Statin use improves survival of patients with known or suspected lower extremity artery disease on all ankle brachial index levels.

Background: Statin medication improves the prognosis of patients with lower extremity artery disease (LEAD). Research has previously focused on patients with a lowered ankle brachial index (ABI) excluding patients with a normal or elevated ankle brachial index. The aim of this study was to analyze the impact of statin use on survival and cardiovascular mortality in patients with LEAD of different severity depicted by the ABI level. Patients and methods: 4128 ABI measurements by trained and experienced nurses between 2000 and 2009 were combined with medication data from the Social Insurance Institution and causes of death data from the national causes of death registry. End of follow-up was set at the end of 2014. The data of statin use included all statin medication with the Anatomical Therapeutic Chemical (ATC) classification codes between C10AA01 and C10AA08. Results: 1956 (47.4%) patients had statin medication. Statin use was associated with improved overall survival and amputation free survival (AFS) on all ABI levels. When adjusted for age, sex and diabetes the greatest overall survival benefit from statin use was for the patients with ABI>1.3 (hazard ratio, HR: 0.67, 95% CI: 0.48-0.94, p=0.020, reference group statin non-users) and ABI 0.9-1.3 (HR: 0.78, 95% CI: 0.65-0.94, p=0.008). In propensity score matched pairs statin treatment was associated with significantly lower all-cause mortality (p<0.0001), cardiovascular mortality (p=0.034), cerebrovascular mortality (p=0.003) and embolic stroke related mortality (p=0.001) in patients with ABI >1.3 or <0.9. Overall survival benefit was significant in females with ABI<0.5 and in males across several ABI levels. Conclusions: According to our study, statins seem to improve overall and amputation free survival regardless of ABI level. Statin use was associated with lower mortality from cerebrovascular disease, overall mortality and in the propensity score matched patients with ABI<0.9 or >1.3 with cardiovascular mortality.

High relative amount of nodular calcification in femoral plaques is associated with milder lower extremity arterial disease.

BACKGROUND: Clinical implications of different types of vascular calcification are poorly understood. The two most abundant forms of calcification, nodular and sheet calcification, have not been quantitatively analyzed in relation to the clinical presentation of lower extremity arterial disease (LEAD). METHODS: The study analyzed 51 femoral artery plaques collected during femoral endarterectomy, characterized by the presence of > 90% stenosis. Comprehensive clinical data was obtained from patient records, including magnetic resonance angiography (MRA) images, toe pressure and ankle brachial index measurements and laboratory values. The plaques were longitudinally sectioned, stained with Hematoxylin and Eosin and digitized in a deep learning platform for quantification of the relative area of nodular and sheet calcification to the plaque section area. A deep learning artificial intelligence algorithm was designed and independently validated to reliably quantify nodular calcification and sheet calcification. Vessel measurements and quantity of each calcification category was compared to the risk factors and clinical presentation. RESULTS: On average, > 90% stenosed vessels contained 22.4 ± 12.3% of nodular and 14.5 ± 11.8% of sheet calcification. Nodular calcification area proportion in lesions with > 90% stenosis is associated with reduced risk of critically low toe pressure (< 30 mmHg) (OR = 0.910, 95% CI = 0.835-0.992, p < 0.05), severely lowered ankle brachial index (< 0.4) (OR = 0.912, 95% CI = 0.84-0.986, p < 0.05), and semi-urgent operation (OR = 0.882, 95% CI = 0.797-0.976, p < 0.05). Sheet calcification did not show any significant association. CONCLUSIONS: Large amount of nodular calcification is associated with less severe LEAD. Patients with nodular calcification may have better flow reserves despite local obstruction.

Incompressible ankle arteries predict increased morbidity and mortality in patients with an elevated ankle brachial index.

OBJECTIVES: Patients with an elevated ankle brachial index (ABI) > 1.3 have a high burden of disease and poorer outcome compared to patients with a lower ABI. Previously differences between patients with ABI > 1.3 have not been studied in detail. The aim of this study was to analyze the morbidity and mortality of patients with ABI > 1.3. METHODS: ABI measurements were performed in the vascular laboratory of Turku university hospital 2011-2013. Patients with ABI>1.3 in at least one lower limb were included in the study and divided into 3 groups: At least one lower limb ABI 1.3-2.5 but both limbs <2.5 (group 1), one limb ABI ≥2.5 (group 2), both limbs ABI ≥ 2.5 (group 3). RESULTS: 534 patients were included in the study. The patients in groups 2 and 3 were more often female (p < .001), older (p < .001), had more diabetes (p = .013), coronary artery disease (p = .001) and chronic heart (p = .010) and kidney failure (p = .013) compared to patients in group 1. The survival of patients in group 2 and 3 was significantly poorer compared to the patients in group 1 (HR1.6, 95% CI 1.2-2.2, p = .002 and 1.7, 95% CI 1.2-2.3, p < .001, respectively). Overall and cardiovascular mortality was higher in groups 2 and 3 than group 1.39.5% of patients with incompressible ankle arteries (ABI ≥ 2.5) in both lower limbs had toe pressure (TP) <50 mmHg and a poorer survival compared to patients with a higher TP. CONCLUSIONS: Patients with incompressible ankle arteries have significantly higher overall and cardiovascular mortality and a greater burden of disease compared to the patients with a measurable yet abnormally high ABI. TP is a useful diagnostic tool when ABI is immeasurably high. All patients with ABI > 1.3 should be considered as high cardiovascular risk patients.

Tankyrase Inhibition Attenuates Cardiac Dilatation and Dysfunction in Ischemic Heart Failure.

Hyperactive poly(ADP-ribose) polymerases (PARP) promote ischemic heart failure (IHF) after myocardial infarction (MI). However, the role of tankyrases (TNKSs), members of the PARP family, in pathogenesis of IHF remains unknown. We investigated the expression and activation of TNKSs in myocardium of IHF patients and MI rats. We explored the cardioprotective effect of TNKS inhibition in an isoproterenol-induced zebrafish HF model. In IHF patients, we observed elevated TNKS2 and DICER and concomitant upregulation of miR-34a-5p and miR-21-5p in non-infarcted myocardium. In a rat MI model, we found augmented TNKS2 and DICER in the border and infarct areas at the early stage of post-MI. We also observed consistently increased TNKS1 in the border and infarct areas and destabilized AXIN in the infarct area from 4 weeks onward, which in turn triggered Wnt/ß-catenin signaling. In an isoproterenol-induced HF zebrafish model, inhibition of TNKS activity with XAV939, a TNKSs-specific inhibitor, protected against ventricular dilatation and cardiac dysfunction and abrogated overactivation of Wnt/ß-catenin signaling and dysregulation of miR-34a-5p induced by isoproterenol. Our study unravels a potential role of TNKSs in the pathogenesis of IHF by regulating Wnt/ß-catenin signaling and possibly modulating miRNAs and highlights the pharmacotherapeutic potential of TNKS inhibition for prevention of IHF.

The Cardiovascular-Mortality-Based Estimate for Normal Range of the Ankle-Brachial Index (ABI).

Background: The ankle−brachial index (ABI) is a first-line examination in cardiovascular risk evaluation. Since cut-off values for normal ABI vary, the aim of the present study was to identify the cardiovascular-mortality-based estimate for the normal range of the ABI. After determining the reference range for the ABI, the corresponding toe−brachial index (TBI) and toe pressure for normal ABI were analyzed. Methods: All consecutive non-invasive pressure measurements in the vascular laboratory of a large university hospital 2011−2013 inclusive were collected and combined with patient characteristics and official dates and causes of death. Patients with an ABI range of 0.8−1.4 on both lower limbs were included in this study. Results: From 2751 patients, 868 had bilateral ABI values within the inclusion. Both ABI category ranges 0.80−0.89 and 0.90−0.99 had poorer survival compared to ABI categories 1.00−1.29 (p < 0.05). The 1-, 3-, and 5-year cardiovascular-death-free survival for respective ABI categories 0.80−0.99 vs. 1.00−1.29 were 90% vs. 96%, 84% vs. 92%, and 60% vs. 87%. The 1-, 3-, and 5-year overall survival for ABI categories 0.80−0.99 vs. 1.00−1.29 were 85% vs. 92%, 75% vs. 83%, and 42% vs. 74%. Conclusions: Borderline ABI (0.90−0.99) associates with higher overall and cardiovascular mortality compared to ABI values 1.00−1.29.

Toe pressure should be part of a vascular surgeon's first-line investigation in the assessment of lower extremity artery disease and cardiovascular risk of a patient.

OBJECTIVE: Toe pressure (TP) is an accurate indicator of the peripheral vascular status of a patient and thus cardiovascular risk, with less susceptibility to errors than ankle-brachial index (ABI). This study aimed to analyze how ABI and TP measurements associate with overall survival and cardiovascular death and to analyze the TP of patients with ABI of 0.9 to 1.3. METHODS: The first ABI and TP measurements of a consecutive 6784 patients treated at the Helsinki University Hospital vascular surgery clinic between 1990 and 2009 were analyzed. Helsinki University Vascular Registry and the national Cause of Death Registry provided the data. RESULTS: The poorest survival was in patients with ABI >1.3 (10-year survival, 15.3%; hazard ratio, 2.2; 95% confidence interval, 1.9-2.6; P < .0001; reference group, ABI 0.9-1.3), followed by the patients with TP <30 mm Hg (10-year survival, 19.6%; hazard ratio, 2.0; 95% confidence interval, 1.7-2.2; P < .0001; reference group, TP ≥80 mm Hg). The best 10-year survival was in patients with TP ≥80 mm Hg (43.9%). Of the 642 patients with normal ABI (0.9-1.3), 18.7% had a TP <50 mm Hg. The highest cardiovascular death rate (64.6%) was in the patients with TP <30 mm Hg, and it was significantly lower than for the patients with TP >50 mm Hg. CONCLUSIONS: Low TP is associated significantly with survival and cardiovascular mortality. Patients with a normal ABI may have lower extremity artery disease (LEAD) and a considerable risk for a cardiovascular event. If only the ABI is measured in addition to clinical examination, a substantial proportion of patients may be left without LEAD diagnosis or adequate treatment of cardiovascular risk factors. Thus, especially if ABI is normal, LEAD is excluded only if TPs are also measured and are normal.

Osteoid Metaplasia in Femoral Artery Plaques Is Associated With the Clinical Severity of Lower Extremity Artery Disease in Men.

Lamellar metaplastic bone, osteoid metaplasia (OM), is found in atherosclerotic plaques, especially in the femoral arteries. In the carotid arteries, OM has been documented to be associated with plaque stability. This study investigated the clinical impact of OM load in femoral artery plaques of patients with lower extremity artery disease (LEAD) by using a deep learning-based image analysis algorithm. Plaques from 90 patients undergoing endarterectomy of the common femoral artery were collected and analyzed. After decalcification and fixation, 4-µm-thick longitudinal sections were stained with hematoxylin and eosin, digitized, and uploaded as whole-slide images on a cloud-based platform. A deep learning-based image analysis algorithm was trained to analyze the area percentage of OM in whole-slide images. Clinical data were extracted from electronic patient records, and the association with OM was analyzed. Fifty-one (56.7%) sections had OM. Females with diabetes had a higher area percentage of OM than females without diabetes. In male patients, the area percentage of OM inversely correlated with toe pressure and was significantly associated with severe symptoms of LEAD including rest pain, ulcer, or gangrene. According to our results, OM is a typical feature of femoral artery plaques and can be quantified using a deep learning-based image analysis method. The association of OM load with clinical features of LEAD appears to differ between male and female patients, highlighting the need for a gender-specific approach in the study of the mechanisms of atherosclerotic disease. In addition, the role of plaque characteristics in the treatment of atherosclerotic lesions warrants further consideration in the future.

Data on association of ankle pressure and ankle brachial index of symptomatic and contralateral lower extremities with overall and cardiovascular mortality in patients with lower extremity peripheral artery disease.

Data on survival curves for overall survival and freedom from cardiovascular death at different ankle brachial index (ABI) and ankle pressure (AP) are shown separately for symptomatic and contralateral lower limbs in 721 patients with lower extremity peripheral artery disease at up to 7 years follow-up. Cox regression analysis with confounding factors for ABI and AP are also shown. Dates and causes of death were collected from the Finnish national statistics registry.