Abstract-Arterial stiffness is a growing epidemic associated with increased risk of cardiovascular events, dementia, and death. Decreased compliance of the central vasculature alters arterial pressure and flow dynamics and impacts cardiac performance and coronary perfusion. This article reviews the structural, cellular, and genetic contributors to arterial stiffness, including the roles of the scaffolding proteins, extracellular matrix, inflammatory molecules, endothelial cell function, and reactive oxidant species. Additional influences of atherosclerosis, glucose regulation, chronic renal disease, salt, and changes in neurohormonal regulation are discussed. A review of the hemodynamic impact of arterial stiffness follows. A number of lifestyle changes and therapies that reduce arterial stiffness are presented, including weight loss, exercise, salt reduction, alcohol consumption, and neuroendocrine-directed therapies, such as those targeting the renin-angiotensin aldosterone system, natriuretic peptides, insulin modulators, as well as novel therapies that target advanced glycation end products. Key Words: arterial stiffness Ⅲ isolated systolic hypertension Ⅲ mechanisms Ⅲ therapeutics Ⅲ pathophysiology I ncreased central arterial stiffening is a hallmark of the aging process and the consequence of many disease states such as diabetes, atherosclerosis, and chronic renal compromise. Accordingly, there is a marked increase in the incidence and prevalence of clinical surrogate markers of vascular stiffness, such as pulse pressure and isolated systolic hypertension, with age and these associated conditions. [1][2][3][4][5][6] Arterial stiffening is also a marker for increased cardiovascular disease risk, including myocardial infarction, heart failure, and total mortality, as well as stroke, dementia, and renal disease. [7][8][9][10][11][12][13][14] This has been recently reviewed by Safar et al. 15 By altering the resting and stress-induced hemodynamics and energy expenditure, vascular stiffness not only contributes to these clinical repercussions and lowers the threshold for their symptoms but also likely contributes to more dyspnea with exertion and orthostatic hypotension in older adults. Although the structural and cellular changes that underlie arterial stiffness may predispose the vasculature to further insult by atherosclerotic disease, the mechanisms explaining this link are still undergoing investigation. Wang and Fitch provide a recent summary of the putative relationship between arterial stiffness and atherosclerosis. 16 Earlier work on arterial properties focused on fluid mechanics and the impact of hemodynamic and reflective wave properties on the development of arterial stiffness and the arterial waveforms. 17,18 The development of methods to measure and assess specific aspects of arterial stiffness, as recently reviewed by Oliver and Webb,19 greatly facilitated understanding of its role in cardiovascular disease. Here, we build on this earlier review to discuss more recent theories on the mechanisms co...

Making a firm diagnosis of chronic heart failure with preserved ejection fraction (HFpEF) remains a challenge. We recommend a new stepwise diagnostic process, the ‘HFA–PEFF diagnostic algorithm’. Step 1 (P=Pre-test assessment) is typically performed in the ambulatory setting and includes assessment for HF symptoms and signs, typical clinical demographics (obesity, hypertension, diabetes mellitus, elderly, atrial fibrillation), and diagnostic laboratory tests, electrocardiogram, and echocardiography. In the absence of overt non-cardiac causes of breathlessness, HFpEF can be suspected if there is a normal left ventricular ejection fraction, no significant heart valve disease or cardiac ischaemia, and at least one typical risk factor. Elevated natriuretic peptides support, but normal levels do not exclude a diagnosis of HFpEF. The second step (E: Echocardiography and Natriuretic Peptide Score) requires comprehensive echocardiography and is typically performed by a cardiologist. Measures include mitral annular early diastolic velocity (e′), left ventricular (LV) filling pressure estimated using E/e′, left atrial volume index, LV mass index, LV relative wall thickness, tricuspid regurgitation velocity, LV global longitudinal systolic strain, and serum natriuretic peptide levels. Major (2 points) and Minor (1 point) criteria were defined from these measures. A score ≥5 points implies definite HFpEF; ≤1 point makes HFpEF unlikely. An intermediate score (2–4 points) implies diagnostic uncertainty, in which case Step 3 (F1: Functional testing) is recommended with echocardiographic or invasive haemodynamic exercise stress tests. Step 4 (F2: Final aetiology) is recommended to establish a possible specific cause of HFpEF or alternative explanations. Further research is needed for a better classification of HFpEF.

Background Heart failure (HF) with preserved ejection fraction (HFpEF) is a heterogeneous syndrome. Phenotyping patients into pathophysiologically homogenous groups may enable better targeting of treatment. Obesity is common in HFpEF and has many cardiovascular effects, suggesting it may be a viable candidate for phenotyping. We compared cardiovascular structure, function, and reserve capacity in subjects with obese HFpEF, non-obese HFpEF, and controls. Methods Subjects with obese HFpEF (BMI≥35kg/m2, n=99), non-obese HFpEF (BMI<30kg/m2, n=96), and non-obese controls free of HF (n=71) underwent detailed clinical assessment, echocardiography and invasive hemodynamic exercise testing. Results Compared to both non-obese HFpEF and controls, subjects with obese HFpEF displayed increased plasma volume (3907 [3563,4333] vs. 2772 [2555,3133] and 2680 [2380,3006] ml, p<0.0001), more concentric left ventricular remodeling, greater right ventricular dilatation (base 34±7 vs. 31±6 and 30±6 mm, p=0.0005; length 66±7 vs. 61±7 and 61±7 mm, p<0.0001), more right ventricular dysfunction, increased epicardial fat thickness (10±2 vs. 7±2 and 6±2 mm, p<0.0001), and greater total epicardial heart volume (945 [831,1105] vs. 797 [643,979] and 632 [517,768] ml, p<0.0001), despite lower NT-proBNP levels. Pulmonary capillary wedge pressure was correlated with body mass and plasma volume in obese HFpEF (r=0.22 and 0.27, both p<0.05), but not in non-obese HFpEF (p≥0.3). The increase in heart volumes in obese HFpEF was associated with greater pericardial restraint and heightened ventricular interdependence, reflected by increased ratio of right to left heart filling pressures (0.64±0.17 vs. 0.56±0.19 and 0.53±0.20, p=0.0004), higher pulmonary venous pressure relative to left ventricular transmural pressure, and greater left ventricular eccentricity index (1.10±0.19 vs 0.99±0.06 and 0.97±0.12, p<0.0001). Interdependence was enhanced as pulmonary artery pressure load increased (interaction p<0.05). As compared to non-obese HFpEF and controls, obese HFpEF subjects displayed worse exercise capacity (peak oxygen consumption 7.7±2.3 vs. 10.0±3.4 and12.9±4.0 ml/min*kg, p<0.0001), higher biventricular filling pressures with exercise and depressed pulmonary artery vasodilator reserve. Conclusions Obesity-related HFpEF is a genuine form of cardiac failure and a clinically relevant phenotype that may require specific treatments.

Making a firm diagnosis of chronic heart failure with preserved ejection fraction (HFpEF) remains a challenge. We recommend a new stepwise diagnostic process, the ‘HFA–PEFF diagnostic algorithm’. Step 1 (P=Pre‐test assessment) is typically performed in the ambulatory setting and includes assessment for heart failure symptoms and signs, typical clinical demographics (obesity, hypertension, diabetes mellitus, elderly, atrial fibrillation), and diagnostic laboratory tests, electrocardiogram, and echocardiography. In the absence of overt non‐cardiac causes of breathlessness, HFpEF can be suspected if there is a normal left ventricular (LV) ejection fraction, no significant heart valve disease or cardiac ischaemia, and at least one typical risk factor. Elevated natriuretic peptides support, but normal levels do not exclude a diagnosis of HFpEF. The second step (E: Echocardiography and Natriuretic Peptide Score) requires comprehensive echocardiography and is typically performed by a cardiologist. Measures include mitral annular early diastolic velocity (e′), LV filling pressure estimated using E/e′, left atrial volume index, LV mass index, LV relative wall thickness, tricuspid regurgitation velocity, LV global longitudinal systolic strain, and serum natriuretic peptide levels. Major (2 points) and Minor (1 point) criteria were defined from these measures. A score ≥5 points implies definite HFpEF; ≤1 point makes HFpEF unlikely. An intermediate score (2–4 points) implies diagnostic uncertainty, in which case Step 3 (F1: Functional testing) is recommended with echocardiographic or invasive haemodynamic exercise stress tests. Step 4 (F2: Final aetiology) is recommended to establish a possible specific cause of HFpEF or alternative explanations. Further research is needed for a better classification of HFpEF.