Intentional coronary revascularization versus conservative therapy in patients after peripheral artery revascularization due to critical limb ischemia: the INCORPORATE trial.

OBJECTIVES: INCORPORATE trial was designed to evaluate whether default coronary-angiography (CA) and ischemia-targeted revascularization is superior compared to a conservative approach for patients with treated critical limb ischemia (CLI). Registered at clinicaltrials.gov (NCT03712644) on October 19, 2018. BACKGROUND: Severe peripheral artery disease is associated with increased cardiovascular risk and poor outcomes. METHODS: INCORPORATE was an open-label, prospective 1:1 randomized multicentric trial that recruited patients who had undergone successful CLI treatment. Patients were randomized to either a conservative or invasive approach regarding potential coronary artery disease (CAD). The conservative group received optimal medical therapy alone, while the invasive group had routine CA and fractional flow reserve-guided revascularization. The primary endpoint was myocardial infarction (MI) and 12-month mortality. RESULTS: Due to COVID-19 pandemic burdens, recruitment was halted prematurely. One hundred eighty-five patients were enrolled. Baseline cardiac symptoms were scarce with 92% being asymptomatic. Eighty-nine patients were randomized to the invasive approach of whom 73 underwent CA. Thirty-four percent had functional single-vessel disease, 26% had functional multi-vessel disease, and 90% achieved complete revascularization. Conservative and invasive groups had similar incidences of death and MI at 1 year (11% vs 10%; hazard ratio 1.21 [0.49-2.98]). Major adverse cardiac and cerebrovascular events (MACCE) trended for hazard in the Conservative group (20 vs 10%; hazard ratio 1.94 [0.90-4.19]). In the per-protocol analysis, the primary endpoint remained insignificantly different (11% vs 7%; hazard ratio 2.01 [0.72-5.57]), but the conservative approach had a higher MACCE risk (20% vs 7%; hazard ratio 2.88 [1.24-6.68]). CONCLUSION: This trial found no significant difference in the primary endpoint but observed a trend of higher MACCE in the conservative arm.

Cardiovascular Outcomes in Hypertension-Treated Patients With Peripheral Artery Disease: The VALUE Trial.

BACKGROUND: Systolic blood pressure (BP) is a key predictor of cardiovascular events, but patients with peripheral artery disease (PAD) are rarely included in hypertension trials. The VALUE trial (Valsartan Antihypertensive Long-Term Use Evaluation) investigated the long-term effects of valsartan- or amlodipine-based treatments on cardiovascular outcomes in patients with hypertension with a high cardiovascular risk. The aim of this subanalysis was to clarify the relationship between achieved BP on treatment and cardiovascular outcomes in patients with hypertension with PAD. METHODS: Patients were followed for 4 to 6 years, and BP was measured regularly. The primary end point was time to the first major adverse cardiovascular event, including myocardial infarction, stroke, cardiovascular death, and heart failure requiring hospitalization. Statistical analyses were performed using Cox regression, adjusting for various baseline covariates. RESULTS: Of the 13 803 participants, 1898 (13.8%) had PAD. During a median follow-up of 4.5 years, patients with PAD had a 23% increased risk of major adverse cardiovascular events compared with patients without PAD. Patients with an achieved systolic BP <130 mm Hg and 130 to 139 mm Hg, compared with those with systolic BP ≥140 mm Hg, were associated with a decreased risk of a major adverse cardiovascular event (hazard ratio, 0.65 [95% CI, 0.43-0.97]; P=0.037; 0.85 [95% CI, 0.74-0.97]; P=0.016, respectively). Additionally, systolic BP <130 mm Hg was associated with a decreased risk of cardiovascular death (hazard ratio, 0.33 [95% CI, 0.12-0.92]; P=0.034). The incidence of the primary outcome did not differ between antihypertensive treatment regimens (P=0.365). CONCLUSIONS: Our results indicate that more intensive BP control is associated with a reduction in cardiovascular morbidity and mortality in patients with hypertensive PAD.

UROMODULIN - A LINK BETWEEN SODIUM EXCRETION AND ALTERATION IN CIRCADIAN BLOOD PRESSURE PATTERN IN PREHYPERTENSIVES.

Although changes in dietary sodium intake alter blood pressure (BP) in salt-sensitive individuals, pathophysiological mechanisms are still unknown. It has been reported that uromodulin is involved in sodium tubular transport, and genome-wide association studies pointed to UMOD gene as one of the most important gene candidates for arterial hypertension. Our aim was to analyze urinary uromodulin, salt intake and BP in 326 young middle-aged subjects (mean age 36±8 years, 49.4% male). In a subgroup of 175 individuals, ambulatory blood pressure monitoring and echocardiogram were performed. Uromodulin was determined by ELISA. According to the JNC-7 criteria, subjects were classified as optimal BP (n=103, men 72%), prehypertension (PHT) (n=143, men 43%) and hypertension (HT) (n= 80, men 38%). There were no differences in age, salt intake, estimated glomerular filtration rate, sodium excretion and uromodulin among BP groups. However, in PHT subjects, uromodulin was positively associated with fractional sodium excretion and negatively with 24-h sodium excretion and diastolic BP dip. These findings point to the effect of uromodulin on sodium reabsorption along the nephron and consequently circadian BP alteration in prehypertensives.

LEFT-SIDED INFERIOR VENA CAVA ASSOCIATED WITH PROXIMAL DEEP VENOUS THROMBOSIS OF THE LEFT LOWER EXTREMITY.

Left-sided inferior vena cava (IVC) is a rare congenital venous anomaly that is most frequently detected incidentally during abdominal computer tomography scanning. However, as in the case presented, the first clinical manifestation of this anomaly may be deep venous thrombosis (DVT) of lower extremities. Therefore, left-sided IVC should be kept in mind in case of inferior DVT, especially in young patients with no predisposing thrombotic risk factors.

Cardiac troponins predict mortality and cardiovascular outcomes in patients with peripheral artery disease: A systematic review and meta-analysis of adjusted observational studies.

BACKGROUND: A significant proportion of patients (pts) with peripheral artery disease (PAD) have concomitant coronary artery disease and polyvascular involvement contributes to increased risk of death and unfavorable cardiovascular events. HYPOTHESIS: Cardiac troponins are associated with adverse cardiovascular outcomes in PAD pts. METHODS: We systematically searched Medline and Scopus to identify all observational cohort studies published before June 2021 (combining terms "troponin," "peripheral artery disease," "peripheral arterial disease," "intermittent claudication," and "critical limb ischemia") that evaluated the prognostic impact of troponin rise on admission on all-cause mortality and/or major cardiovascular events (MACEs; composite of myocardial infarction, stroke, and cardiovascular death) in PAD pts followed up at least 6 months. A meta-analysis was conducted using the generic inverse variance method. Heterogeneity between studies was investigated using Cochrane's Q test and I2 statistic. RESULTS: Eight studies were included in the final analysis (5313 pts) with a median follow-up of 27 months (interquartile range: 12-59 months). The prevalence of troponin positivity was 5.3% (range: 4.4%-8.7%) in pts with intermittent claudication, and 62.6% (range: 33.6%-85%) in critical limb ischemia. Elevated troponins were significantly associated with an increased risk of all-cause mortality (hazard ratio [HR]: 2.85, 95% confidence interval [CI]: 2.28-3.57; I2 = 50.97%), and MACE (HR: 2.58, 95% CI: 2.04-3.26; I2 = 4.00%) without publication bias (p = .24 and p = .10, respectively). CONCLUSION: Troponin rise on admission is associated with adverse long-term cardiovascular outcomes in symptomatic PAD.

THE ROLE OF ANTHROPOMETRIC PARAMETERS AND PHYSICAL ACTIVITY LEVEL IN PATIENTS WITH ACUTE CORONARY SYNDROME ADMITTED TO THE INTENSIVE CARDIAC CARE UNIT.

Anthropometric parameters have a role in diagnosing obesity, which increases the risk of acute coronary syndrome (ACS). The aim of the study was to assess the impact of obesity and physical activity level on the severity and long-term prognosis of ACS. A total of 116 patients with ACS were analyzed according to baseline (demography, medical history, anthropometry), severity (clinical presentation, in-hospital complications, laboratory, echocardiography, coronary angiography) and prognostic parameters (major adverse cardiovascular events during a six-year period). The levels of obesity and physical activity (Baecke/Lipid Research Clinics physical activity questionnaires) were compared with a sample of the Croatian general population. Study results showed the subjects with a higher number of narrowed coronary arteries (CAs) to have higher body mass index (BMI) and waist circumference (WC); those with stenosed left anterior descending artery and anterior myocardial infarction (MI) had higher BMI; waist-to-hip ratio (WHR) positively correlated with creatine kinase and negatively with left ventricle ejection fraction (p<0.05). Inactive patients more often had multi-vessel coronary disease and anterior MI; patients with a higher leisure physical activity index had a lower number of affected CAs, lower rate of stent implantations and lower stent length, while those with a higher work physical activity index had a lower rate of anterior MI (p<0.05). During the follow-up, inactive patients had more strokes and deaths (p<0.05). Our patients had higher body weight, WC and WHR, as well as lower leisure time and total physical activity indices than the general population (p<0.05). In conclusion, ACS is less severe and has better long-term prognosis in less obese patients with a higher level of physical activity. Patients with ACS are more obese and have lower total, as well as leisure time physical activity indices than the general population.

ADMISSION CARDIAC TROPONINS PREDICT HOSPITAL MORTALITY IN TYPE A ACUTE AORTIC DISSECTION: A META-ANALYSIS OF ADJUSTED RISK ESTIMATES.

Acute aortic dissection (AAD) is a serious medical emergency that requires early diagnosis and rapid treatment. Whether cardiac troponin could be an independent prognostic marker in patients with type A AAD is still unknown. We systematically searched Medline and Scopus to identify all observational cohort studies published before January 2020 that compared outcome (in-hospital mortality) in patients with type A AAD with and without troponin elevation on admission. Four studies with 412 patients were included in final analysis (median age 59 years, 65% of males). A total of 124 (30%) patients died during in-hospital stay, and 73% underwent surgery. Elevated troponins (39.6% of patients) were associated with an increased risk of short-term mortality (adjusted odds ratio 1.26; 95% confidence interval 1.08-1.47), with low heterogeneity among studies (I2 =29.81%). Elevated troponins on admission are independently associated with increased in-hospital mortality in type A AAD.

Sex Differences in Characteristics and Outcomes among Low-Risk Non-ST-Elevation Acute Coronary Syndrome Patients during Long Term Follow-Up.

Previous heterogenous studies show conflicting data about sex-based outcomes of non-ST-elevation acute coronary syndrome (NSTE-ACS) patients. This study evaluated 300 NSTE-ACS patients undergoing a coronary angiography between September 2012 and May 2015 that were managed with all-treatment strategies. The sample was stratified by sex and analyzed for the baseline characteristics and outcomes. The main outcome included major adverse cardiovascular and cerebrovascular events (MACCE), which were a composite of cardiac death, nonfatal myocardial infarction, ischemic stroke or urgent coronary revascularization. The female patients were older (median of 69.0 vs. 63.0 years, p = 0.008) and had lower values of BMI (median of 26.3 vs. 28.2 kg/m2, p < 0.001) and eGFR (76.44 ± 22.43 vs. 94.04 ± 27.91 mL/min, p < 0.001). There was no significant difference in the treatment strategies, angiographic characteristics and discharge therapy between the groups (p > 0.05). The female patients had significantly higher unadjusted rates of ischemic stroke (4.2% vs. 0.5%, p = 0.023), cardiac mortality (11.3%, vs. 3.9%, p = 0.022) and MACCE (33.8%, vs. 19.5%, p = 0.014); female sex was a significant predictor of MACCE in the univariate analysis (HR 1.86, 95%CI 1.12-3.09, p = 0.014); and the cumulative incidence of MACCE was higher in female patients (p = 0.014). After the adjustment, the predictive effect of female sex became non-significant (HR 1.60, 95%CI 0.94-2.73, p = 0.083), while there was no difference in the cumulative incidence of MACCE among the propensity score matched cohort (p = 0.177). Female NSTE-ACS patients have worse long-term outcomes compared to their male counterparts. However, the differences disappear after adjustment and propensity score matching. Continuing efforts and health measures are required to alleviate any sex-based differences in the NSTE-ACS population.

ACEF performed better than other risk scores in non-ST-elevation acute coronary syndrome during long term follow-up.

BACKGROUND: Risk stratification of patients with non-ST-elevation acute coronary syndrome (NSTE-ACS) is an important clinical method, but long-term studies on patients subjected to all-treatment strategies are lacking. Therefore, the aim was to compare several established risk scores in the all-treatment NSTE-ACS cohort during long-term follow-up. METHODS: Consecutive patients (n = 276) with NSTE-ACS undergoing coronary angiography were recruited between September 2012 and May 2015. Six risk scores for all patients were calculated, namely GRACE 2.0, ACEF, SYNTAX, Clinical SYNTAX, SYNTAX II PCI and SYNTAX II CABG. The primary end-point was Major Adverse Cardiovascular Events (MACE) which was a composite of cardiac death, nonfatal myocardial infarction, ischemic stroke or urgent coronary revascularization. RESULTS: During a median follow-up of 33 months, 64 MACE outcomes were recorded (23.2%). There was no difference between risk score categories, except in the highest risk group of ACEF and SYNTAX II PCI scores which exhibited significantly more MACE (51.6%, N = 33 and 45.3%, N = 29, P = 0.024, respectively). In the multivariate Cox regression analysis of individual variables, only age and atrial fibrillation were significant predictors for MACE (HR 1.03, 95% CI 1.00-1.05, P = 0.023 and HR 2.02, 95% CI 1.04-3.89, P = 0.037, respectively). Furthermore, multivariate analysis of the risk scores showed significant prediction of MACE only with ACEF score (HR 2.16, 95% CI 1.36-3.44, P = 0.001). The overall performance of GRACE, SYNTAX, Clinical SYNTAX and SYNTAX II CABG was poor with AUC values of 0.596, 0.507, 0.530 and 0.582, respectively, while ACEF and SYNTAX II PCI showed the best absolute AUC values for MACE (0.630 and 0.626, respectively). CONCLUSIONS: ACEF risk score showed better discrimination than other risk scores in NSTE-ACS patients undergoing all-treatment strategies over long-term follow-up and it could represent a fast and user-friendly tool to stratify NSTE-ACS patients.

N-terminal pro-brain natriuretic peptide and short-term mortality in acute aortic dissection: A meta-analysis.

BACKGROUND: Acute aortic dissection (AAD) is a life-threatening medical emergency that requires immediate diagnosis and rapid treatment. There is a paucity of data on the role of biomarkers in risk stratification of patients with AAD. HYPOTHESIS: N-terminal pro-brain natriuretic peptide (NT-proBNP) is associated with short-term mortality in AAD patients. METHODS: We systematically searched Medline and Scopus to identify all observational cohort studies published before January 2020 that compared outcome (short-term mortality) in patients with AAD with high vs low levels of baseline NT-proBNP combining terms "brain natriuretic peptide" and "aortic dissection." A meta-analysis was conducted using the generic inverse variance method. Heterogeneity between studies was investigated using the Cochrane's Q test and I2 statistic. RESULTS: Four studies were included in final analysis including a total of 950 patients, and 105 (11%) patients died. Baseline NT-proBNP concentrations were significantly higher in nonsurvivors (median 2240 pg/mL, range 1678-16 347 pg/mL) when compared to survivors (665 pg/mL, 328-1252 pg/mL). Elevated NT-proBNP values were significantly associated with an increased risk of short-term mortality (odds ratio 4.13, 95% CI [confidence interval] 2.33-7.33), with low heterogeneity (I2 = 8.77%, Cochran Q = 2.19, P = .33), and no publication bias. The pooled standardized mean difference between groups was 1.28 (95% CI 0.99-1.56), with low heterogeneity (I2 = 38.73%, Cochran Q = 3.26, P = .19). CONCLUSION: Elevated NT-proBNP levels on admission are associated with an increased risk of short-term mortality in AAD.

Antithrombotic Therapy in Lower Extremity Artery Disease.

Lower extremity artery disease (LEAD) is a marker of a more advanced atherosclerotic process often affecting multiple vascular beds beyond the lower limbs, with a consequent increased risk for all-cause and cardiovascular mortality. Antithrombotic therapy is the cornerstone of management of these patients to prevent ischaemic cardiovascular and limb events and death. In patients with symptomatic LEAD, the efficacy of aspirin has been established long ago for the prevention of cardiovascular events. In the current guidelines, clopidogrel may be preferred over aspirin following its incremental ability to prevent cardiovascular events, while ticagrelor is not superior to clopidogrel in reducing cardiovascular outcomes. Dual antiplatelet therapy (DAPT, aspirin with clopidogrel) is currently recommended for at least 1 month after endovascular interventions irrespective of the stent type. Antiplatelet monotherapy is recommended after infra-inguinal bypass surgery, and DAPT may be considered in below-the-knee bypass with a prosthetic graft. In symptomatic LEAD, the addition of anticoagulant (vitamin K antagonists) to antiplatelet therapy increased the risk of major and life-threatening bleeding without benefit regarding cardiovascular outcomes. In a recent trial, low dose of direct oral anticoagulant rivaroxaban plus aspirin showed promising results, not only to reduce death and major cardiovascular events, but also major limb events including amputation. Yet, this option should be considered especially in very high risk patients, after considering also the bleeding risk. Despite all the evidence accumulated since >40 years, many patients with LEAD remain undertreated and deserve close attention and implementation of guidelines advocating the use of antithrombotic therapies, tailored according to their level of risk.

Admission C-reactive protein and outcomes in acute aortic dissection: a systematic review.

AIM: To assess the prognostic role of admission C-reactive protein (CRP) in patients with acute aortic dissection (AAD). METHODS: We searched Medline and Scopus for studies published before January 2019 that evaluated the prognostic impact of CRP on all-cause mortality during short- and mid-term follow-up period in patients with AAD. Additional studies were identified by manual search of the references from the original studies. Receiver-operating characteristic curves were used to determine the optimal cut-off values of admission CRP for the prediction of mortality, and patients were categorized into two groups based on the CRP cut-off levels. RESULTS: Medline, Scopus, and manual literature search yielded 138 citations. Based on the title and abstract analysis and review of potentially relevant studies, five studies, involving 711 patients, were included in the final analysis. Multivariate statistical analysis was performed in all the studies. The median admission CRP value across the studies was 13 mg/L (range 4-21 mg/L). Two out of three studies that evaluated in-hospital outcome and all of the studies that evaluated medium-term outcome reported a significant association between elevated CRP values and mortality. The studies that included treatment strategy (surgery vs conservative treatment) as a confounding variable confirmed a significant effect of elevated CRP values on both in-hospital and mid-term unfavorable outcomes. CONCLUSION: This systematic review demonstrated a clear association between elevated admission serum CRP levels and increased in-hospital and mid-term mortality risk in AAD.

Atrial fibrillation and risk of cardiovascular events and mortality in patients with symptomatic peripheral artery disease: A meta-analysis of prospective studies.

BACKGROUND: Atrial fibrillation (AF) is associated with adverse outcomes in terms of survival and morbidity. Peripheral artery disease (PAD) and AF share several common risk factors and often coexist. Whether AF has a prognostic role in patients with PAD has not been extensively studied. HYPOTHESIS: AF is associated with major adverse cardiac events (MACE) and mortality in symptomatic PAD patients. METHODS: Using MEDLINE and Scopus, we searched for studies published before December 2016 that evaluated cardiovascular outcomes based on the presence/absence of AF in a prospective manner with a follow-up period of ≥12 months. The outcomes were reported using a random-effects model, and heterogeneity was assessed using the I2 statistic. Sensitivity analyses were performed to test the contribution of each study to the overall results. RESULTS: Six prospective studies (Newcastle-Ottawa score range, 7-9) with 14 656 patients were included in the final analysis (age range, 66-70 years; median follow-up, 1.4 years). Our pooled analysis found a significant association between AF and mortality (odds ratio: 2.52, 95% confidence interval: 1.91-3.34, I2 = 32.6%), without evidence of publication bias (P = 0.63). Meta-analysis showed a significant impact of AF on MACE (odds ratio: 2.54, 95% confidence interval: 1.78-3.63, I2 = 74.3%), without detected publication bias (P = 0.08). CONCLUSIONS: AF is associated with increased risk of mortality and MACE in symptomatic PAD.

Correlation Between Concentration of Air Pollutants and Occurrence of Cardiac Arrhythmias in a Region with Humid Continental Climate

In this study, we investigated the correlation of air temperature, pressure and concentration of air pollutants with the rate of admissions for cardiac arrhythmias at two clinical centers in the area with a humid continental climate. This retrospective study included 3749 patients with arrhythmias admitted to emergency department (ED). They were classified into four groups: supraventricular tachycardia (SVT), ventricular tachycardia (VT), atrial fibrillation/undulation (Afib/Aund), and palpitations (with no ECG changes, or with sinus tachycardia and extrasystoles). The number of patients, values of meteorological parameters (average daily values of air temperature, pressure and relative humidity) and concentrations of air pollutants (particles of dimensions ~10 micrometers or less (PM(10)), ozone (O(3)) and nitrogen dioxide (NO(2))) were collected during a two-year period ( July 2008-June 2010). There were 1650 (44.0%), 1525 (40.7%), 451 (12.0%) and 123 (3.3%) patients with palpitations, Afib/Aund, SVT and VT, respectively. Spearman's correlation yielded positive correlation between the occurrence of arrhythmias and air humidity on the day (r=0.07), and 1 (r=0.08), 2 (r=0.09) and 3 days before (r=0.09), and NO(2) particles on the day (r=0.08) of ED admission; palpitations and air humidity on the day (r=0.11), and 1 (r=0.09), 2 (r=0.07) and 3 days before (r=0.10), and PM(10) (r=0.11) and NO(2) (r=0.08) particles on the day of ED admission; and Afi b/Aund and air humidity 2 days before (r=0.08) ED admission (p<0.05 all). In conclusion, there was a very weak positive correlation of the occurrence of cardiac arrhythmias with air humidity and concentration of air pollutants in the region with a humid continental climate.