Unfolded Protein Response Signaling Pathway Regulates Cardiac Function in Heart Failure with Preserved Ejection Fraction

Heart failure with preserved ejection fraction (HFpEF) is a clinical syndrome effecting more than 3 million people in the United States alone. HFpEF patients have a 5-year survival rate of less than 50% with no change in prognosis over the last 30 years. The lack of clinical treatments point to an urgent need for mechanistic studies of HFpEF pathogenesis. The cardiac remodeling and dysfunction in HFpEF is driven by comorbidities such as obesity, diabetes, arterial hypertension and endothelial dysfunction which lead to systemic inflammation. Here we report that, in mice, simultaneous metabolic and hypertensive stress, through the combination of high fat diet (HFD) and constitutive nitric oxide (NO) synthase inhibition by administration of N[w]-nitro-l-arginine methyl ester (L-NAME) recapitulates systemic and cardiovascular alterations of human HFpEF. The heart failure phenotype was only observed under combined treatment with HFD and L-NAME and was associated with molecular changes within the cardiomyocytes. Specifically, the spliced form of X-box binding protein 1 (Xbp1s), a downstream effector of the unfolded protein response (UPR), exhibited a significant reduction in the HFpEF model hearts and cardiomyocytes. This decrease in Xbp1s was also observed in human HFpEF hearts. Reduction in Xbp1s was caused by increased inducible NO synthase (iNOS) activity and S-nitrosylation of IRE1a, which ultimately led to a defect in XBP1 splicing activity. Importantly, cardiomyocyte-specific inducible overexpression of Xbp1s partially ameliorated diastolic dysfunction, exercise intolerance and pulmonary congestion in HFpEF mice. We have developed a novel preclinical model of HFpEF, unveiling iNOS-driven dysregulation of Xbp1s as a crucial mechanism of cardiomyocyte dysfunction. These results demonstrate the essential role of protein homeostasis dysregulation in HFpEF cardiomyocytes and suggest that inhibiting iNOS activity may be a viable therapeutic strategy in this condition

Rotational atherectomy for the treatment of isolated femoral artery traumatic lesion: a case report

We describe the case of a 50-year-old man with an isolated plaque of the left distal superficial femoral artery (SFA), probably not related to atherosclerosis, but rather to a traumatic event. He was admitted to our hospital because of intermittent claudication. The critical distal SFA stenosis was documented by angiography and the lesion was treated by rotational atherectomy without stent implantation. At 1-year follow up, Doppler Ultrasound scan demonstrated a normal flow pattern of the left SFA and downstream districts in the absence of any complication. Therefore, rotational atherectomy is a safe and effective technique particularly in cases of peripheral arterial disease wherein stent implantation is dangerous

Epigenetic Switch at Atp2a2 and Myh7 Gene Promoters in Pressure Overload-Induced Heart Failure

Re-induction of fetal genes and/or re-expression of postnatal genes represent hallmarks of pathological cardiac remodeling, and are considered important in the progression of the normal heart towards heart failure (HF). Whether epigenetic modifications are involved in these processes is currently under investigation. Here we hypothesized that histone chromatin modifications may underlie changes in the gene expression program during pressure overload-induced HF. We evaluated chromatin marks at the promoter regions of the sarcoplasmic reticulum Ca2+ATPase (SERCA-2A) and β-myosin-heavy chain (β-MHC) genes (Atp2a2 and Myh7, respectively) in murine hearts after one or eight weeks of pressure overload induced by transverse aortic constriction (TAC). As expected, all TAC hearts displayed a significant reduction in SERCA-2A and a significant induction of β-MHC mRNA levels. Interestingly, opposite histone H3 modifications were identified in the promoter regions of these genes after TAC, including H3 dimethylation (me2) at lysine (K) 4 (H3K4me2) and K9 (H3K9me2), H3 trimethylation (me3) at K27 (H3K27me3) and dimethylation (me2) at K36 (H3K36me2). Consistently, a significant reduction of lysine-specific demethylase KDM2A could be found after eight weeks of TAC at the Atp2a2 promoter. Moreover, opposite changes in the recruitment of DNA methylation machinery components (DNA methyltransferases DNMT1 and DNMT3b, and methyl CpG binding protein 2 MeCp2) were found at the Atp2a2 or Myh7 promoters after TAC. Taken together, these results suggest that epigenetic modifications may underlie gene expression reprogramming in the adult murine heart under conditions of pressure overload, and might be involved in the progression of the normal heart towards HF

Total occlusion of the abdominal aorta in a patient with renal failure and refractory hypertension: a case report

Total occlusion of the abdominal aorta is unusual, and potentially catastrophic. It occurs in patients with advanced atherosclerotic occlusive disease, and can cause severe ischemic manifestations, depending on the site of obstruction. Prompt and appropriate diagnostic and therapeutic approaches are important whenever this condition is suspected, in order to avoid a fatal outcome. The development of a complex network of collaterals may prevent the manifestation of acute ischemic phenomena, and cause a delay in diagnosis and treatment. Here we report the clinical case of a 59-year-old man who was referred to our Department for evaluation of renal failure and refractory hypertension. Ultrasonography and 99mTc-DTPA scintigraphy showed a shrunken, non-functioning left kidney, while CT angiography and aortography showed the complete occlusion of the aorta from below the right renal artery down to the bifurcation of both common iliac arteries, with a critical stenosis of the origin of the right renal artery, an occlusion of the left renal artery as well as of the origin of the inferior mesenteric artery. The patient was referred to the surgery department for aorto-bifemoral bypass surgery and re-implantation of the right renal artery

Abdominal aortic aneurysm in patients affected by intermittent claudication: prevalence and clinical predictors

BACKGROUND: Abdominal aortic aneurysm (AAA) is a frequent cause of death among elderly. Patients affected by lower extremity peripheral arterial disease (LE-PAD) seem to be particularly at high risk for AAA. We aimed this study at assessing the prevalence and the clinical predictors of the presence of AAA in a homogeneous cohort of LE-PAD patients affected by intermittent claudication. METHODS: We performed an abdominal ultrasound in 213 consecutive patients with documented LE-PAD (ankle/brachial index ≤ 0.90) attending our outpatient clinic for intermittent claudication. For each patient we registered cardiovascular risk factors and comorbidities, and measured neutrophil count. RESULTS: The ultrasound was inconclusive in 3 patients (1.4%), thus 210 patients (169 males, 41 females, mean age 65.9 ± 9.8 yr) entered the study. Overall, AAA was present in 19 patients (9.0%), with a not significant higher prevalence in men than in women (10.1% vs 4.9%, p = 0.300). Patients with AAA were older (71.2 ± 7.0 vs 65.4 ± 9.9 years, p = 0.015), were more likely to have hypertension (94.7% vs 71.2%, p = 0.027), and greater neutrophil count (5.5 [4.5 - 6.2] vs 4.1 [3.2 - 5.5] x 10(3)/μL, p = 0.010). Importantly, the c-statistic for neutrophil count (0.73, 95% CI 0.60 - 0.86, p = 0.010) was higher than that for age (0.67, CI 0.56-0.78, p = 0.017). The prevalence of AAA in claudicant patients with a neutrophil count ≥ 5.1 x 10(3)/μL (cut-off identified at ROC analysis) was as high as 29.0%. CONCLUSIONS: Prevalence of AAA in claudicant patients is much higher than that reported in the general population. Ultrasound screening should be considered in these patients, especially in those with an elevated neutrophil count

AngioJet® rheolytic thrombectomy for acute superficial femoral artery stent or femoropopliteal by-pass thrombosis

Thrombosis of superficial femoral artery (SFA) nitinol stents or polytetrafluoroethylene (PTFE) femoropopliteal bypass grafts after discontinuation of antiplatelet therapy is an emergent clinical challenge of acute limb ischemia (ALI), requiring immediate percutaneous intervention. Currently, there is no evidence-based approach for the management of such complications. We describe the cases of two patients presenting with ALI due to nitinol stent thrombosis after discontinuation of antiplatelet therapy and the case of a patient presenting with ALI due to PTFE femoropopliteal graft thrombosis in which limb salvage was obtained by AngioJet® rheolytic thrombectomy and re-stenting. In both cases, the thrombus was successfully removed using the Possis AngioJet® mechanical thrombectomy catheter and percutaneous transluminal angioplasty (PTA) was performed to recanalize two femoropopliteal nitinol stents and a femoropopliteal PTFE graft. In both cases, optimal angiographic result was obtained. To the best of our knowledge, these are the first three cases reporting the use of the AngioJet rheolytic thrombectomy in ALI due to stent or graft thrombosis. Taken together, these cases suggest that AngioJet® rheolytic thrombectomy might represent a novel effective strategy in the percutaneous treatment of stent or graft thrombosis determining ALI

Endovascular treatment of carotid artery stenosis: evidences from randomized controlled trials and actual indications

Atherosclerotic stenosis of common and internal carotid arteries is a well-recognized risk factor for ischemic stroke, and revascularization has been proven to be the main tool of prevention, particularly for patients with stenosis- related symptoms. While for many years surgical carotid endarterectomy (CEA) has been considered the gold-standard strategy to restore vascular patency, recently the endovascular treatment through percutaneous angioplasty and stent implantation (CAS) has become a valid alternative. In the last years, interesting data about the comparison of these strategies have emerged. CAS seems to cause more peri-procedural strokes, but may also avoid many adverse events related to surgery and general anaesthesia, including peri-procedural myocardial infarction. For these reasons, it was initially considered a second-choice strategy to be adopted in patients for whom surgery was contraindicated. However, more recent trials have shown that CAS might be considered an effective alternative to CEA. Moreover, the rapid evolution of CAS technique and materials suggests its potential to improve outcome and possible superiority compared to CEA in the next future. Purpose of this review is to discuss the most recent clinical evidences concerning the treatment of carotid artery stenosis, with a special focus on the endovascular treatment

Akap1 deficiency promotes mitochondrial aberrations and exacerbates cardiac injury following permanent coronary ligation via enhanced mitophagy and apoptosis

A-kinase anchoring proteins (AKAPs) transmit signals cues from seven-transmembrane receptors to specific sub-cellular locations. Mitochondrial AKAPs encoded by the Akap1 gene have been shown to modulate mitochondrial function and reactive oxygen species (ROS) production in the heart. Under conditions of hypoxia, mitochondrial AKAP121 undergoes proteolytic degradation mediated, at least in part, by the E3 ubiquitin ligase Seven In-Absentia Homolog 2 (Siah2). In the present study we hypothesized that Akap1 might be crucial to preserve mitochondrial function and structure, and cardiac responses to myocardial ischemia. To test this, eight-week-old Akap1 knockout mice (Akap1(-/-)), Siah2 knockout mice (Siah2(-/-)) or their wild-type (wt) littermates underwent myocardial infarction (MI) by permanent left coronary artery ligation. Age and gender matched mice of either genotype underwent a left thoracotomy without coronary ligation and were used as controls (sham). Twenty-four hours after coronary ligation, Akap1(-/-) mice displayed larger infarct size compared to Siah2(-/-) or wt mice. One week after MI, cardiac function and survival were also significantly reduced in Akap1(-/-) mice, while cardiac fibrosis was significantly increased. Akap1 deletion was associated with remarkable mitochondrial structural abnormalities at electron microscopy, increased ROS production and reduced mitochondrial function after MI. These alterations were associated with enhanced cardiac mitophagy and apoptosis. Autophagy inhibition by 3-methyladenine significantly reduced apoptosis and ameliorated cardiac dysfunction following MI in Akap1(-/-) mice. These results demonstrate that Akap1 deficiency promotes cardiac mitochondrial aberrations and mitophagy, enhancing infarct size, pathological cardiac remodeling and mortality under ischemic conditions. Thus, mitochondrial AKAPs might represent important players in the development of post-ischemic cardiac remodeling and novel therapeutic targets