Left ventricular myocardial performance

Recentemente Tei e collaboratori, hanno proposto un nuovo indice Doppler-derivato in grado di valutare simultaneamente la funzione sistolica e diastolica. Questo indice di performance cardiaca (MPI), definito come la somma del tempo di contrazione isovolumetrica e tempo di rilasciamento isovolumetrico diviso per il tempo di eiezione ventricolare sinistro, è considerato di facile esecuzione, non dipendente dalla geometria ventricolare, non invasivo, riproducibile e indipendente dalla frequenza cardiaca e dalla pressione arteriosa. L’MPI ha dimostrato di avere un’importante utilità clinica. È infatti prolungato in molte malattie cardiache, anche in assenza di segni clinici. Studi hanno dimostrato che l’MPI correla bene con misure invasive di funzione sistolica e diastolica, fornendo informazioni prognostiche su morbilità e mortalità nei pazienti con cardiopatia ischemica, amiloidosi cardiaca, cardiomiopatia dilatativa, ipertensione polmonare primitiva e variazioni di funzione ventricolare sinistra come risultato di terapie farmacologiche. L’MPI risulta essere modificato anche in pazienti asintomatici che presentano fattori di rischio come il diabete mellito e l’ipertensione arteriosa. Orem et al. ha registrato variazioni dell’MPI in una popolazione diabetica con diversi gradi di albuminuria. Più recentemente, l’MPI ha mostrato risultati promettenti nella valutazione della funzione ventricolare prenatale e in bambini e adulti con malattie cardiache congenite. L'obiettivo di questa tesi è quello di analizzare le applicazioni cliniche dell’ MPI in diverse condizioni fisiologiche e patologiche, chiarendo alcuni aspetti della dinamica ventricolare sinistra. Nel primo studio, abbiamo dimostrato che la geometria ventricolare sinistra rappresenta un fattore determinante della performance del miocardio. In realtà, i nostri dati dimostrano una correlazione tra MPI e spessore relativo di parete ma non con la massa indicizzata con la superficie corporea. La dipendenza dell’MPI dalla geometria di camera ventricolare deve essere presa in considerazione durante l'applicazione dell’indice per la valutazione della performance miocardica come marcatore prognostico nella malattia cardiaca in cui la geometria ventricolare può essere modificata. Nel secondo studio l’MPI è stato valutato per l’identificazione delle anomalie cardiache subcliniche in un gruppo omogeneo di pazienti asintomatici con diabete mellito tipo 2, di recente diagnosi, con o senza ipertensione arteriosa. L’incremento dell’MPI è dovuto principalmente ad un prolungamento della IRT. Una correlazione tra MPI e il valore di HbA1c è risultata significativa indicando il suo ruolo come marker precoce di controllo metabolico. I nostri risultati potrebbero avere importanti implicazioni cliniche. In primo luogo, questo indice potrebbe rappresentare un facile approccio per individuare una fase precoce di cardiomiopatia diabetica che preceda la disfunzione diastolica, quindi monitorare la storia naturale della malattia diabetica stessa. In secondo luogo, l’MPI potrebbe essere utile per valutare indirettamente il controllo metabolico o suggerire un rapido avvio di specifici trattamenti farmacologici che possano aiutare il decorso clinico della cardiomiopatia diabetica. Una diagnosi precoce di cardiomiopatia diabetica tramite l’MPI non è solo importante, ma può anche rivelarsi essenziale per testare nuovi approcci terapeutici in corso di malattia diabetica. Infine, nel terzo studio, l’MPI sembra essere una tecnica non invasiva sensibile per l’individuazione sub-clinica di una disfunzione ventricolare sinistra in pazienti con sclerosi multipla trattati con basse dosi di mitoxantrone, un agente antineoplastico della famiglia degli antracenedioni. Tale indice sembra fornire migliori informazioni prognostiche per quanto concerne il rischio di cardiotossicità, rispetto alle misurazioni ecocardiografiche convenzionali. Pensiamo che l’MPI possa essere un parametro aggiuntivo all'ecocardiografia convenzionale nel monitoraggio degli effetti collaterali cardiaci, in grado di individuare una cardiotossicità subclinica da mitoxantrone. In conclusione, una semplice misura Doppler-derivata in grado di esprimere la performance globale del miocardio, è correlata alla complessa funzione cardiaca e sembra essere un indicatore utile di risultati clinici, rappresentando un indice aggiuntivo per la diagnosi e per la gestione clinica dei pazienti con molte malattie non solo cardiache ma anche sistemiche.Recently, a conceptually new Doppler index that combines the assessment of systolic and diastolic left ventricular (LV) performance was proposed by Tei and co-workers. This Myocardial Performance Index (MPI), which is defined as the sum of isovolumetric contraction time and isovolumetric relaxation time divided by the ejection time, was reported to be simple, non-geometrical, non-invasive, reproducible and independent of the heart rate and blood pressure. The MPI has been shown to have significant clinical utility. It is prolonged in many cardiac diseases even in the absence of clinical signs. Studies have demonstrated that MPI correlates well with invasive measures of both systolic and diastolic function in adults and provides prognostic information about morbidity and mortality in patients with ischemic heart disease, cardiac amyloidosis, dilated cardiomyopathy, primary pulmonary hypertension and detects early LV functional improvement as a result of drug therapy. MPI is also abnormal in individuals without overt cardiac disease who have risk factors such as diabetes mellitus and treated and untreated hypertension. Orem et al. demonstrated progressively more abnormal MPI with increasing degrees of albuminuria in a diabetic population. More recently, the MPI has shown promise in the assessment of right ventricular function in fetus, children and adults with various heart disease. The aim of this thesis was to analyse the LV myocardial performance, applying the MPI in various physiological and pathological conditions to elucidate some aspects of LV myocardial dynamic. In the first study, we demonstrated that LV geometry represents an important determinant of the myocardial performance. In fact, our data demonstrates a correlation between MPI and RWT but not with LVM/BSA. The MPI geometry-dependence must be taken into consideration during the application of the Index for the evaluation of myocardial performance, and when used as a prognostic marker in cardiac disease where the LV geometry could be modified. In the second study the MPI has been confirmed able to identify the earliest abnormalities of cardiac performance at echocardiography in a homogeneous group of uncomplicated asymptomatic type 2 diabetic patients with very short duration of disease with or without hypertension. The MPI increase was mainly due to a prolongation of IRT. A correlation between MPI and the HbA1c value, was found indicating its role as an early marker of metabolic control. Our findings may have important clinical implications. First, this index could provide an easy approach to detect an earliest phase of diabetic cardiomyopathy that precede diastolic dysfunction, and to monitor the natural history of the diabetic disease. Second, MPI could be useful for indirectly assess the metabolic control or suggest an early start of specific pharmacological treatments that may help the clinical course of diabetic cardiomyopathy. Most importantly, whether such abnormalities may be reverted by optimal metabolic control and/or pharmacologic treatments could be determined. Diagnosing pre-clinical diabetic cardiomyopathy early through MPI is not only important but also may turn out to be essential for the appropriate clinical testing of new therapeutic approaches to diabetic disease. Finally, the MPI appears to be a sensitive noninvasive technique for detecting significant subclinical left ventricular dysfunction, in patients with multiple sclerosis treated with low dose of mitoxantrone, an antracenedione antineoplastic agent. Besides, provides important prognostic information for the risk of future cardiotoxicity, beyond other conventional echocardiographic measurements. We expect that MPI may be an adjunctive parameter to the conventional echocardiography in monitoring cardiac side effects and for detecting sub-clinical cardiotoxicity of mitoxantrone. In conclusion, a simple measure of Doppler index, combining systolic and diastolic time interval as an expression of global myocardial performance, correlates with overall cardiac function, seem to be a useful predictor of clinical outcome and could be an adjunctive index for the diagnosis and for the clinical management of patients with many cardiac and systemic disease

Left ventricular myocardial performance

Recentemente Tei e collaboratori, hanno proposto un nuovo indice Doppler-derivato in grado di valutare simultaneamente la funzione sistolica e diastolica. Questo indice di performance cardiaca (MPI), definito come la somma del tempo di contrazione isovolumetrica e tempo di rilasciamento isovolumetrico diviso per il tempo di eiezione ventricolare sinistro, è considerato di facile esecuzione, non dipendente dalla geometria ventricolare, non invasivo, riproducibile e indipendente dalla frequenza cardiaca e dalla pressione arteriosa. L’MPI ha dimostrato di avere un’importante utilità clinica. È infatti prolungato in molte malattie cardiache, anche in assenza di segni clinici. Studi hanno dimostrato che l’MPI correla bene con misure invasive di funzione sistolica e diastolica, fornendo informazioni prognostiche su morbilità e mortalità nei pazienti con cardiopatia ischemica, amiloidosi cardiaca, cardiomiopatia dilatativa, ipertensione polmonare primitiva e variazioni di funzione ventricolare sinistra come risultato di terapie farmacologiche. L’MPI risulta essere modificato anche in pazienti asintomatici che presentano fattori di rischio come il diabete mellito e l’ipertensione arteriosa. Orem et al. ha registrato variazioni dell’MPI in una popolazione diabetica con diversi gradi di albuminuria. Più recentemente, l’MPI ha mostrato risultati promettenti nella valutazione della funzione ventricolare prenatale e in bambini e adulti con malattie cardiache congenite. L'obiettivo di questa tesi è quello di analizzare le applicazioni cliniche dell’ MPI in diverse condizioni fisiologiche e patologiche, chiarendo alcuni aspetti della dinamica ventricolare sinistra. Nel primo studio, abbiamo dimostrato che la geometria ventricolare sinistra rappresenta un fattore determinante della performance del miocardio. In realtà, i nostri dati dimostrano una correlazione tra MPI e spessore relativo di parete ma non con la massa indicizzata con la superficie corporea. La dipendenza dell’MPI dalla geometria di camera ventricolare deve essere presa in considerazione durante l'applicazione dell’indice per la valutazione della performance miocardica come marcatore prognostico nella malattia cardiaca in cui la geometria ventricolare può essere modificata. Nel secondo studio l’MPI è stato valutato per l’identificazione delle anomalie cardiache subcliniche in un gruppo omogeneo di pazienti asintomatici con diabete mellito tipo 2, di recente diagnosi, con o senza ipertensione arteriosa. L’incremento dell’MPI è dovuto principalmente ad un prolungamento della IRT. Una correlazione tra MPI e il valore di HbA1c è risultata significativa indicando il suo ruolo come marker precoce di controllo metabolico. I nostri risultati potrebbero avere importanti implicazioni cliniche. In primo luogo, questo indice potrebbe rappresentare un facile approccio per individuare una fase precoce di cardiomiopatia diabetica che preceda la disfunzione diastolica, quindi monitorare la storia naturale della malattia diabetica stessa. In secondo luogo, l’MPI potrebbe essere utile per valutare indirettamente il controllo metabolico o suggerire un rapido avvio di specifici trattamenti farmacologici che possano aiutare il decorso clinico della cardiomiopatia diabetica. Una diagnosi precoce di cardiomiopatia diabetica tramite l’MPI non è solo importante, ma può anche rivelarsi essenziale per testare nuovi approcci terapeutici in corso di malattia diabetica. Infine, nel terzo studio, l’MPI sembra essere una tecnica non invasiva sensibile per l’individuazione sub-clinica di una disfunzione ventricolare sinistra in pazienti con sclerosi multipla trattati con basse dosi di mitoxantrone, un agente antineoplastico della famiglia degli antracenedioni. Tale indice sembra fornire migliori informazioni prognostiche per quanto concerne il rischio di cardiotossicità, rispetto alle misurazioni ecocardiografiche convenzionali. Pensiamo che l’MPI possa essere un parametro aggiuntivo all'ecocardiografia convenzionale nel monitoraggio degli effetti collaterali cardiaci, in grado di individuare una cardiotossicità subclinica da mitoxantrone. In conclusione, una semplice misura Doppler-derivata in grado di esprimere la performance globale del miocardio, è correlata alla complessa funzione cardiaca e sembra essere un indicatore utile di risultati clinici, rappresentando un indice aggiuntivo per la diagnosi e per la gestione clinica dei pazienti con molte malattie non solo cardiache ma anche sistemiche.Recently, a conceptually new Doppler index that combines the assessment of systolic and diastolic left ventricular (LV) performance was proposed by Tei and co-workers. This Myocardial Performance Index (MPI), which is defined as the sum of isovolumetric contraction time and isovolumetric relaxation time divided by the ejection time, was reported to be simple, non-geometrical, non-invasive, reproducible and independent of the heart rate and blood pressure. The MPI has been shown to have significant clinical utility. It is prolonged in many cardiac diseases even in the absence of clinical signs. Studies have demonstrated that MPI correlates well with invasive measures of both systolic and diastolic function in adults and provides prognostic information about morbidity and mortality in patients with ischemic heart disease, cardiac amyloidosis, dilated cardiomyopathy, primary pulmonary hypertension and detects early LV functional improvement as a result of drug therapy. MPI is also abnormal in individuals without overt cardiac disease who have risk factors such as diabetes mellitus and treated and untreated hypertension. Orem et al. demonstrated progressively more abnormal MPI with increasing degrees of albuminuria in a diabetic population. More recently, the MPI has shown promise in the assessment of right ventricular function in fetus, children and adults with various heart disease. The aim of this thesis was to analyse the LV myocardial performance, applying the MPI in various physiological and pathological conditions to elucidate some aspects of LV myocardial dynamic. In the first study, we demonstrated that LV geometry represents an important determinant of the myocardial performance. In fact, our data demonstrates a correlation between MPI and RWT but not with LVM/BSA. The MPI geometry-dependence must be taken into consideration during the application of the Index for the evaluation of myocardial performance, and when used as a prognostic marker in cardiac disease where the LV geometry could be modified. In the second study the MPI has been confirmed able to identify the earliest abnormalities of cardiac performance at echocardiography in a homogeneous group of uncomplicated asymptomatic type 2 diabetic patients with very short duration of disease with or without hypertension. The MPI increase was mainly due to a prolongation of IRT. A correlation between MPI and the HbA1c value, was found indicating its role as an early marker of metabolic control. Our findings may have important clinical implications. First, this index could provide an easy approach to detect an earliest phase of diabetic cardiomyopathy that precede diastolic dysfunction, and to monitor the natural history of the diabetic disease. Second, MPI could be useful for indirectly assess the metabolic control or suggest an early start of specific pharmacological treatments that may help the clinical course of diabetic cardiomyopathy. Most importantly, whether such abnormalities may be reverted by optimal metabolic control and/or pharmacologic treatments could be determined. Diagnosing pre-clinical diabetic cardiomyopathy early through MPI is not only important but also may turn out to be essential for the appropriate clinical testing of new therapeutic approaches to diabetic disease. Finally, the MPI appears to be a sensitive noninvasive technique for detecting significant subclinical left ventricular dysfunction, in patients with multiple sclerosis treated with low dose of mitoxantrone, an antracenedione antineoplastic agent. Besides, provides important prognostic information for the risk of future cardiotoxicity, beyond other conventional echocardiographic measurements. We expect that MPI may be an adjunctive parameter to the conventional echocardiography in monitoring cardiac side effects and for detecting sub-clinical cardiotoxicity of mitoxantrone. In conclusion, a simple measure of Doppler index, combining systolic and diastolic time interval as an expression of global myocardial performance, correlates with overall cardiac function, seem to be a useful predictor of clinical outcome and could be an adjunctive index for the diagnosis and for the clinical management of patients with many cardiac and systemic disease

Bi-Ventricular Myocardial Performance in Heart Failure: A New Approach to Evaluate Interventricular Dyssynchrony

Aims: Patients with heart failure (HF) exhibit ventricular dyssynchrony with negative effects on ventricular systolic and diastolic performance and poor prognosis. There is no consensus about the best approach for estimating the dyssynchrony and for selecting candidates for resynchronization therapy (CRT). We sought to evaluate whether Myocardial Performance Index (MPI), calculated as differences between left and right ventricle (LV, RV), ΔMPI, represents a marker of interventricular dyssynchrony. Methods: The study included 40 patients (22 males, 18 females, mean age 71±13) with NYHA functional class II-III, chronic heart failure (77% ischaemic), in optimal drug therapy for at least three months. All patients underwent a complete two-dimensional and Tissue Doppler Echocardiography (TDE), including an assessment of MPI in both ventricles. Results: Significant correlations were found between ΔMPI and QRS (r = 0.41, p < 0.001), with NYHA (r = 0.66, p < 0.001), with SPWMD (r = 0.32, p < 0.05), with LV ejection fraction (r = -0.32, p < 0.05), with Spv wave at the septal site of LV (r = -0.32, p < 0.05), and with IVMD (r = 0.44, p < 0.001). Ten patients have been re-evaluated six months after CRT implantation, and ΔMPI significantly correlated with the difference between basal LVEF and six months after CRT implantation (r = 0.43, p < 0.04). Conclusion: The ΔMPI could represent an integrative marker of interventricular dyssynchrony and could be considered as a new parameter in the patient selection process to be undergone CRT

Evaluation of the myocardial performance index for early detection of mitoxantrone-induced cardiotoxicity in patients with multiple sclerosis

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Myocardial involvement during the early course of type 2 diabetes mellitus: usefulness of Myocardial Performance Index

To evaluate whether myocardial performance index detects a subclinical impairment of left ventricular systolic and diastolic function in patients with early stage of type 2 diabetes, without coronary artery disease, with or without hypertension. Furthermore, to evaluate whether some echocardiographic parameters relate to the metabolic control. Fourty-five consecutive male patients (mean age 52.5 years) with type 2 diabetes mellitus of recent onset (23 hypertensives and 22 normotensives) and 22 age matched healthy controls males were analysed. All participants had normal exercise ECG. All subjects underwent standard and Doppler echocardiography for the assessment of the isovolumic Doppler time interval and Doppler-derived myocardial performance index. In all diabetic patients a glycated haemoglobin test was also performed

Mitoxantrone, pixantrone, and mitoxantrone (2-hydroxyethyl)piperazine are toll-like receptor 4 antagonists, inhibit NF-κB activation, and decrease TNF-alpha secretion in primary microglia

Toll-like receptor 4 (TLR4) recognizes various endogenous and microbial ligands and is an essential part in the innate immune system. TLR4 signaling initiates transcription factor NF-κB and production of proinflammatory cytokines. TLR4 contributes to the development or progression of various diseases including stroke, neuropathic pain, multiple sclerosis, rheumatoid arthritis and cancer, and better therapeutics are currently sought for these conditions. In this study, a library of 140 000 compounds was virtually screened and a resulting hit-list of 1000 compounds was tested using a cellular reporter system. The topoisomerase II inhibitor mitoxantrone and its analogues pixantrone and mitoxantrone (2-hydroxyethyl)piperazine were identified as inhibitors of TLR4 and NF-κB activation. Mitoxantrone was shown to bind directly to the TLR4, and pixantrone and mitoxantrone (2- hydroxyethyl)piperazine were shown to inhibit the production of proinflammatory cytokines such as tumor necrosis factor alpha (TNFα) in primary microglia. The inhibitory effect on NF-κB activation or on TNFα pro-duction was not mediated through cytotoxity at ≤ 1 μM concentration for pixantrone and mitoxantrone (2- hydroxyethyl)piperazine treated cells, as assessed by ATP counts. This study thus identifies a new mechanism of action for mitoxantrone, pixantrone, and mitoxantrone (2-hydroxyethyl)piperazine through the TLR4.Peer reviewe

Serum Albumin Is Inversely Associated With Portal Vein Thrombosis in Cirrhosis

We analyzed whether serum albumin is independently associated with portal vein thrombosis (PVT) in liver cirrhosis (LC) and if a biologic plausibility exists. This study was divided into three parts. In part 1 (retrospective analysis), 753 consecutive patients with LC with ultrasound-detected PVT were retrospectively analyzed. In part 2, 112 patients with LC and 56 matched controls were entered in the cross-sectional study. In part 3, 5 patients with cirrhosis were entered in the in vivo study and 4 healthy subjects (HSs) were entered in the in vitro study to explore if albumin may affect platelet activation by modulating oxidative stress. In the 753 patients with LC, the prevalence of PVT was 16.7%; logistic analysis showed that only age (odds ratio [OR], 1.024; P = 0.012) and serum albumin (OR, -0.422; P = 0.0001) significantly predicted patients with PVT. Analyzing the 112 patients with LC and controls, soluble clusters of differentiation (CD)40-ligand (P = 0.0238), soluble Nox2-derived peptide (sNox2-dp; P < 0.0001), and urinary excretion of isoprostanes (P = 0.0078) were higher in patients with LC. In LC, albumin was correlated with sCD4OL (Spearman's rank correlation coefficient [r(s)], -0.33; P < 0.001), sNox2-dp (r(s), -0.57; P < 0.0001), and urinary excretion of isoprostanes (r(s), -0.48; P < 0.0001) levels. The in vivo study showed a progressive decrease in platelet aggregation, sNox2-dp, and urinary 8-iso prostaglandin F2 alpha-III formation 2 hours and 3 days after albumin infusion. Finally, platelet aggregation, sNox2-dp, and isoprostane formation significantly decreased in platelets from HSs incubated with scalar concentrations of albumin. Conclusion: Low serum albumin in LC is associated with PVT, suggesting that albumin could be a modulator of the hemostatic system through interference with mechanisms regulating platelet activation

Frequency of left ventricular hypertrophy in non-valvular atrial fibrillation

Left ventricular hypertrophy (LVH) is significantly related to adverse clinical outcomes in patients at high risk of cardiovascular events. In patients with atrial fibrillation (AF), data on LVH, that is, prevalence and determinants, are inconsistent mainly because of different definitions and heterogeneity of study populations. We determined echocardiographic-based LVH prevalence and clinical factors independently associated with its development in a prospective cohort of patients with non-valvular (NV) AF. From the "Atrial Fibrillation Registry for Ankle-brachial Index Prevalence Assessment: Collaborative Italian Study" (ARAPACIS) population, 1,184 patients with NVAF (mean age 72 \ub1 11 years; 56% men) with complete data to define LVH were selected. ARAPACIS is a multicenter, observational, prospective, longitudinal on-going study designed to estimate prevalence of peripheral artery disease in patients with NVAF. We found a high prevalence of LVH (52%) in patients with NVAF. Compared to those without LVH, patients with AF with LVH were older and had a higher prevalence of hypertension, diabetes, and previous myocardial infarction (MI). A higher prevalence of ankle-brachial index 640.90 was seen in patients with LVH (22 vs 17%, p = 0.0392). Patients with LVH were at significantly higher thromboembolic risk, with CHA2DS2-VASc 652 seen in 93% of LVH and in 73% of patients without LVH (p <0.05). Women with LVH had a higher prevalence of concentric hypertrophy than men (46% vs 29%, p = 0.0003). Logistic regression analysis demonstrated that female gender (odds ratio [OR] 2.80, p <0.0001), age (OR 1.03 per year, p <0.001), hypertension (OR 2.30, p <0.001), diabetes (OR 1.62, p = 0.004), and previous MI (OR 1.96, p = 0.001) were independently associated with LVH. In conclusion, patients with NVAF have a high prevalence of LVH, which is related to female gender, older age, hypertension, and previous MI. These patients are at high thromboembolic risk and deserve a holistic approach to cardiovascular prevention