AS, Hylek EM, Phillips KA, Chang Y, Henault LE, Selby JV, et al. Prevalence of diagnosed atrial fibrillation in adults: national implications for rhythm management and stroke prevention: the AnTicoagulation and Risk Factors in Atrial Fibrillation (ATRIA) Study. JAMA. 2001;285(18):2370–2375. doi: 10.1001/jama.285.18.2370. [DOI] [PubMed] [Google Scholar]
- 4.Rahman F, Kwan GF, Benjamin EJ. Global epidemiology of atrial fibrillation. Nat Rev Cardiol. 2014;11(11):639–654. doi: 10.1038/nrcardio.2014.118. [DOI] [PubMed] [Google Scholar]
- 5.Marcus GM, Alonso A, Peralta CA, Lettre G, Vittinghoff E, Lubitz SA, et al. European ancestry as a risk factor for atrial fibrillation in African Americans. Circulation. 2010;122(20):2009–2015. doi: 10.1161/CIRCULATIONAHA.110.958306. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6.Chugh SS, Havmoeller R, Narayanan K, Singh D, Rienstra M, Benjamin EJ, et al. Worldwide epidemiology of atrial fibrillation: a Global Burden of Disease 2010 Study. Circulation. 2014;129(8):837–847. doi: 10.1161/CIRCULATIONAHA.113.005119. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7.Wong CX, Brown A, Tse HF, Albert CM, Kalman JM, Marwick TH, et al. Epidemiology of atrial fibrillation: the australian and asia-pacific perspective. Heart Lung Circ. 2017;26(9):870–879. doi: 10.1016/j.hlc.2017.05.120. [DOI] [PubMed] [Google Scholar]
- 8.Chamberlain AM, Agarwal SK, Ambrose M, Folsom AR, Soliman EZ, Alonso A. Metabolic syndrome and incidence of atrial fibrillation among blacks and whites in the Atherosclerosis Risk in Communities (ARIC) Study. Am Heart J. 2010;159(5):850–856. doi: 10.1016/j.ahj.2010.02.005. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9.Alonso A, Krijthe BP, Aspelund T, Stepas KA, Pencina MJ, Moser CB, et al. Simple risk model predicts incidence of atrial fibrillation in a racially and geographically diverse population: the CHARGE-AF consortium. J Am Heart Assoc. 2013;2(2) doi: 10.1161/JAHA.112.000102. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10.de Vos CB, Pisters R, Nieuwlaat R, Prins MH, Tieleman RG, Coelen RJ, et al. Progression from paroxysmal to persistent atrial fibrillation clinical correlates and prognosis. J Am Coll Cardiol. 2010;55(8):725–731. doi: 10.1016/j.jacc.2009.11.040. [DOI] [PubMed] [Google Scholar]
- 11.London GM, Safar ME, Weiss YA, Corvol PL, Lehner JP, Menard JM, et al. Volume-dependent parameters in essential hypertension. Kidney Int. 1977;11(3):204–208. doi: 10.1038/ki.1977.29. [DOI] [PubMed] [Google Scholar]
- 12.Caro CG, Pedley TJ, Schroter RC, Seed WA, Fung YC. The mechanics of the circulation. J Biomech Eng. 1980;102(2):161. doi: 10.1115/1.3138216. [DOI] [Google Scholar]
- 13.Nichols WW, O'Rourke MF, Vlachopoulos C, Hoeks AP, Reneman RS. McDonald's blood flow in arteries theoretical, experimental, and clinical principles. McDonald's Blood Flow Arter Sixth Ed Theor Exp Clin Princ. 2011:1–742. [Google Scholar]
- 14.Safar ME, Levy BI. Struijker-Boudier H. Current perspectives on arterial stiffness and pulse pressure in hypertension and cardiovascular diseases. Circulation. 2003;107(22):2864–2869. doi: 10.1161/01.CIR.0000069826.36125.B4. [DOI] [PubMed] [Google Scholar]
- 15.Lacolley P, Regnault V, Segers P, Laurent S. Vascular smooth muscle cells and arterial stiffening: relevance in development, aging, and disease. Physiol Rev. 2017;97(4):1555–1617. doi: 10.1152/physrev.00003.2017. [DOI] [PubMed] [Google Scholar]
- 16.Laurent S, Boutouyrie P. The structural factor of hypertension: large and small artery alterations. Circ Res. 2015;116(6):1007–1021. doi: 10.1161/CIRCRESAHA.116.303596. [DOI] [PubMed] [Google Scholar]
- 17.Stehouwer CD, Henry RM, Ferreira I. Arterial stiffness in diabetes and the metabolic syndrome: a pathway to cardiovascular disease. Diabetologia. 2008;51(4):527–539. doi: 10.1007/s00125-007-0918-3. [DOI] [PubMed] [Google Scholar]
- 18.Valbusa F, Bonapace S, Bertolini L, Zenari L, Arcaro G, Targher G. Increased pulse pressure independently predicts incident atrial fibrillation in patients with type 2 diabetes. Diabetes Care. 2012;35(11):2337–2339. doi: 10.2337/dc12-0314. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 19.Mendes-Pinto D, Rodrigues-Machado MDG. Applications of arterial stiffness markers in peripheral arterial disease. J Vasc Bras. 2019;18 doi: 10.1590/1677-5449.009318. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 20.Kim CW, Pokutta-Paskaleva A, Kumar S, Timmins LH, Morris AD, Kang DW, et al. Disturbed flow promotes arterial stiffening through thrombospondin-1. Circulation. 2017;136(13):1217–1232. doi: 10.1161/CIRCULATIONAHA.116.026361. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 21.Liu M, Gomez D. Smooth muscle cell phenotypic diversity. Arterioscler Thromb Vasc Biol. 2019;39(9):1715–1723. doi: 10.1161/ATVBAHA.119.312131. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 22.Kohn JC, Zhou DW, Bordeleau F, Zhou AL, Mason BN, Mitchell MJ, et al. Cooperative effects of matrix stiffness and fluid shear stress on endothelial cell behavior. Biophys J. 2015;108(3):471–478. doi: 10.1016/j.bpj.2014.12.023. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 23.Kapustin AN, Schoppet M, Schurgers LJ, Reynolds JL, McNair R, Heiss A, et al. Prothrombin loading of vascular smooth muscle cell-derived exosomes regulates coagulation and calcification. Arterioscler Thromb Vasc Biol. 2017;37(3):e22–e32. doi: 10.1161/ATVBAHA.116.308886. [DOI] [PubMed] [Google Scholar]
- 24.Goettsch C, Hutcheson JD, Aikawa M, Iwata H, Pham T, Nykjaer A, et al. Sortilin mediates vascular calcification via its recruitment into extracellular vesicles. J Clin Invest. 2016;126(4):1323–1336. doi: 10.1172/JCI80851. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 25.Tejero J, Shiva S, Gladwin MT. Sources of vascular nitric oxide and reactive oxygen species and their regulation. Physiol Rev. 2019;99(1):311–379. doi: 10.1152/physrev.00036.2017. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 26.Zekavat SM, Aragam K, Emdin C, Khera AV, Klarin D, Zhao H, et al. Genetic association of finger photoplethysmography-derived arterial stiffness index with blood pressure and coronary artery disease. Arterioscler Thromb Vasc Biol. 2019;39(6):1253–1261. doi: 10.1161/ATVBAHA.119.312626. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 27.Lyle AN, Raaz U. Killing me un-softly: causes and mechanisms of arterial stiffness. Arterioscler Thromb Vasc Biol. 2017;37(2):e1–e11. doi: 10.1161/ATVBAHA.116.308563. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 28.Paneni F, Diaz Cañestro C, Libby P, Lüscher TF, Camici GG. The aging cardiovascular system: understanding it at the cellular and clinical levels. J Am Coll Cardiol. 2017;69(15):1952–1967. doi: 10.1016/j.jacc.2017.01.064. [DOI] [PubMed] [Google Scholar]
- 29.Hill MA, Meininger GA. Small artery mechanobiology: Roles of cellular and non-cellular elements. Microcirculation. 2016;23(8):611–613. doi: 10.1111/micc.12323. [DOI] [PubMed] [Google Scholar]
- 30.Humphrey JD, Schwartz MA, Tellides G, Milewicz DM. Role of mechanotransduction in vascular biology: focus on thoracic aortic aneurysms and dissections. Circ Res. 2015;116(8):1448–1461. doi: 10.1161/CIRCRESAHA.114.304936. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 31.Raaz U, Toh R, Maegdefessel L, Adam M, Nakagami F, Emrich FC, et al. Hemodynamic regulation of reactive oxygen species: implications for vascular diseases. Antioxidants Redox Signal. 2014;20(6):914–928. doi: 10.1089/ars.2013.5507. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 32.Forrester SJ, Kikuchi DS, Hernandes MS, Xu Q, Griendling KK. Reactive oxygen species in metabolic and inflammatory signaling. Circ Res. 2018;122(6):877–902. doi: 10.1161/CIRCRESAHA.117.311401. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 33.Death AK, Fisher EJ, McGrath KC, Yue DK. High glucose alters matrix metalloproteinase expression in two key vascular cells: potential impact on atherosclerosis in diabetes. Atherosclerosis. 2003;168(2):263–269. doi: 10.1016/s0021-9150(03)00140-0. [DOI] [PubMed] [Google Scholar]
- 34.Lavrentyev EN, Estes AM, Malik KU. Mechanism of high glucose induced angiotensin II production in rat vascular smooth muscle cells. Circ Res. 2007;101(5):455–464. doi: 10.1161/CIRCRESAHA.107.151852. [DOI] [PubMed] [Google Scholar]
- 35.Bornfeldt K, Tabas I. Insulin resistance, hyperglycemia, and atherosclerosis. Cell Metab. 2011;14(5):575–585. doi: 10.1016/j.cmet.2011.07.015. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 36.Haydar AA, Covic A, Colhoun H, Rubens M, Goldsmith DJ. Coronary artery calcification and aortic pulse wave velocity in chronic kidney disease patients. Kidney Int. 2004;65(5):1790–1794. doi: 10.1111/j.1523-1755.2004.00581.x. [DOI] [PubMed] [Google Scholar]
- 37.Tyson KL, Reynolds JL, McNair R, Zhang Q, Weissberg PL, Shanahan CM. Osteo/chondrocytic transcription factors and their target genes exhibit distinct patterns of expression in human arterial calcification. Arterioscler Thromb Vasc Biol. 2003;23(3):489–494. doi: 10.1161/01.ATV.0000059406.92165.31. [DOI] [PubMed] [Google Scholar]
- 38.Schurgers LJ, Uitto J, Reutelingsperger CP. Vitamin K-dependent carboxylation of matrix Gla-protein: a crucial switch to control ectopic mineralization. Trends Mol Med. 2013;19(4):217–226. doi: 10.1016/j.molmed.2012.12.008. [DOI] [PubMed] [Google Scholar]
- 39.Pivin E, Ponte B, Pruijm M, Ackermann D, Guessous I, Ehret G, et al. Inactive matrix gla-protein is associated with arterial stiffness in an adult population-based study. Hypertension. 2015;66(1):85–92. doi: 10.1161/HYPERTENSIONAHA.115.05177. [DOI] [PubMed] [Google Scholar]
- 40.Mayer O, Jr, Seidlerová J, Wohlfahrt P, Filipovský J, Vaněk J, Cífková R, et al. Desphospho-uncarboxylated matrix Gla protein is associated with increased aortic stiffness in a general population. J Hum Hypertens. 2016;30(7):418–423. doi: 10.1038/jhh.2015.55. [DOI] [PubMed] [Google Scholar]
- 41.Sardana M, Vasim I, Varakantam S, Kewan U, Tariq A, Koppula MR, et al. Inactive matrix gla-protein and arterial stiffness in type 2 diabetes mellitus. Am J Hypertens. 2017;30(2):196–201. doi: 10.1093/ajh/hpw146. [DOI] [PubMed] [Google Scholar]
- 42.Chirinos JA, Sardana M, Syed AA, Koppula MR, Varakantam S, Vasim I, et al. Aldosterone, inactive matrix gla-protein, and large artery stiffness in hypertension. J Am Soc Hypertens. 2018;12(9):681–689. doi: 10.1016/j.jash.2018.06.018. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 43.Puzantian H, Akers SR, Oldland G, Javaid K, Miller R, Ge Y, et al. Circulating dephospho-uncarboxylated matrix gla-protein is associated with kidney dysfunction and arterial stiffness. Am J Hypertens. 2018;31(9):988–994. doi: 10.1093/ajh/hpy079. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 44.Hashmath Z, Lee J, Gaddam S, Ansari B, Oldland G, Javaid K, et al. Vitamin K status, warfarin use, and arterial stiffness in heart failure. Hypertension. 2019;73(2):364–370. doi: 10.1161/HYPERTENSIONAHA.118.12157. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 45.Knapen MH, Braam LA, Drummen NE, Bekers O, Hoeks AP, Vermeer C. Menaquinone-7 supplementation improves arterial stiffness in healthy postmenopausal women: A double-blind randomised clinical trial. Thromb Haemost. 2015;113(5):1135–1144. doi: 10.1160/TH14-08-0675. [DOI] [PubMed] [Google Scholar]
- 46.Wagenseil JE, Mecham RP. Vascular extracellular matrix and arterial mechanics. Physiol Rev. 2009;89(3):957–989. doi: 10.1152/physrev.00041.2008. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 47.Olsen MH, Angell SY, Asma S, Boutouyrie P, Burger D, Chirinos JA, et al. A call to action and a lifecourse strategy to address the global burden of raised blood pressure on current and future generations: the Lancet Commission on hypertension. Lancet. 2016;388(10060):2665–2712. doi: 10.1016/S0140-6736(16)31134-5. [DOI] [PubMed] [Google Scholar]
- 48.Cruickshank JK, Silva MJ, Molaodi OR, Enayat ZE, Cassidy A, Karamanos A, et al. Ethnic differences in and childhood influences on early adult pulse wave velocity: the determinants of adolescent, now young adult, social wellbeing, and health longitudinal study. Hypertension. 2016;67(6):1133–1141. doi: 10.1161/HYPERTENSIONAHA.115.07079. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 49.Belz GG. Elastic properties and Windkessel function of the human aorta. Cardiovasc Drugs Ther. 1995;9(1):73–83. doi: 10.1007/BF00877747. [DOI] [PubMed] [Google Scholar]
- 50.Roetker NS, Chen LY, Heckbert SR, Nazarian S, Soliman EZ, Bluemke DA, et al. Relation of systolic, diastolic, and pulse pressures and aortic distensibility with atrial fibrillation (from the Multi-Ethnic Study of Atherosclerosis) Am J Cardiol. 2014;114(4):587–592. doi: 10.1016/j.amjcard.2014.05.041. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 51.Gumprecht J, Domek M, Lip GYH, Shantsila A. Invited review: hypertension and atrial fibrillation: epidemiology, pathophysiology, and implications for management. J Hum Hypertens. 2019;33(12):824–836. doi: 10.1038/s41371-019-0279-7. [DOI] [PubMed] [Google Scholar]
- 52.Chen LY, Foo DC, Wong RC, Seow SC, Gong L, Benditt DG, et al. Increased carotid intima-media thickness and arterial stiffness are associated with lone atrial fibrillation. Int J Cardiol. 2013;168(3):3132–3134. doi: 10.1016/j.ijcard.2013.04.034. [DOI] [PubMed] [Google Scholar]
- 53.Cui R, Yamagishi K, Muraki I, Hayama-Terada M, Umesawa M, Imano H, et al. Association between markers of arterial stiffness and atrial fibrillation in the Circulatory Risk in Communities Study (CIRCS) Atherosclerosis. 2017;263:244–248. doi: 10.1016/j.atherosclerosis.2017.06.918. [DOI] [PubMed] [Google Scholar]
- 54.Cremer A, Lainé M, Papaioannou G, Yeim S, Gosse P. Increased arterial stiffness is an independent predictor of atrial fibrillation in hypertensive patients. J Hypertens. 2015;33(10):2150–2155. doi: 10.1097/HJH.0000000000000652. [DOI] [PubMed] [Google Scholar]
- 55.Lantelme P, Laurent S, Besnard C, Bricca G, Vincent M, Legedz L, et al. Arterial stiffness is associated with left atrial size in hypertensive patients. Arch Cardiovasc Dis. 2008;101(1):35–40. doi: 10.1016/s1875-2136(08)70253-5. [DOI] [PubMed] [Google Scholar]
- 56.Yoshida Y, Nakanishi K, Daimon M, Ishiwata J, Sawada N, Hirokawa M, et al. Association of arterial stiffness with left atrial structure and phasic function: a community-based cohort study. J Hypertens. 2020;38(6):1140–1148. doi: 10.1097/HJH.0000000000002367. [DOI] [PubMed] [Google Scholar]
- 57.Shaikh AY, Maan A, Khan UA, Aurigemma GP, Hill JC, Kane JL, et al. Speckle echocardiographic left atrial strain and stiffness index as predictors of maintenance of sinus rhythm after cardioversion for atrial fibrillation: a prospective study. Cardiovasc Ultrasound. 2012;10:48. doi: 10.1186/1476-7120-10-48. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 58.Ma XX, Boldt LH, Zhang YL, Zhu MR, Hu B, Parwani A, et al. Clinical relevance of left atrial strain to predict recurrence of atrial fibrillation after catheter ablation: a meta-analysis. Echocardiography. 2016;33(5):724–733. doi: 10.1111/echo.13184. [DOI] [PubMed] [Google Scholar]
- 59.Parwani AS, Morris DA, Blaschke F, Huemer M, Pieske B, Haverkamp W, et al. Left atrial strain predicts recurrence of atrial arrhythmias after catheter ablation of persistent atrial fibrillation. Open Hear. 2017;4(1) doi: 10.1136/openhrt-2016-000572. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 60.Chung GE, Park HE, Lee H, Choi SY. Clinical significance of increased arterial stiffness associated with atrial fibrillation, according to Framingham risk score. Sci Rep. 2021;11(1):4955. doi: 10.1038/s41598-021-84311-9. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 61.Hyman MC, Levin MG, Gill D, Walker VM, Georgakis MK, Davies NM, et al. Genetically predicted blood pressure and risk of atrial fibrillation. Hypertension. 2021;77(2):376–382. doi: 10.1161/HYPERTENSIONAHA.120.16191. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 62.Zekavat SM, Roselli C, Hindy G, Lubitz SA, Ellinor PT, Zhao H, et al. Genetic link between arterial stiffness and atrial fibrillation. Circ Genom Precis Med. 2019;12(6) doi: 10.1161/CIRCGEN.118.002453. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 63.Georgiopoulos G, Ntritsos G, Stamatelopoulos K, Tsioufis C, Aimo A, Masi S, et al. The relationship between blood pressure and risk of atrial fibrillation: a Mendelian randomization study. Eur J Prev Cardiol. 2021:zwab005. doi: 10.1093/eurjpc/zwab005. [DOI] [PubMed] [Google Scholar]
- 64.Laurent S, Chatellier G, Azizi M, Calvet D, Choukroun G, Danchin N, et al. SPARTE Study: normalization of arterial stiffness and cardiovascular events in patients with hypertension at medium to very high risk. Hypertension. 2021;78(4):983–995. doi: 10.1161/HYPERTENSIONAHA.121.17579. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 65.O'Donovan C, Lithander FE, Raftery T, Gormley J, Mahmud A, Hussey J. Inverse relationship between physical activity and arterial stiffness in adults with hypertension. J Phys Act Health. 2014;11(2):272–277. doi: 10.1123/jpah.2012-0075. [DOI] [PubMed] [Google Scholar]
- 66.Tahara N, Yamagishi SI, Bekki M, Kodama N, Nakamura T, Sugiyama Y, et al. Anagliptin, a dipeptidyl peptidase-4 inhibitor ameliorates arterial stiffness in association with reduction of remnant-like particle cholesterol and alanine transaminase levels in type 2 diabetic patients. Curr Vasc Pharmacol. 2016;14(6):552–562. doi: 10.2174/1570161114666160625090212. [DOI] [PubMed] [Google Scholar]
- 67.Duvnjak L, Blaslov K. Dipeptidyl peptidase-4 inhibitors improve arterial stiffness, blood pressure, lipid profile and inflammation parameters in patients with type 2 diabetes mellitus. Diabetol Metab Syndr. 2016;8:26. doi: 10.1186/s13098-016-0144-6. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 68.Bekki M, Tahara N, Tahara A, Igata S, Honda A, Sugiyama Y, et al. Switching dipeptidyl peptidase-4 inhibitors to tofogliflozin, a selective inhibitor of sodium-glucose cotransporter 2 improve arterial stiffness evaluated by cardio-ankle vascular index in patients with type 2 diabetes: a pilot study. Curr Vasc Pharmacol. 2019;17(4):411–420. doi: 10.2174/1570161116666180515154555. [DOI] [PubMed] [Google Scholar]
- 69.Lee DM, Battson ML, Jarrell DK, Hou S, Ecton KE, Weir TL, et al. SGLT2 inhibition via dapagliflozin improves generalized vascular dysfunction and alters the gut microbiota in type 2 diabetic mice. Cardiovasc Diabetol. 2018;17(1):62. doi: 10.1186/s12933-018-0708-x. [DOI] [PMC free article] [PubMed] [Google Scholar]