Cardiovascular disease in Alpha 1 antitrypsin deficiency: an observational study assessing the role of neutrophil proteinase activity and the suitability of validated screening tools.

BACKGROUND: Alpha 1 Antitrypsin Deficiency (AATD) is a rare, inherited lung disease which shares features with Chronic Obstructive Pulmonary Disease (COPD) but has a greater burden of proteinase related tissue damage. These proteinases are associated with cardiovascular disease (CVD) in the general population. It is unclear whether patients with AATD have a greater risk of CVD compared to usual COPD, how best to screen for this, and whether neutrophil proteinases are implicated in AATD-associated CVD. This study had three aims. To compare CVD risk in never-augmented AATD patients to non-AATD COPD and healthy controls (HC). To assess relationships between CVD risk and lung physiology. To determine if neutrophil proteinase activity was associated with CVD risk in AATD. Cardiovascular risk was assessed by QRISK2® score and aortic stiffness measurements using carotid-femoral (aortic) pulse wave velocity (aPWV). Medical history, computed tomography scans and post-bronchodilator lung function parameters were reviewed. Systemic proteinase 3 activity was measured. Patients were followed for 4 years, to assess CVD development. RESULTS: 228 patients with AATD, 50 with non-AATD COPD and 51 healthy controls were recruited. In all COPD and HC participants, QRISK2® and aPWV gave concordant results (with both measures either high or in the normal range). This was not the case in AATD. Once aPWV was adjusted for age and smoking history, aPWV was highest and QRISK2® lowest in AATD patients compared to the COPD or HC participants. Higher aPWV was associated with impairments in lung physiology, the presence of emphysema on CT scan and proteinase 3 activity following adjustment for age, smoking status and traditional CVD risk factors (using QRISK2® scores) in AATD. There were no such relationships with QRISK2® in AATD. AATD patients with confirmed CVD at four-year follow up had a higher aPWV but not QRISK2® at baseline assessment. CONCLUSION: aPWV measured CVD risk is elevated in AATD. This risk is not captured by QRISK2®. There is a relationship between aPWV, lung disease and proteinase-3 activity. Proteinase-driven breakdown of elastin fibres in large arteries and lungs is a putative mechanism and forms a potential therapeutic target for CVD in AATD.

Non-albumin proteinuria marks tubular involvement and is associated with arterial stiffness in subjects affected by severe obesity.

INTRODUCTION: Obesity is a well-established risk factor for kidney disease, and tubular damage can play a pivotal role in the development of obesity-related kidney damage. This study aimed to investigate the pathophysiological pathways involved in the development of non-albumin proteinuria (NAP), a marker of tubular involvement, in a cohort of subjects with severe obesity and preserved kidney function. METHODS: A total of 106 subjects with BMI ≥ 35 kg/m2 in waiting list for bariatric surgery underwent blood chemistry analysis including metabolic and lipid profile, vascular tests for cardiovascular risk stratification and a comprehensive assessment of kidney function, including renal resistive index (RRI) and NAP measurement. RESULTS: Nineteen patients with ACR ≥ 30 mg/g regardless of NAP values (ALB+), nineteen with NAP≥ 150 mg/g and albuminuria < 30 mg/g (iNAP) and sixty-eight without proteinuria (No-P) were found. Both ALB+ and iNAP groups exhibited a higher prevalence of hypertension and anti-hypertensive treatment compared to No-P, while the prevalence of diabetes was similar between groups. Concerning lipid profile, no differences in total, HDL and LDL cholesterol were found, while ALB+ patients had higher serum triglyceride levels than the other two groups. RRI and carotid-femoral pulse wave velocity (cf-PWV) was significantly higher in ALB+ and iNAP groups compared to No-P. Remarkably, cf-PWV remained still significant after adjustment for age, sex and MBP (p = 0.0004). In overall population, a multiple regression analysis showed that cf-PWV was an independent determinant of NAP in a model including age, sex, glycated hemoglobin, systolic and mean blood pressure (R2 =0.17, p = 0.031). CONCLUSION: iNAP subjects showed increased arterial stiffness comparable to that observed in ALB+ group, suggesting that they may represent a subgroup at higher cardiovascular risk, often unrecognized in clinical practice.

Hypertension-Mediated Organ Damage In Young Patients With First-Diagnosed And Never Treated Systolic Hypertension.

OBJECTIVE: Early onset of untreated arterial hypertension is associated with an increased risk for cardiovascular (CV) diseases. The evaluation of hypertension-mediated organ damage (HMOD) helps estimating CV risk. We investigated the incidence of HMOD in young first, diagnosed and nevertreated patients with systolic arterial hypertension (SH) to identify high CV-risk patients based on the presence of HMOD. METHODS: CV risk factors [smoking, obesity (body mass index, BMI)], hyperlipidemia and 5 HMODs [arterial stiffness (pulse wave velocity, PWV), left ventricular diastolic dysfunction [(DD (E/Ea)], cardiac hypertrophy (left ventricular mass index, LVMI), coronary artery microcirculation (CFR), and carotid intima-media thickness (cIMT)] were evaluated before treatment initiation in 220 patients, aged ≤50 years [median (interquartile range, IQR) age=43(38-47)], with SH diagnosed by ambulatory blood pressure monitoring (24-h ABPM). RESULTS: Smoking (40%) and obesity [median (IQR) BMI=30(26-32) kg/m2](40%) were found in young hypertensives. HMOD was found in 50% of hypertensives (10% had ≥2 HMOD). The most prevalent HMODs were increased by cIMT (32%) and PWV (19%), LVH (9%), impaired CFR (6%) and DD (1%). Only PWV (beta=0.27, p<0.001) and LVMI (beta=0.41, p<0.001) were associated with systolic BP burden. In a subgroup analysis, patients with ≥2 HMOD were older with increased office BP and 24- h ABPM, impaired lipid profile, and increased LVMI, PWV, CFR, and cIMT compared with the rest of the hypertensives. CONCLUSION: The presence of ≥2 of the studied HMOD (PWV, LVMI, cIMT, E/Ea, CFR) in young hypertensives characterizes a "high-risk population". Arterial stiffness represents the predominant HMOD and in the whole population and "high-risk population".

Effect of bariatric surgery on NAFLD/NASH: a single-centre observational prospective cohort study.

INTRODUCTION: The prevalence of non-alcoholic fatty liver disease (NAFLD) ranges from 25% in the general population to 90% in patients with obesity scheduled for bariatric surgery. NAFLD can progress towards non-alcoholic steatohepatitis (NASH) associated with complications such as cirrhosis, hepatocellular carcinoma and cardiovascular disease. To date, losing weight and lifestyle modifications are the best known treatments for NASH. Bariatric surgery significantly improves NAFLD/NASH in the short term. However, the extent of this improvement is not yet clear and long-term data on the natural course of NAFLD/NASH after bariatric surgery are lacking. The factors involved in NAFLD/NASH regression after bariatric surgery have not been elucidated. METHODS AND ANALYSIS: This is an observational prospective cohort study including patients scheduled for bariatric surgery. Extensive metabolic and cardiovascular analyses will be carried out including measurements of carotid intima media thickness and pulse wave velocity. Genomic, proteomic, lipidomic and metabolomic studies will be done. Microbioma analyses before and 1 year after surgery will be done. Transient elastography measurements will be performed before and at 1, 3 and 5 years after surgery. For those with an elevated preoperative transient elastography measurement by Fibroscan, a laparoscopic liver biopsy will be performed during surgery. Primary outcome measures are the change of steatosis and liver fibrosis 5 years after surgery. Secondary outcome measure is the comparison of the transient elastography measurements with the NAFLD Activity Score from the biopsies. ETHICS AND DISSEMINATION: The protocol has been approved by the Medical Research Ethics Committees United, Nieuwegein, on 1 March 2022 (registration code R21.103/NL79423.100.21). The study results will be submitted for publication in peer-reviewed journals and data will be presented at scientific meetings. TRIAL REGISTRATION NUMBER: NCT05499949.

Markers of arterial stiffness and urinary metabolomics in young adults with early cardiovascular risk: the African-PREDICT study.

INTRODUCTION: Increased exposure to risk factors in the young and healthy contributes to arterial changes, which may be accompanied by an altered metabolism. OBJECTIVES: To increase our understanding of early metabolic alterations and how they associate with markers of arterial stiffness, we profiled urinary metabolites in young adults with cardiovascular disease (CVD) risk factor(s) and in a control group without CVD risk factors. METHODS: We included healthy black and white women and men (N = 1202), aged 20-30 years with a detailed CVD risk factor profile, reflecting obesity, physical inactivity, smoking, excessive alcohol intake, masked hypertension, hyperglycemia, dyslipidemia and low socio-economic status, forming the CVD risk group (N = 1036) and the control group (N = 166). Markers of arterial stiffness, central systolic blood pressure (BP) and pulse wave velocity were measured. A targeted metabolomics approach was followed by measuring amino acids and acylcarnitines using a liquid chromatography-tandem mass spectrometry method. RESULTS: In the CVD risk group, central systolic BP (adjusted for age, sex, ethnicity) was negatively associated with histidine, arginine, asparagine, serine, glutamine, dimethylglycine, threonine, GABA, proline, methionine, pyroglutamic acid, aspartic acid, glutamic acid, branched chain amino acids (BCAAs) and butyrylcarnitine (all P ≤ 0.048). In the same group, pulse wave velocity (adjusted for age, sex, ethnicity, mean arterial pressure) was negatively associated with histidine, lysine, threonine, 2-aminoadipic acid, BCAAs and aromatic amino acids (AAAs) (all P ≤ 0.044). In the control group, central systolic BP was negatively associated with pyroglutamic acid, glutamic acid and dodecanoylcarnitine (all P ≤ 0.033). CONCLUSION: In a group with increased CVD risk, markers of arterial stiffness were negatively associated with metabolites related to AAA and BCAA as well as energy metabolism and oxidative stress. Our findings may suggest that metabolic adaptations may be at play in response to increased CVD risk to maintain cardiovascular integrity.

Arterial Stiffness as a Predictor of the Index of Atherosclerotic Cardiovascular Disease in Hypertensive Patients.

OBJECTIVE: The aim of this study was to evaluate the predictive value of carotid-femoral pulse wave velocity (cfPWV) and cardiovascular disease in the hypertensive population in China and to determine the specific cfPWV cut-off value for assessing future cardiovascular disease (CVD) risk. METHODS: This cross-sectional study included 630 hospital patients with primary hypertension and multiple cardiovascular risk factors or complications involving damage to clinical target organs. The study was conducted between July 2007 and October 2008. Atherosclerotic cardiovascular disease (ASCVD) risk calculations were computed according to criteria presented by the American College of Cardiology and the American Heart Association. Patients were stratified by a predefined risk threshold of 10% and divided into two groups: ASCVD ≥ 10% or ASCVD < 10%. cfPWV was used as a marker of arterial stiffness. A receiver operating characteristics (ROC) curve was applied to establish the optimal cfPWV cut-off point to differentiate between participants with and without ASCVD risk. RESULTS: In the study cohort of 630 patients (age 63.55.2 ± 8.6 years, 61.7% male) with primary hypertension, the pressure indices (augmented pressure, augmentation index [AIx], aortic pulse pressure, aortic systolic pressure [SBP]) and Framingham Risk Scores (FRS) were greater in females than in males (p < 0.001); ASCVD risk scores and peripheral diastolic pressure (DBP) were higher in males (p < 0.05). All hemodynamic indices showed a significant positive correlation with ASCVD risk scores and FRS; AIx was not correlated with ASCVD risk scores. In multivariate logistic analysis, cfPWV was significantly associated with ASCVD risk (OR: 1.324, 95% confidence interval: 1.119-1.565, p < 0.001) after adjusting for age, gender, smoking, body mass index, total cholesterol, fasting blood glucose, antihypertensive treatment, statin treatment, and DBP. In the ROC analysis, the area under the curve was 0.758 and 0.672 for cfPWV and aortic SBP (p < 0.001 and p < 0.001, respectively); the optimal critical value of cfPWV and aortic SBP was 12.45 m/s (sensitivity 63.2%, specificity 77.8%) and 124.5 mmHg (sensitivity 63.9%, specificity 65.3%). CONCLUSIONS: cfPWV is significantly correlated with the risk of ASCVD. The best cut-off value of cfPWV for assessing future CVD risk in the hypertensive population in China is 12.45 m/s.

Minimal vascular flows cause strong heat sink effects in hepatic radiofrequency ablation ex vivo.

BACKGROUND: The present paper aims to assess the lower threshold of vascular flow rate on the heat sink effect in bipolar radiofrequency ablation (RFA) ex vivo. METHODS: Glass tubes (vessels) of 3.4 mm inner diameter were introduced in parallel to bipolar RFA applicators into porcine liver ex vivo. Vessels were perfused with flow rates of 0 to 1,500 ml/min. RFA (30 W power, 15 kJ energy input) was carried out at room temperature and 37°C. Heat sink effects were assessed in RFA cross sections by the decrease in ablation radius, area and by a high-resolution sector planimetry. RESULTS: Flow rates of 1 ml/min already caused a significant cooling effect (P ≤ 0.001). The heat sink effect reached a maximum at 10 ml/min (18.4 mm/s) and remained stable for flow rates up to 1,500 ml/min. CONCLUSIONS: Minimal vascular flows of ≥1 ml/min cause a significant heat sink effect in hepatic RFA ex vivo. A lower limit for volumetric flow rate was not found. The maximum of the heat sink effect was reached at a flow rate of 10 ml/min and remained stable for flow rates up to 1,500 ml/min. Hepatic inflow occlusion should be considered in RFA close to hepatic vessels.