Il rimodellamento inadeguato del ventricolo sinistro è associato con i markers di apoptosi miocitaria in pazienti con scompenso cardiaco cronico.

Tra i numerosi fattori che sono coinvolti nello sviluppo e nella progressione dello scompenso cardiaco cronico (SCC), la perdita di cardiomiociti dovuta a morte cellulare per fenomeni apoptotici contribuisce in maniera rilevante ad una alterazione strutturale della parete del ventricolo sinistro (VS) e spesso alla dilatazione della camera cardiaca, realizzando il quadro morfologico e funzionale tipico del rimodellamento ventricolare. Il rimodellamento ventricolare sinistro, che è caratterizzato da dilatazione ventricolare sinistra, diminuita frazione di eiezione e ipertrofia inappropriata, è uno dei processi fisiopatologici che porta allo scompenso cardiaco diastolico e sistolico. In particolare, il rimodellamento inadeguato del ventricolo sinistro è caratterizzato dall’instaurarsi di una disproporzione tra la massa del VS e il volume telediastolico dello stesso, a cui consegue un alterato rapporto massa/volume (M/V), con importanti modificazioni funzionali sulla meccanica cardiaca e sull’impatto prognostico del paziente. Attualmente è possibile valutare direttamente in “vivo” il tasso di apoptosi tissutale tramite la misurazione dei livelli plasmatici di Fas/Apo-1, una molecola presente sulla superficie cellulare che trasduce segnali di apoptosi all’interno della cellula. Di conseguenza, abbiamo ipotizzato che l’associazione tra un ridotto rapporto M/V ed elevati livelli plasmatici della forma solubile di FAS/Apo-1 possa riflettere il processo di rimodellamento inadeguato del VS e dunque essere associato ad un ruolo prognostico sfavorevole nei pazienti in cui tali parametri risultano alterati. Sono stati arruolati nello studio ottantuno pazienti con disfunzione sistolica ventricolare sinistra, frazione di eiezione (EF) del VS≤45% e volume telediastolico ventricolare > 75 ml/m² s. Tutti i pazienti sono stati sottoposti ad un esame ecocardiografico per via transtoracica per la valutazione del volume VS, della FE, della massa VS, del rapporto M/V e parametri di funzione diastolica (onda E, onda A, E/A, tempo di decelerazione dell'onda E rilevati durante campionamento PW-Doppler del flusso transmitralico). Sono stati dosati i valori circolanti di Fas/Apo-1, TNF-alfa, forma solubile del recettore di tipo 1 per il TNF (sTNFR1), forma solubile del recettore di tipo 2 per il TNF (sTNFR2) e Nt-proBNP. I pazienti che hanno mostrato un ridotto rapporto M/V e aumentati livelli di FAS/Apo-1 hanno mostrato la più bassa FE (p=0.0035), più alti livelli di TNF-alfa (p=0.0008), sTNFR1 (p=0.0039) e sTNFR2 (p=0.012). La sopravvivenza globale è stata del 17% nei pazienti con un ridotto rapporto M/V e livelli aumentati di FAS/Apo-1, rispetto al 53% dei pazienti con un normale rapporto M/V e aumentati livelli di FAS/Apo-1, al 71% di quelli con un ridotto rapporto M/V e normali livelli di FAS/Apo-1, e al 94% di quelli con un normale rapporto M/V e normali valori di FAS/Apo-1 (log-rank:12.81, p=0.0051). Pertanto i dati preliminari in nostro possesso sembrano indicare che in pazienti con disfunzione sistolica ventricolare sinistra, una riduzione del rapporto M/V e l'aumento del valore plasmatico di FAS/Apo-1 siano associati con alterazioni più severe di funzionalità sisto-diastolica del ventricolo sinistro e con una prognosi peggiore

Cardiovascular Disease in People with and without Diabetes: Current Trends and Emerging Risk Factors

Cardiovascular disease (CVD) remains the leading cause of morbidity and mortality worldwide. That can be ascribed to population growth and aging as well as to the ever-increasing prevalence of type 2 diabetes (T2D) and obesity. While death rates from atherosclerotic CVD (ASCVD) among older age groups are falling, the number of persons with heart failure (HF) is projected to increase, and more than half of them have HF with preserved ejection faction (HFpEF). Within this framework, it is necessary to develop incrementally sophisticated risk scores implementing emerging risk factors, for an improved cardiovascular risk estimation and stratification both in people with and without diabetes. This would allow to identify people with higher risk of developing CVD and thus to apply preventive strategies. Such strategies should take into account important sex-differences that concern cardiac and vascular responses to risk factors, CVD burden and mortality. Besides, because the HFpEF epidemic continue to grow and therapeutic interventions being tested are failing, efforts should be directed towards a more accurate diagnosis and definition and improved categorization of phenotypes and stages. The main objectives of this thesis were: 1) to describe trends of CVD in people with diabetes; 2) to evaluate the association between established and emerging risk factors, cardiovascular outcomes and mortality in people with and without diabetes; 3) to investigate the pathophysiological mechanisms of HFpEF in people with and without diabetes and how novel markers can improve its detection. Overall, this thesis indicated that the ongoing epidemics of diabetes and CVD call for improved risk stratification models implementing emerging risk factors, in order to identify people at higher cardiovascular risk. We found that several emerging cardiovascular risk factors such as kidney function measures, vitamin D and K status, could indeed be potentially useful in this regard, as significantly and prospectively associated to measures of cardiovascular health, cardiovascular outcomes and mortality. Some of these associations differed between men and women, suggesting important sex differences in cardiovascular pathophysiology, CVD risk and burden. HFpEF gained a prominent role among CVD both in people with and without diabetes and has emerged as a critical public health problem with increasing prevalence. Accordingly, innovative integrated approaches for the diagnosis of diastolic dysfunction and HFpEF that take into account its phenotypic diversity as well as sex disparities are urgently needed

Plasma natriuretic peptides relate to distintict patterns of left ventricular dysfunction in chronic heart failure with preserved ejection fraction.

Aims: In HFpEF patients plasma levels of natriuretic peptides (NP) are frequently low and in several HFpEF trials outcomes differed between patients with low and high NP levels. Structural and functional differences of echocardiographic LV remodeling in chronic HFpEF patients with low and high NP levels were therefore investigated. Methods and Results: Data of 83 stable HFpEF patients were derived from routine outpatient clinic visits. A gender-matched control group without cardiovascular disease (n=33) was identified. Median NT-proBNP was 161 pg/ml with 34.9 % of HFpEF patients below the diagnostic cut-off value of 125 pg/ml and 68.7 % of HFpEF patients below the eligibility threshold used in trials (<300 pg/ml). When HFpEF patients with below median NT-proBNP were compared to controls, HFpEF patients had LV concentric remodeling, worse LV systolic function, slower LV relaxation and higher LV diastolic stiffness. When HFpEF patients with below median NT-proBNP were compared to HFpEF patients with above median NT-proBNP, LV concentric remodeling, LV systolic function and LV relaxation were comparable but LV diastolic stiffness continued to deteriorate. On multiple linear regression analysis especially measures of LV stiffness significantly related to NT-proBNP. Conclusions: When echocardiographic LV remodeling and dysfunction were compared in HFpEF patients with below and above median NT-proBNP, concentric LV remodeling, systolic LV dysfunction and slow LV relaxation were similar in both groups but diastolic LV stiffness worse in patients with above median NT-proBNP. Failure to improve LV stiffness could have contributed to the neutral outcome of trials in patients with high NT-proBNP

Distinct Myocardial Targets for Diabetes Therapy in Heart Failure With Preserved or Reduced Ejection Fraction

Noncardiac comorbidities such as diabetes mellitus (DM) have different outcomes in heart failure with preserved ejection fraction (HFpEF) compared with heart failure with reduced ejection fraction (HFrEF). These different outcomes are the result of distinct myocardial effects of DM on HFpEF and HFrEF, which relate to different mechanisms driving myocardial remodeling in each heart failure phenotype. Myocardial remodeling is driven by microvascular endothelial inflammation in HFpEF and by cardiomyocyte cell death in HFrEF. Evidence consists of: different biomarker profiles, in which inflammatory markers are prominent in HFpEF and markers of myocardial injury or wall stress are prominent in HFrEF; reduced coronary flow reserve with microvascular rarefaction in HFpEF; and upregulation of free radical-producing enzymes in endothelial cells in HFpEF and in cardiomyocytes in HFrEF. As biopsies from patients with diabetic cardiomyopathy reveal, DM affects failing myocardium by phenotype-specific mechanisms. In HFpEF, DM mainly increases cardiomyocyte hypertrophy and stiffness, probably because of hyperinsulinemia and microvascular endothelial inflammation. In HFrEF, DM augments replacement fibrosis because of cardiomyocyte cell death induced by lipotoxicity or advanced glycation end products. Because DM exerts distinct effects on myocardial remodeling in HFpEF and HFrEF, the heart failure phenotype is important for DM therapy

Renal denervation for resistant hypertension: no

In recent years, catheter-based radiofrequency denervation of the renal arteries (RDN) has emerged as a potential treatment for resistant hypertension. Though initial non-randomized and randomized small studies demonstrate large reductions in office blood pressure, RDN superiority to conventional treatment is not confirmed either by randomized controlled trials or by large international registries. Increasing evidence supports the hypothesis that a rational pharmacological therapeutic scheme is equally or more effective; this approach, together with an intervention aimed at increasing patient’s compliance with treatment, might solve most of the cases of refractory hypertension. Thus, based on current evidence, renal denervation should not be routinely used to treat resistant hypertension. Though the possibility that RDN might be useful in other subsets of hypertensive patients exists, it has never been proven. Thus, its use should be limited to extreme situations, when all other possible treatments have failed

Arterial-ventricular coupling and parameters of vascular stiffness in hypertensive patients:Role of gender

Objective Non-invasive estimation of arterial–ventricular coupling has been extensively used for the evaluation of cardiovascular performance, however, a relative small amount of data is available regarding arterial–ventricular coupling and its components in hypertension. The present study was designed to investigate the relationship between left ventricular elastance, arterial elastance, parameters of vascular stiffness and the influence of gender in a population of hypertensive individuals. Methods In 102 patients, trans-thoracic cardiac ultrasound, parameters of aortic stiffness (carotid-femoral pulse wave velocity) and wave reflection (augmentation index) were recorded. Ultrasound images of common carotid arteries were acquired for the assessment of intima-media thickness as well as carotid compliance and distensibility coefficient. Results Mean age was 61 years, 32% diabetes, 56% dyslipidemia, 9% previous cardiovascular events; women (n = 32) and men were superimposable for cardiovascular risk factors prevalence. In the population, ventricular elastance was significantly correlated with arterial elastance (r = 0.887), age (r = 0.334), gender (r = −0.494), BMI (r = −0.313), augmentation index (r = 0.479) (all p < 0.001); and with carotid compliance and distensibility coefficient (r = 0.229 and r = − 0.250, respectively, both p < 0.05); however, only arterial elastance and gender were independently associated with ventricular elastance in multiple regression models adjusted for confounding factors. Gender-specific analysis revealed that arterial elastance and augmentation index remained statistically significant associated with ventricular elastance in men (r = 0.275, p = 0.04); instead augmentation index was no longer significant (r = 0.052, p = 0.77) in the female sex. Conclusions In hypertensive patients, main determinants of ventricular elastance are arterial elastance, as an integrated index of arterial vascular load, and gender; however, pressure augmentation might play an additional role in men

Diabetes as a cardiovascular risk factor : An overview of global trends of macro and micro vascular complications

The global prevalence of diabetes is predicted to increase dramatically in the coming decades as the population grows and ages, in parallel with the rising burden of overweight and obesity, in both developed and developing countries. Cardiovascular disease represents the principal cause of death and morbidity among people with diabetes, especially in those with type 2 diabetes mellitus. Adults with diabetes have 2–4 times increased cardiovascular risk compared with adults without diabetes, and the risk rises with worsening glycaemic control. Diabetes has been associated with 75% increase in mortality rate in adults, and cardiovascular disease accounts for a large part of the excess mortality. Diabetes-related macrovascular and microvascular complications, including coronary heart disease, cerebrovascular disease, heart failure, peripheral vascular disease, chronic renal disease, diabetic retinopathy and cardiovascular autonomic neuropathy are responsible for the impaired quality of life, disability and premature death associated with diabetes. Given the substantial clinical impact of diabetes as a cardiovascular risk factor, there has been a growing focus on diabetes-related complications. While some population-based studies suggest that the epidemiology of such complications is changing and that rates of all-cause and cardiovascular mortality among individuals with diabetes are decreasing in high-income countries, the economic and social burden of diabetes is expected to rise due to changing demographics and lifestyle especially in middle- and low-income countries. In this review we outline data from population-based studies on recent and long-term trends in diabetes-related complications

Diabetes as a cardiovascular risk factor: An overview of global trends of macro and micro vascular complications

The global prevalence of diabetes is predicted to increase dramatically in the coming decades as the population grows and ages, in parallel with the rising burden of overweight and obesity, in both developed and developing countries. Cardiovascular disease represents the principal cause of death and morbidity among people with diabetes, especially in those with type 2 diabetes mellitus. Adults with diabetes have 2–4 times increased cardiovascular risk compared with adults without diabetes, and the risk rises with worsening glycaemic control. Diabetes has been associated with 75% increase in mortality rate in adults, and cardiovascular disease accounts for a large part of the excess mortality. Diabetes-related macrovascular and microvascular complications, including coronary heart disease, cerebrovascular disease, heart failure, peripheral vascular disease, chronic renal disease, diabetic retinopathy and cardiovascular autonomic neuropathy are responsible for the impaired quality of life, disability and premature death associated with diabetes. Given the substantial clinical impact of diabetes as a cardiovascular risk factor, there has been a growing focus on diabetes-related complications. While some population-based studies suggest that the epidemiology of such complications is changing and that rates of all-cause and cardiovascular mortality among individuals with diabetes are decreasing in high-income countries, the economic and social burden of diabetes is expected to rise due to changing demographics and lifestyle especially in middle- and low-income countries. In this review we outline data from population-based studies on recent and long-term trends in diabetes-related complications

The Association of Vitamin D and Vitamin K Status with Subclinical Measures of Cardiovascular Health and All-Cause Mortality in Older Adults: The Hoorn Study

BACKGROUND: A low vitamin D and K status has been associated with increased cardiovascular disease (CVD) risk but the evidence of their combined effect on cardiovascular health is limited. OBJECTIVES: Our study aimed to investigate the prospective association of vitamin D and K status with subclinical measures of cardiovascular health and all-cause mortality among a population of Dutch Caucasians. METHODS: We performed an observational prospective study on 601 participants of the Hoorn Study (mean ± SD age: 70 ± 6 y, 50.4% women, BMI: 27.2 ± 4.0 kg/m2), of whom 321 underwent an echocardiogram in 2000-2001 and 2007-2009. Vitamin D and K status was assessed at baseline by serum 25-hydroxyvitamin D [25(OH)D] and plasma desphospho-uncarboxylated matrix-gla protein (dp-ucMGP)-high concentrations indicate low vitamin K status. Vital status was assessed from baseline until 2018. We studied the association of categories of 25(OH)D (stratified by the clinical cutoff of 50 mmol/L) and dp-ucMGP (stratified by the median value of 568 pmol/L) with echocardiographic measures using linear regression and with all-cause mortality using Cox regression, adjusted for confounders. RESULTS: Compared with markers of normal vitamin D and K status, markers of low vitamin D and K status were prospectively associated with increased left ventricular mass index (5.9 g/m2.7; 95% CI: 1.8, 10.0 g/m2.7). Participants with low vitamin D and K status were also at increased risk of all-cause mortality with an HR of 1.64 (95% CI: 1.12, 2.39) compared with normal vitamin D and K status. CONCLUSIONS: A combination of low vitamin D and K status is associated with adverse cardiac remodeling and increased risk of all-cause mortality in men and women. Future studies should investigate whether vitamin D and K supplementation could help to improve cardiovascular health and to decrease CVD risk