Background—: Endothelial dysfunction promotes atherosclerosis and precedes acute cardiovascular events. We investigated whether in vivo magnetic resonance imaging with the use of an albumin-binding contrast agent, gadofosveset, could detect endothelial damage associated with atherosclerosis in apolipoprotein E–deficient (ApoE ^−/− ) mice. Furthermore, we tested whether magnetic resonance imaging could noninvasively assess endothelial function by measuring the endothelial-dependent vasodilation in response to acetylcholine. Methods and Results—: ApoE ^−/− mice were imaged at 4, 8, and 12 weeks after commencement of a high-fat diet. Statin-treated ApoE ^−/− mice were scanned after 12 weeks of a high-fat diet. Wild-type mice were imaged before and 48 hours after injection of Russell's viper venom, an endothelial toxin. Delayed enhancement magnetic resonance imaging and T1 mapping of the brachiocephalic artery, 30 minutes after injection of gadofosveset, showed increased vessel wall enhancement and relaxation rate (R ₁ ) with progression of atherosclerosis in ApoE ^−/− (R ₁ [s ⁻¹ ]: R _{4 weeks} 2.42±0.35, R _{8 weeks} 3.45±0.54, R _{12 weeks} 3.83±0.52) and Russell's viper venom–injected wild-type mice (R ₁ =4.57±0.86). Conversely, wild-type (R ₁ =2.15±0.34) and statin-treated ApoE ^−/− (R ₁ =3.0±0.65) mice showed less enhancement. Uptake of gadofosveset correlated with Evans blue staining, morphological changes of endothelial cells, and widening of the cell-cell junctions, suggesting that uptake occurs in regions of increased vascular permeability. Endothelial-dependent vasomotor responses showed vasoconstriction of the arteries of the ApoE ^−/− (−22.22±7.95%) and Russell's viper venom–injected (−10.37±17.60%) mice compared with wild-type mice (32.45±12.35%). Statin treatment improved endothelium morphology and function (−8.12±8.22%). Conclusions—: We demonstrate the noninvasive assessment of endothelial permeability and function with the use of an albumin-binding magnetic resonance contrast agent. Blood albumin leakage could be a surrogate marker for the in vivo evaluation of interventions that aim to restore the endothelium.

Chile's gallbladder cancer rates are among the highest in the world, being the leading cause of cancer deaths among Chilean women. To provide insights into the etiology of gallbladder cancer, we conducted an ecologic study examining the geographical variation of gallbladder cancer and several putative risk factors. The relative risk of dying from gallbladder cancer between 1985 and 2003 was estimated for each of the 333 Chilean counties, using a hierarchical Poisson regression model, adjusting for age, sex and geographical location. The risk of gallbladder cancer mortality was analyzed in relation to region, poverty, Amerindian (Mapuche) population, typhoid fever and access to cholecystectomy, using logistic regression analysis. There were 27,183 gallbladder cancer deaths, with age and sex‐adjusted county mortality rates ranging from 8.2 to 12.4 per 100,000 inhabitants. Rates were highest in inland and southern regions. Compared to the northern‐coast, the northern‐inland region had a 10‐fold risk (95% of confidence interval (95% CI): 2.4–42.2) and the southern‐inland region had a 26‐fold risk (95% CI: 6.0–114.2). Independent of region, other risk factors for gallbladder cancer included a high Mapuche population (Odds ratio (OR):3.9, 95% CI 1.8–8.7), high typhoid fever incidence (OR:2.9, 95% CI 1.2–6.9), high poverty (OR:5.1, 95% CI 1.6–15.9), low access to cholecystectomy (OR:3.9, 95% CI 1.5–10.1), low access to hospital care (OR:14.2, 95% CI 4.2–48.7) and high urbanization (OR:8.0, 95% CI 3.4–18.7). Our results suggest that gallbladder cancer in Chile may be related to both genetic factors and poor living conditions. Future analytic studies are needed to further clarify the role of these factors in gallbladder cancer etiology.

We assessed population incidence rates 1998–2002 and 5‐year survival rates of 317 primary gallbladder cancer (GBC) entered in the population‐based cancer registry in Valdivia. We analyzed GBC incidence (Poisson regression) and GBC survival (Cox regression). Cases were identified by histology (69.4%), clinical work‐up (21.8%), or death certificate only (8.8%). Main symptoms were abdominal pain (82.8%), jaundice (53.6%) nausea (42.6%), and weight loss (38.2%); at diagnosis, 64% had Stage TNM IV. In the period, 4% of histopathological studies from presumptively benign cholecystectomies presented GBC. GBC cases were mainly females (76.0%), urban residents (70.3%), Hispanic (83.7%) of low schooling <4 years (64.0%). GBC standardized incidence rate per 100,000 (SIR) were all 17.5 (95%CI: 15.5–19.4), women 24.3, and men 8.6 (p < 0.00001); Mapuche 25.0, Hispanic 16.2 (p = 0.09). The highest SIRs were in Mapuche (269.2) and Hispanic women (199.6) with 8 years of schooling. Low schooling, female and urban residence were independent risk factors. By December 31, 2007, 6 (1.9%) cases were living, 280 (88.3%) died from GBC, 32 (10.1%) were lost of follow‐up. Kaplan Meier Global 5‐year survival was: 10.3%, 85% at stage I and 1.9% at stage IV; median survival: 3.4 months. Independent poor prognostic factors were TNM IV, jaundice and nonincidental diagnoses. Our results suggest that women of Mapuche ancestry with low schooling (>50 years) are at the highest risk of presenting and dying from GBC and should be the target for early detection programs.

Background—: The magnetic resonance longitudinal relaxation time (T ₁ ) changes with thrombus age in humans. In this study, we investigate the possible mechanisms that give rise to the T ₁ signal in venous thrombi and whether changes in T ₁ relaxation time are informative of the susceptibility to lysis. Methods and Results—: Venous thrombosis was induced in the vena cava of BALB/C mice, and temporal changes in T ₁ relaxation time correlated with thrombus composition. The mean T ₁ relaxation time of thrombus was shortest at 7days following thrombus induction and returned to that of blood as the thrombus resolved. T ₁ relaxation time was related to thrombus methemoglobin formation and further processing. Studies in inducible nitric oxide synthase ( iNOS ^−/− )–deficient mice revealed that inducible nitric oxide synthase mediates oxidation of erythrocyte lysis–derived iron to paramagnetic Fe ³⁺ , which causes thrombus T ₁ relaxation time shortening. Studies using chemokine receptor-2–deficient mice ( Ccr2 ^−/− ) revealed that the return of the T ₁ signal to that of blood is regulated by removal of Fe ³⁺ by macrophages that accumulate in the thrombus during its resolution. Quantification of T ₁ relaxation time was a good predictor of successful thrombolysis with a cutoff point of <747 ms having a sensitivity and specificity to predict successful lysis of 83% and 94%, respectively. Conclusions—: The source of the T ₁ signal in the thrombus results from the oxidation of iron (released from the lysis of trapped erythrocytes in the thrombus) to its paramagnetic Fe ³⁺ form. Quantification of T ₁ relaxation time appears to be a good predictor of the success of thrombolysis.

Myocardial infarction (MI) remains the leading cause of death globally, imposing a significant burden on healthcare systems and patients. The gut–heart axis, a bidirectional network connecting gut health to cardiovascular outcomes, has recently emerged as a critical factor in MI pathophysiology. Disruptions in this axis, including gut dysbiosis and compromised intestinal barrier integrity, lead to systemic inflammation driven by gut-derived metabolites like lipopolysaccharides (LPSs) and trimethylamine N-oxide (TMAO), both of which exacerbate MI progression. In contrast, metabolites such as short-chain fatty acids (SCFAs) from a balanced microbiota exhibit protective effects against cardiac damage. This review examines the molecular mediators of the gut–heart axis, considering the role of factors like sex-specific hormones, aging, diet, physical activity, and alcohol consumption on gut health and MI outcomes. Additionally, we highlight therapeutic approaches, including dietary interventions, personalized probiotics, and exercise regimens. Addressing the gut–heart axis holds promise for reducing MI risk and improving recovery, positioning it as a novel target in cardiovascular therapy.

Objective—: Deep venous thrombosis is a major health problem. Thrombolytic therapies are effective in recanalizing the veins and preventing post-thrombotic complications, but there is no consensus on selection criteria. The aim of this study was to investigate a fibrin-specific MRI contrast agent (EP-2104R) for the accurate quantification of thrombus’ fibrin content in vivo and for the identification of thrombus suitable for thrombolysis. Approach and Results—: Venous thrombosis was induced in the inferior vena cava of 8- to 10-week-old male BALB/C mice and MRI performed 2, 4, 7, 10, 14, and 21 days later. Eighteen mice were scanned at each time point pre and 2 hours post injection of EP-2104R (8.0 μmol/kg) with 12 mice at each time point used to correlate fibrin contrast uptake with thrombus’ histological stage and fibrin content. Six mice at each time point were immediately subjected to intravascular thrombolytic therapy (10 mg/kg of tissue-type plasminogen activator). Mice were imaged to assess response to lytic therapy 24 hours after thrombolytic treatment. Two mice at each time point were scanned post injection of 0.2 mmol/kg of Gd-DTPA (gadolinium with diethylenetriaminepentacetate, Magnevist, Schering AG, Berlin, Germany) for control purpose. Contrast uptake was correlated positively with the fibrin content of the thrombus measured by Western blotting ( R ² =0.889; P <0.001). Thrombus relaxation rate ( R ₁ ) post contrast and the change in visualized thrombus size on late gadolinium enhancement inversion recovery MRI pre–EP-2104R and post–EP-2104R injection were the best predictors for successful thrombolysis (area under the curve, 0.989 [95% confidence interval, 0.97–1.00] and 0.994 [95% confidence interval, 0.98–1.00] respectively). Conclusions—: MRI with a fibrin-specific contrast agent accurately estimates thrombus fibrin content in vivo and identifies thrombi that are amenable for thrombolysis.