Current Vascular Pharmacology - Volume 19, Issue 1, 2021

Background: Among patients with end-stage kidney disease (ESKD), arterial stiffness is considered as a powerful predictor of cardiovascular (CV) morbidity and mortality. However, the relevance of aortic pulse wave velocity (PWV) as a prognostic biomarker for CV risk estimation is not yet fully clear. Methods: We performed a systematic search of Medline/PubMed database from inception through August 21, 2019 to identify observational cohort studies conducted in ESKD patients and exploring the association of PWV with CV events and mortality. Results: Whereas “historical” cohort studies showed aortic PWV to be associated with higher risk of CV and all-cause mortality, recent studies failed to reproduce the independent predictive value of aortic PWV in older ESKD patients. Studies using state-of-the-art prognostic tests showed that the addition of aortic PWV to standard clinical risk scores could only modestly improve CV risk reclassification. Studies associating improvement in PWV in response to blood pressure (BP)-lowering with improvement in survival cannot demonstrate direct cause-and-effect associations due to their observational design and absence of accurate methodology to assess the BP burden. Conclusion: Despite the strong pathophysiological relevance of arterial stiffness as a mediator of CV disease in ESKD, the assessment of aortic PWV for CV risk stratification in this population appears to be of limited value. Whether aortic PWV assessment is valuable in guiding CV risk factor management and whether such a therapeutic approach is translated into improvement in clinical outcomes, is an issue of clinical relevance that warrants investigation in properly-designed randomized trials.

Background: Blood pressure (BP)-lowering with the use of antihypertensive drugs appears to protect the cardiovascular (CV) system in hemodialysis patients. However, the optimal treatment algorithm of hypertension remains elusive; extrapolation of clinical-trial evidence from the general population may not be optimal. Methods: For this narrative review, we searched the Medline/PubMed database (inception to August 01, 2019) to identify randomized clinical trials evaluating the efficacy of antihypertensive drugs on CV outcomes and mortality in patients on hemodialysis. Results: Randomized trials with angiotensin-converting-enzyme-inhibitors (ACEIs) or angiotensinreceptor- blockers (ARBs) failed to provide consistent cardioprotection. β-blockers may provide a more consistent CV benefit. Although some early clinical trials have shown that mineralocorticoid-receptorantagonists (MRAs) reduce CV mortality, the associated risk of hyperkalemia raises important safety concerns on the use of MRAs as add-on therapy. Conclusion: Our first-line therapy of hypertension in hemodialysis is the assessment and management of dry-weight and optimization of dialysis prescription. Based on the available clinical-trial evidence, we prescribe atenolol 3 times/week after dialysis as the first-line pharmacological option of hypertension to our patients without specific indications for other agents. Long-acting dihydropyridines and ACEIs/ARBs are our second-line and third-line choices, respectively. We avoid using MRAs and await results from ongoing trials testing their safety and efficacy. In patients receiving maintenance hemodialysis, randomized trials are clearly warranted in order to define BP targets and the comparative effectiveness of different antihypertensive drugs.

Hemodialysis (HD) remains the most utilized treatment for End-Stage Kidney Disease (ESKD) globally, mainly as conventional HD administered in 4 h sessions thrice weekly. Despite advances in HD delivery, patients with ESKD carry a heavy cardiovascular morbidity and mortality burden. This is associated with cardiac remodeling, left ventricular hypertrophy (LVH), myocardial stunning, hypertension, decreased heart rate variability, sleep apnea, coronary calcification and endothelial dysfunction. Therefore, intensive HD regimens closer to renal physiology were developed. They include longer, more frequent dialysis or both. Among them, Nocturnal Hemodialysis (NHD), carried out at night while asleep, provides efficient dialysis without excessive interference with daily activities. This regimen is closer to the physiology of the native kidneys. By providing increased clearance of small and middle molecular weight molecules, NHD can ameliorate uremic symptoms, control hyperphosphatemia and improve quality of life by allowing a liberal diet and free time during the day. Lastly, it improves reproductive biology leading to successful pregnancies. Conversion from conventional to NHD is followed by improved blood pressure control with fewer medications, regression of LVH, improved LV function, improved sleep apnea, and stabilization of coronary calcifications. These beneficial effects have been associated, among others, with better extracellular fluid volume control, improved endothelial- dependent vasodilation, decreased total peripheral resistance, decreased plasma norepinephrine levels and restoration of heart rate variability. Some of these effects represent improvements in outcomes used as surrogates of hard outcomes related to cardiovascular morbidity and mortality. In this review, we consider the cardiovascular effects of NHD.

Volume overload is the most common complication in end-stage renal disease (ESRD) patients, being directly related to numerous complications including resistant hypertension, cardiac hypertrophy, congestive heart failure or arterial stiffness, among others. Therefore, volume overload is now considered an important risk factor for hard outcomes, like all-cause or cardiovascular mortality. Relying solely on clinical examination for assessing volume overload in ESRD patients lacks sensitivity and specificity. Numerous efforts have been made to identify new methods that could objectively assess volume status; however, each of them has important limitations. This review aims to discuss the most frequently used methods (biomarkers, inferior vena cava assessment, lung ultrasonography, bioimpedance analysis and blood volume monitoring) and to compare the advantage of each method vs. the overall/ clinical strategy.

In end-stage renal disease patients, the leading causes of mortality are of cardiovascular (CV) origin. The underlying mechanisms are complex, given that sudden heart failure is more common than acute myocardial infarction. A contributing role of oxidative stress is postulated, which is increased even at early stages of chronic kidney disease, is gradually augmented in parallel to progression to endstage renal disease and is further accelerated by renal replacement therapy. Oxidative stress ensues when there is an imbalance between reactive pro-oxidants and physiologically occurring electron donating antioxidant defence systems. During the last decade, a close association of oxidative stress with accelerated atherosclerosis and increased risk for CV and all-cause mortality has been established. Lipid peroxidation has been identified as a trigger for endothelial dysfunction, the first step towards atherogenesis. In order to counteract the deleterious effects of free radicals and thereby ameliorate, or delay, CV disease, exogenous administration of antioxidants has been proposed. Here, we attempt to summarize existing data from studies that test antioxidants for CV protection, such as vitamins E and C, statins, omega-3 fatty acids and N-acetylcysteine.

Alterations of fibroblast growth factor 23 (FGF-23) and Klotho levels are considered to be the earliest biochemical abnormality of chronic kidney disease – mineral and bone disease (CKDMBD) syndrome. Moreover, emerging data suggests that the dysregulated FGF-23 and Klotho axis has many effects on the cardiovascular (CV) system and contributes significantly to the increased CV morbidity and mortality rates of CKD patients. This review examines recent evidence on the role of FGF-23 and Klotho in the development and progression of CV complications of uremia namely cardiac hypertrophy, uremic cardiomyopathy, and atherosclerotic and arteriosclerotic vascular lesions. Moreover, the available evidence on their associations with adverse clinical outcomes are summarized. Undoubtedly, more studies are needed to further elucidate the effects of FGF-23 and Klotho on the heart and vessels and to gain insights into their prognostic value as CV risk factors. Finally, large prospective studies are required to test the hypothesis that modification of their levels would have a favourable impact on the unacceptably high mortality rates of these patient populations.

Adverse innate immune responses have been implicated in several disease processes, including cardiovascular disease (CVD) and chronic kidney disease (CKD). The monocyte subsets natural killer (NK) cells and natural killer T (NKT) cells are involved in innate immunity. Monocytes subsets are key in atherogenesis and the inflammatory cascade occurring in heart failure. Upregulated activity and counts of proinflammatory CD16+ monocyte subsets are associated with clinical indices of atherosclerosis, heart failure syndromes and CKD. Advanced CKD is a complex state of persistent systemic inflammation characterized by elevated expression of proinflammatory and pro-atherogenic CD14++CD16+ monocytes, which are associated with cardiovascular events and death both in the general population and among patients with CKD. Diminished NK cells and NKT cells counts and aberrant activity are observed in both coronary artery disease and end-stage kidney disease. However, evidence of the roles of NK cells and NKT cells in atherogenesis in advanced CKD is circumstantial and remains to be clarified. This review describes the available evidence regarding the roles of specific immune cell subsets in the pathogenesis of CVD in patients with CKD. Future research is expected to further uncover the links between CKD associated innate immune system dysregulation and accelerated CVD and will ideally be translated into therapeutic targets.

In Chronic Kidney Disease, vascular calcification (VC) is highly prevalent even at early stages and is gradually enhanced, along with disease progression to End-Stage Renal Disease (ESRD). The calcification pattern in uremia includes all types of mineralization and contributes to the heavy cardiovascular (CV) burden that is common in these patients. Ectopic mineralization is the result of the imbalance between inhibitors and promoters of vascular calcification, with the latter overwhelming the former. The most powerful, natural inhibitor of calcification is Matrix Gla Protein (MGP), a small vitamin K dependent protein, secreted by chondrocytes and vascular smooth muscle cells. In uremia, MGP was reported as the only molecule able to reverse VC by “sweeping” calcium and hydroxyapatite crystals away from the arterial wall. To become biologically active, this protein needs to undergo carboxylation and phosphorylation, reactions highly dependent on vitamin K status. The inactive form of MGP reflects the deficiency of vitamin K and has been associated with CV events and mortality in ESRD patients. During the past decade, vitamin K status has emerged as a novel risk factor for vascular calcification and CV disease in various populations, including dialysis patients. This review presents evidence regarding the association between vitamin K and CV disease in ESRD patients, which are prone to atherosclerosis and atheromatosis.

Background: The research on the association between the relative glycemic level postpercutaneous coronary intervention (PCI) and adverse prognosis in non-ST-segment elevation acute coronary syndrome (NSTE-ACS) patients is relatively inadequate. Objective: The study aimed to identify whether the glycemic level post-PCI predicts adverse prognosis in NSTE-ACS patients. Methods: Patients (n=2465) admitted with NSTE-ACS who underwent PCI were enrolled. The relative glycemic level post-procedure was calculated as blood glucose level post-PCI divided by HbA1c level, which was named post-procedural glycemic index (PGI). The primary observational outcome of this study was major adverse cardiovascular events (MACE) [defined as a composite of all-cause death, non-fatal myocardial infarction (MI) and any revascularization]. Results: The association between PGI and MACE rate is presented as a U-shape curve. Higher PGIs [hazard ratio (HR): 1.669 (95% confidence interval (CI): 1.244-2.238) for the third quartile (Q3) and 2.076 (1.566-2.753) for the fourth quartile (Q4), p<;0.001], adjusted for confounding factors, were considered to be one of the independent predictors of MACE. The association between the PGI and the risk of MACE was more prominent in the non-diabetic population [HR (95%CI) of 2.356 (1.456-3.812) for Q3 and 3.628 (2.265-5.812) for Q4, p<0.001]. There were no significant differences in MACE risk between PGI groups in the diabetic population. Conclusion: Higher PGI was a significant and independent predictor of MACE in NSTE-ACS patients treated with PCI. The prognostic effect of the PGI is more remarkable in subsets without pre-existing diabetes than in the overall population. The predictive value of PGI was not identified in the subgroup with diabetes.

Background: The rising prevalence of type 2 diabetes mellitus (T2DM) with the huge burden of diabetic foot amputation is a challenge to the health economy of Pakistan and other countries. Identification of various risk factors for amputation, along with its financial burden, is needed to address this problem. Objectives: This study aimed to determine the financial burden and risk factors associated with T2DMrelated foot amputation. Methods: Retrospective hospital-based study from January 2017 to December 2018. Patients with T2DM with and without amputation were enrolled. The direct medical costs of amputation along with various risk factors, were determined. Risk factors were evaluated by logistic regression analysis. Results: A total of 1460 patients with T2DM were included; 484 (33%) patients had an amputation. The mean total cost of below knee, fingers and toe amputation was 886.63±23.91, 263.35 ±19.58 and 166.68 ± 8.47 US$, respectively. This difference among groups was significant (p<0.0001). Male gender (odds ratio, OR: 1.29, 1.01-1.63, p=0.037), peripheral artery disease (OR: 1.93, 1.52-2.46, p=0.000), peripheral neuropathy (OR: 1.31, 1.40-1.63, p=0.000), prior diabetic foot ulcer (OR: 2.02, 1.56- 2.56, p=0.000) and raised glycated haemoglobin (HbA1c) (OR: 3.50, 2.75-4.4, p=0.000) were risk factors for amputation. Conclusion: The health-related financial impact of amputations is high. Peripheral artery disease, peripheral neuropathy, prior diabetic foot ulcer and raised HbA1c were risk factors for amputation.