Roberta Della Bona

Sex-Related Differences in Myocardial Remodeling

Sex has a profound impact on myocardial remodeling, which is defined as the molecular and cellular events after an injury to the myocardium (i.e., necrosis, pressure overload, volume overload, and aging) leading to a change in shape, dimension, and function of cardiac chambers. Indeed, experimental studies and post-mortem and observational clinical studies suggest the presence of important differences in myocardial remodeling between females and males in response to different types of injures including aging, pressure and volume overload, and myocardial infarction. Interestingly, the remodeling process appears to be more favorable in women versus men; women are more likely to present heart failure with preserved systolic function and are at greater risk for low output syndrome acutely. These differences between men and women are widely held to be related to sex hormones such as estrogen, although the molecular effects of estrogen on ventricular cardiomyocytes are incompletely understood. In this review, we summarize the evidence supporting these notions and discuss the underlying mechanisms and the clinical implications.

Stress cardiomyopathy (tako-tsubo) triggered by nervous system diseases: A systematic review of the reported cases

BACKGROUND It is not clarified whether the transient, regional left ventricular dysfunction (TRLVD) associated with several neurological disorders shares the same pathophysiology with the classical tako-tsubo cardiomyopathy occurring without overt neurological disease, and whether it is appropriate to include these patients in a single stress cardiomyopathy (SCM) condition. METHODS In February 2012, we systematically explored major electronic medical information sources to identify cases of TRLVD triggered by neurological disorders. RESULTS The 81 selected papers reported a total of 124 patients, suffering from neurological disorders, in whom TRLVD occurred: 117 with central nervous system diseases, 6 with peripheral nervous system diseases and 1 with both systems involved. Most patients were females (n=102), mean age was 63 ± 15 years, and the majority presented with an apex-involving pattern. The most common disease described was subarachnoid hemorrhage (n=52), followed by stroke/transient ischemic attack (n=24), and seizures (n=18). TRLVD in neurological patients was often associated with need of inotropic support, orotracheal intubation, cerebrovascular spasm and delayed surgery. CONCLUSIONS TRLVD is a complication of neurological diseases, in particular in female patients in post-menopausal phase. The predilection for neurological damage at or close to the insular cortex highlights the pivotal role of sympathetic over-activation. Many other similarities with tako-tsubo support the inclusion in a single SCM category.

Inflammatory biomarkers and coronary heart disease: from bench to bedside and back

Inflammation plays a pivotal role in all stages of atherosclerosis from endothelial dysfunction and plaque formation to plaque destabilization and disruption. Inflammatory biomarkers, originally studied to better understand the pathophysiology of atherosclerosis, have generated increasing interest among clinicians, because of their utility in the challenging problems of diagnosis and risk assessment of patients with suspected or proved coronary heart disease. Moreover, in fascinating perspective, they could be used as therapeutic target, counteracting initiation, progression, and development of complications of atherosclerosis. In this review, we will provide an overview of the more promising inflammatory biomarkers, focusing on their utility and limitations in the clinical setting.

Polymorphonuclear neutrophils and instability of the atherosclerotic plaque: a causative role?

ObjectiveThe aim of this review is to examine the role of polymorphonuclear neutrophils (PMNs) in the evolution of atherosclerosis.IntroductionWhile the role of PMNs in the evolution of atherosclerosic process has failed until recently to attract much attention, a body of research carried out over the last decade has disclosed the unexpectedly complex behavior of these cells, unraveling an unexpected key role for PMNs in the onset and progression of atheroma.MethodsA PubMed database search was performed for studies providing evidences on the role of PMNs in the development and progression of atherosclerotic lesion.Results and ConclusionsActivated PMNs were shown to produce and release reactive oxygen species, inflammatory leukotrienes and proteolytic lysosomal enzymes, directly inducing vascular damage. Activated PMNs also secrete myeloperoxidase, involved in lipoprotein oxidation. PMNs have a finite lifespan and typically die through apoptosis, which thus represents a counter-regulatory mechanism limiting the toxic potential of these short-lived, terminally differentiated cells. Dysregulation of this process probably contributes to the pathogenesis and progression of several inflammatory diseases. Moreover, high circulating levels of PMN–platelet aggregates have been reported in patients with clinical atherosclerosis, and recent studies suggest that these aggregates may play a role in vascular response to injury. It has been suggested that this heterotypic interaction between platelets and leukocytes might represent a link between hemostasis/thrombosis and the inflammatory response.

Delayed neutrophil apoptosis in patients with unstable angina: relation to C-reactive protein and recurrence of instability

AIMS To investigate spontaneous polymorphonuclear neutrophils (PMNs) apoptosis in unstable angina (UA) and its association with recurrence of instability. METHODS AND RESULTS We compared PMNs apoptotic rate at 4 and 24 h in patients with UA, stable angina (SA), and controls (H) with two different protocols by flow cytometry. We measured apoptotic rate of isolated PMNs (Protocol 1) in 30 UA patients, 13 SA patients, and 34 H; and apoptosis of PMNs in whole blood culture (Protocol 2) in further 10 UA patients, 7 SA patients, and 6 H. Serum high-sensitivity C-reactive protein was also measured. Polymorphonuclear neutrophils of UA patients showed a decreased apoptotic rate compared with SA patients and H at 4 h in Protocol 1 (both P < 0.01), and at 24 h in Protocol 2 (P < 0.05 and <0.01, respectively). In overall population, a negative correlation was found between apoptotic rate at 4 h and high-sensitivity C-reactive protein levels (P < 0.01). Six among 40 patients with UA had early recurrence of symptoms and their apoptotic rate was significantly reduced compared with UA patients without recurrence of symptoms (P = 0.024). CONCLUSIONS Our study demonstrates delayed PMN apoptosis in UA. This alteration might be involved in the persistence of inflammatory activation and affects recurrence of instability.

Different Apparent Prognostic Value of hsCRP in Type 2 Diabetic and Nondiabetic Patients with Acute Coronary Syndromes

BACKGROUND C-reactive protein (CRP) is an established prognostic marker in acute coronary syndromes (ACS); however, no study has specifically addressed its prognostic role in type 2 diabetes with ACS. We evaluated the prognostic role of CRP separately in diabetic and nondiabetic patients with ACS. METHODS We enrolled 251 patients with unstable angina and measured serum concentrations of high sensitivity (hs)CRP. Ninety-seven patients underwent coronary angiography with evaluation of atherosclerotic disease severity and extent by Bogaty score. Assessed endpoint was the combined occurrence of myocardial infarction (MI) and death at 1 year. RESULTS No significant differences were found in hs-CRP between patients with and without diabetes. By Cox regression, hsCRP was not associated with 1-year follow-up events in diabetic patients but was strongly associated with events in nondiabetic patients (P = 0.0012). Coronary angiography exhibited a higher extent index in patients with diabetes than in those without (P = 0.04). hsCRP concentrations were not associated with angiographic atherosclerotic burden. By Cox analysis, hsCRP and extent score were associated with events in patients who underwent coronary angiography (P < 0.001 and P = 0.034, respectively). In nondiabetic patients, hsCRP was the only predictor of events at 1-year follow-up (P < 0.001), whereas in diabetic patients, hsCRP was not associated with events and a weak association was observed for extent score (P = 0.06). CONCLUSIONS Our study suggests that different pathophysiological mechanisms may be responsible for MI and death in unstable angina patients with or without diabetes and that severity of coronary artery disease plays a major role in diabetes (and inflammation in the absence of diabetes).

Thromboxane production in morbidly obese subjects

Postmortem studies have demonstrated that morbidly obese subjects, surprisingly, have less coronary atherosclerosis than obese subjects. However, the reasons for this apparent protection from atherosclerosis are not yet clear. Thromboxane A2, a marker of platelet activation, is greater in obese subjects than in lean subjects, and this might be a clue to their increased cardiovascular risk. However, data on thromboxane A2 in morbidly obese subjects are lacking; therefore, we hypothesized that lower levels of thromboxane A2 in morbidly obese subjects might play a role in their lower atherothrombotic burden. We measured the serum levels of thromboxane B2 (TxB2), a stable metabolite of thromboxane A2, high-sensitivity C-reactive protein (hs-CRP) and leptin in 17 lean subjects (body mass index [BMI] 22.9 ± 1.6 kg/m(2)), 25 obese subjects (BMI 32.6 ± 2.4 kg/m(2)), and 23 morbidly obese subjects (BMI 48.6 ± 7.1 kg/m(2)), without insulin resistance, diabetes, or overt cardiovascular disease. The serum TxB2 levels were lower in the lean subjects than in the obese subjects (p = 0.046) and in the morbidly obese subjects than in the lean and obese subjects (p = 0.015 and p <0.001, respectively). In contrast, the hs-CRP and leptin levels were greater in the obese than in the lean subjects (hs-CRP, p <0.001; leptin, p <0.001) and in the morbidly obese subjects than in the lean subjects (p <0.001 for both). Leptin was also higher in the morbidly obese subjects than in the obese subjects (p <0.001). TxB2 negatively correlated with leptin and BMI. hs-CRP correlated with leptin, and both also correlated with waist circumference, BMI, and homeostasis model assessment of insulin-resistance. In conclusion, insulin-sensitive morbidly obese subjects had lower levels of TxB2 than the obese subjects and lean subjects, suggesting that reduced platelet activation could play a role in the paradoxical protection of morbidly obese subjects from atherosclerosis, despite the greater levels of leptin.

Microparticles and microRNAs: new players in the complex field of coagulation

Atherosclerosis is a complex process that begins with endothelial dysfunction, and continues with several inflammatory processes leading, eventually, to plaque rupture and formation of arterial thrombus. Increased platelet reactivity and classical coagulation pathways are not the only players of the whole thrombotic process: microparticles (MPs), irregularly shaped small vesicles released from the plasma membrane after cell activation, apoptosis, or exposure to shear stress have been demonstrated to be involved in such a process. MicroRNAs (MiRs), small-non-coding single-strand RNAs acting as post-transcriptional modulator of target gene expression are expressed in the large majority of eukaryotes. MiRs are implicated in several phenomena: control of metabolism, control of cell-differentiation, control of cell-proliferation and control of cell-apoptosis, therefore contributing to physiologic and pathogenic processes in hematologic, genetic, infective and cardiac diseases. Microparticles operate as a delivery system of MiRs, playing an active and important role in processes such as coagulation and thrombosis. These novel findings also suggest MPs and, in particular MIRs, as possible and promising therapeutic targets.

Effects of bariatric surgery on cardiac remodeling: Clinical and pathophysiologic implications

Purpose: To assess the effects of bariatric surgery (BS) on cardiac mass, volumes and function as compared to persistent morbid obesity. Although beneficial effects of weight loss on cardiac function have been reported, systematic studies on the effect of BS as compared to persistent morbid obesity are lacking. Methods: One-hundred morbidly obese patients (body mass index -BMI- 47.7±7 kg/m2) referred for BS prospectively underwent an echocardiogram: 65 underwent BS and 35 did not. Fifty-one operated and 29 non-operated patients underwent repeat imaging after 2 years. Results: Operated patients showed a significant decrease in weight and BMI paralleled by a significant reduction of left ventricular (LV) mass (from 222.9±52.2 to 207.7±50g) and LV end-diastolic and end-systolic volumes (LVEDV from 124.6±29.3 to 119.4±28.7 and LVESV from 55.3±16.5 to 49.4±15ml) and by a significant increase of LV ejection fraction (from 55.9±4.8 to 59.2±4.4%). In contrast, in non-operated patients LV mass (from 226.5±71.4 to 241.4±94.7g), volumes [LVEDV from 52.8±5.1 to 54.2±6.6 and LVESV from 32.1±3.5 to 34.9±6ml] significantly increased and ejection fraction deteriorated (from 57.1±5.1 to 54.7±7.4%). At multivariate analysis, BS was the only significant predictor of change in LV end-systolic volume while weight change predicted change in LV mass. Conclusions: In extreme obesity the sustained weight loss achieved with BS is associated to an improvement of cardiac structure and function, while persistent severe obesity is associated to progressive deterioration. These favorable cardiac effects associated to previously described positive metabolic effects make BS an attractive therapeutic option in this setting of patients.

Serum levels of γ-glutamyltransferase and progression of coronary atherosclerosis.

BackgroundProgression of coronary atherosclerosis (ATS) has clinical implications. Serum levels of &ggr;-glutamyltransferase (GGT), a marker of oxidative stress, predict the risk of cardiovascular events. However, the role of GGT levels in the progression of coronary ATS has never been established. Materials and methodsConsecutive patients undergoing two coronary angiographies (CAs) separated by at least 6 months were prospectively enrolled between May 2008 and June 2010. All patients were discharged on statins after the first CA. The severity and extent of coronary ATS were graded according to Bogaty’s score, and the variation ([INCREMENT]) in stenosis score and extent index between follow-up (S2 and E2) and basal values (S1 and E1) were calculated. Predictors of [INCREMENT]S2−1 and [INCREMENT]E2−1 were assessed among clinical and laboratory data, including GGT levels, analyzed as [INCREMENT] between follow-up and basal values ([INCREMENT]GGT2−1). ResultsWe enrolled 100 consecutive patients (age 64±11 years, 68% men). Compliance with statin therapy was 100%. At multiple regression analysis, [INCREMENT]GGT2−1 was the only independent predictor of [INCREMENT]S2−1 (B=0.18, SE=0.07, P=0.05), with [INCREMENT]low-density lipoprotein-cholesterol2−1 levels being of borderline statistical significance (P=0.07). On multiple regression analysis, [INCREMENT]GGT2−1 was the only independent predictor of [INCREMENT]E2−1 (B=0.32; SE=0.11; P=0.04), with active smoking habit and [INCREMENT]fibrinogen2−1 levels being of borderline statistical significance (P=0.08 and 0.06, respectively). Conclusion[INCREMENT]GGT2−1 is associated with angiographic coronary ATS progression in patients with ischemic heart disease on statin treatment, suggesting that oxidative stress may be another therapeutic target for preventing ATS progression beyond that of lipid-lowering therapies.