Gut hormones and endothelial dysfunction in patients with obesity and diabetes.

Overweight and obesity are the fifth leading risk for global deaths and its prevalence has doubled since 1980. At least 2.8 million adults, worldwide, die each year as a result of being overweight or obese. The deleterious effects of obesity are tightly related to diabetes, as they are often clinically present in combination to confer increased cardiovascular mortality. Thus, patients with diabetes and obesity are known to develop accelerated atherosclerosis characterized by a dysfunctional endothelium and decreased nitric oxide bioavailability. Recent clinical studies support, indeed, the use of incretin-based antidiabetic therapies for vascular protection. Thus, attention has been focusing on gut hormones and their role, not only in the regulation of appetite but also in vascular health. Intervention directed at modulating these molecules has the potential to decrease mortality of patients with diabetes and obesity. This review will cover part of the ongoing research to understand the role of gut hormones on endothelial function and vascular health.

Obesity, inflammation and endothelial dysfunction.

Cardiovascular disease is the leading cause of morbidity and mortality in obese individuals. Obesity dramatically increases the risk of development of metabolic and cardiovascular disease. This risk appears to originate from disruption in adipose tissue function leading to a chronic inflammatory state and to dysregulation of the endocrine and paracrine actions of adipocyte-derived factors. These, in turn, impair vascular homeostasis and lead to endothelial dysfunction. An altered endothelial cell phenotype and endothelial dysfunction are common among all obesity-related complications. A crucial aspect of endothelial dysfunction is reduced nitric oxide (NO) bioavailability. A systemic pro-inflammatory state in combination with hyperglycemia, insulin resistance, oxidative stress and activation of the renin angiotensin system are systemic disturbances in obese individuals that contribute independently and synergistically to decreasing NO bioavailability. On the other hand, pro-inflammatory cytokines are locally produced by perivascular fat and act through a paracrine mechanism to independently contribute to endothelial dysfunction and smooth muscle cell dysfunction and to the pathogenesis of vascular disease in obese individuals. The promising discovery that obesity-induced vascular dysfunction is, at least in part, reversible, with weight loss strategies and drugs that promote vascular health, has not been sufficiently proved to prevent the cardiovascular complication of obesity on a large scale. In this review we discuss the pathophysiological mechanisms underlying inflammation and vascular damage in obese patients.

[Diabetes worsens the clinical manifestations and prognosis of concurrent cardiovascular and kidney disease]. / Come il diabete peggiora espressioni e prognosi della malattia cardio-vasculo-renale.

Numerous studies have shown a marked increase in the incidence of diabetes mellitus worldwide. Diabetes mellitus is currently considered equivalent to coronary artery disease in terms of prognostic risk stratification, and its high prevalence makes this clinical condition the first cause of end-stage renal disease requiring chronic hemodialysis or kidney transplant. Even if chronic kidney disease remains the ''Cinderella of the cardiovascular profile'', the presence of microalbuminuria is closely related to a high risk of development of coronary artery disease. The same risk factors that impair heart function are also harmful to the kidney, and the common pathophysiological features of the two systems are at the origin of a new subspecialty, cardionephrology. A crucial task of cardiologists and nephrologists is the early identification of high risk patients with concurrent cardiovascular and kidney disease. The utilization of simple screening methods such as assessment of microalbuminuria and glomerular filtration rate by family doctors may help in establishing prevention strategies directed towards cardiovascular risk and progression of kidney disease. In conclusion, early stratification of cardiovascular risk, coupled with primary prevention strategies aimed at the general population, is warranted to obtain a significant reduction of kidney and cardiovascular disease and of the need for chronic hemodialysis treatment. This strategy is safe and cost-effective in comparison with the costs of chronic dialysis of patients affected by chronic kidney disease.

Two novel mutations and a new STK11/LKB1 gene isoform in Peutz-Jeghers patients.

Peutz-Jeghers syndrome (PJS) is a rare autosomal dominantly inherited disorder with variable expression and incomplete penetrance characterized by mucocutaneous pigmentation, predisposition to hamartomatous intestinal polyposis, and various other neoplasms. It occurs in approximately 1 in 8,300 to 29,000 live births. In nearly 50% of patients PJS is caused by germ line mutations in the STK11/LKB1 serine/threonine kinase gene, the only kinase gene currently known to act as a tumor suppressor. We have performed a mutation search in the STK11/LKB1 gene in 8 sporadic cases and 3 PJS families using a combination of different screening techniques. We have identified four mutations, two of which I177N and the IVS2+1A->G, were previously unreported. We have also evaluated the presence of cDNA alterations by means of RT-PCR analysis and direct cDNA sequencing and have found two aberrant transcripts in a single PJS case despite the lack of any apparent genomic alteration. Finally, we report the presence of a novel STK11/LKB1 cDNA isoform observed in all the normal subjects studied as well as in the majority of the PJS patients.

Oesophageal electrical cardioversion of atrial fibrillation.

Atrial fibrillation is the most common cardiac arrhythmia and the most frequent cause of hospitalization and utilization expense among all heart diseases. Taking into account persistent atrial fibrillation we know that, in order to cardiovert persistent atrial fibrillation, external direct current cardioversion is the method most frequently used to restore sinus rhythm. But external cardioversion has also some limitations: it requires high energy direct current shocks so that patients have to be anaesthetised, which means a dedicated apparatus and place to adequately assist the patients. The oesophageal cardioversion is an alternative method to restore sinus rhythm, which could obviate some of these limitations of external cardioversion. Compared to external cardioversion oesophageal one has lower defibrillation impedance and requires lower energies to restore sinus rhythm, increasing for the same energy level, success rate. Using low energy shocks, a mild sedation is sufficient to make the procedure well tolerated by most of patients. Other 2 important advantages coming from low energy shocks are the safety in patients with pacemaker or implantable cardioverter-defibrillator and the availability of a back up atrial pacing. Oesophageal cardioversion is not indeed a new technique. Looking at literature, studies in animals and in humans have been performed since the 60s, assessing feasibility, effectiveness and safety of such a procedure. The oesophageal-precordial cardioversion is usually performed on an outpatient regimen, resulting in a very cost-effective method to cardiovert patients with persistent atrial fibrillation, which may definitely represent a real alternative technique to external cardioversion.

Non-invasive hemodynamic analysis in cardiac resynchronization therapy patients wearing quadripolar left ventricular leads: the importance of pacing electrode selection.

AIM: Quadripolar left ventricular (LV) leads offer multiple choices for LV pacing increasing programming flexibility. Aim of this study is to assess the influence of LV pacing vector selection on hemodynamic parameters for patients who underwent cardiac resynchronization therapy (CRT) using quadripolar LV lead chronically evaluated with a non-invasive approach by Nexfin(®) system provided analysis (BMEYE B.V., Amsterdam, The Netherlands). METHODS AND RESULTS: In 16 CRT patients implanted with a quadripolar LV lead (mean follow-up 8,8 ±13,4 months after implantation), we measured Cardiac Output (CO), Mean Blood Pressure (MBP), Total Peripheral Resistance (TPR), LV dP/dt max and Stroke volume (SV) from each one of the ten available bipolar pacing configurations. All the recorded parameters showed marked differences among the ten pacing configurations, but dP/dt max, SV and TPR were those showing the wider range, depending of the selected pacing vector. The average delta for the whole group of subjects between the maximum and minimum hemodynamic values for each pacing configuration were 15.9% for SV, 21.1% for dP/dt max and 20.3% for TPR. Inter-individual analysis of data failed to identify a link between a specific pacing vector and the hemodynamic response. CONCLUSION: Our study demonstrates that different bipolar pacing configurations, even if arising from a single CS branch, substantially modify the hemodynamic effect of LV pacing in CRT patients. Moreover, the non-invasive hemodynamic analysis suggests the better pacing configuration should be established individually and could represent an important issue in optimizing CRT during follow-up.

Towards a personalized and dynamic CRT-D. A computational cardiovascular model dedicated to therapy optimization.

BACKGROUND: In spite of cardiac resynchronization therapy (CRT) benefits, 25-30% of patients are still non responders. One of the possible reasons could be the non optimal atrioventricular (AV) and interventricular (VV) intervals settings. Our aim was to exploit a numerical model of cardiovascular system for AV and VV intervals optimization in CRT. METHODS: A numerical model of the cardiovascular system CRT-dedicated was previously developed. Echocardiographic parameters, Systemic aortic pressure and ECG were collected in 20 consecutive patients before and after CRT. Patient data were simulated by the model that was used to optimize and set into the device the intervals at the baseline and at the follow up. The optimal AV and VV intervals were chosen to optimize the simulated selected variable/s on the base of both echocardiographic and electrocardiographic parameters. RESULTS: Intervals were different for each patient and in most cases, they changed at follow up. The model can well reproduce clinical data as verified with Bland Altman analysis and T-test (p > 0.05). Left ventricular remodeling was 38.7% and left ventricular ejection fraction increasing was 11% against the 15% and 6% reported in literature, respectively. CONCLUSIONS: The developed numerical model could reproduce patients conditions at the baseline and at the follow up including the CRT effects. The model could be used to optimize AV and VV intervals at the baseline and at the follow up realizing a personalized and dynamic CRT. A patient tailored CRT could improve patients outcome in comparison to literature data.

Use of a comprehensive numerical model to improve biventricular pacemaker temporization in patients affected by heart failure undergoing to CRT-D therapy.

Cardiac resynchronization therapy by biventricular pacemaker/ICD implantation is a validated therapy for patients affected by heart failure with asynchrony of ventricular contraction. Considering the large number of parameters which play a role in cardiac resynchronization therapy, a comprehensive numerical model of cardiocirculatory system could be a useful tool to support clinical decisions. A variable elastance model of ventricles was updated to model the interventricular septum and to simulate the interventricular and the intraventricular desynchrony, and the effect of the biventricular stimulation. In addition, a numerical model of the biventricular pacemaker, which drives the beginning of the heart chambers and interventricular septum contraction, was also developed. In order to validate the model, five patients affected by dilated cardiomyopathy were analysed by echocardiography and electrocardiography before implantation, 24 h and 3 months after the implantation. The developed numerical model permits to reproduce clinical data and to estimate the trend of parameters that are difficult to measure (i.e. left ventricular systolic elastance). Furthermore, the model permits to study the effect of different biventricular pacemaker temporizations on hemodynamic variables.