Klinefelter syndrome, insulin resistance, metabolic syndrome, and diabetes: review of literature and clinical perspectives

Klinefelter syndrome (KS), the most frequent chromosomic abnormality in males, is associated with hypergonadotropic hypogonadism and an increased risk of cardiovascular diseases (CVD). The mechanisms involved in increasing risk of cardiovascular morbidity and mortality are not completely understood. Insulin resistance, metabolic syndrome, and type 2 diabetes are more frequently diagnosed in KS than in the general population; however, the contribution of hypogonadism to metabolic derangement is highly controversial. Whether this dangerous combination of risk factors fully explains the CVD burden of KS patients remains unclear. In addition, testosterone replacement therapy only exerts a marginal action on the CVD system. This review summaries the current understandings of the complex relationship between KS, metabolic syndrome and cardiovascular risk in order to plan future studies and improve current strategies to reduce mortality in this high-risk population. Since fat accumulation and distribution seem to play a relevant role in triggering metabolic abnormalities, an early diagnosis and a tailored intervention strategy with drugs aimed at targeting excessive visceral fat deposition appear necessary in patients with KS

Biomarkers in Cardiovascular Disease: The Dilemma of Racial Differences.

See Article Hackler et al. https://doi.org/10.1161/JAHA.119.01272

Differential implications of gut-related metabolites on outcomes between heart failure and myocardial infarction.

Gut metabolites, through their role in atherosclerotic plaque formation,1 myocardial fibrosis,2 and myocardial function suppression,3 have been implicated in the pathophysiology of various cardiovascular (CV) diseases.4,5 Clinical studies have shown the association of gut metabolites with adverse outcomes, severity, and risk stratification in several CV diseases [e.g. heart failure (HF)6 and myocardial infarction (MI)7]. Despite most of the past studies having focused mainly on a single metabolite (i.e. trimethylamine N-oxide—TMAO), it has been suggested that additional metabolites of this pathway, involving choline and carnitine (e.g. acetyl-L-carnitine, L-carnitine, betaine, and γ-butyrobetaine), may have an additional role to play.8,9 However, to date, the proper contribution of the different metabolites in the spectrum of the CV diseases still remains unclear; therefore, the aim of the present study is to investigate whether there is a differential contribution of metabolite biomarkers of the choline/carnitine–metabolic pathway in association with the adverse outcomes of MI and HF.</p

Matrix-assisted laser desorption ionisation (MALDI) mass spectrometry (MS): basics and clinical applications

Background: Matrix-assisted laser desorption ionisation (MALDI) mass spectrometry (MS) has been used for more than 30 years. Compared with other analytical techniques, it offers ease of use, high throughput, robustness, cost-effectiveness, rapid analysis and sensitivity. As advan-tages, current clinical techniques (e.g. immunoassays) are unable to directly measure the biomarker; rather, they measure secondary signals. MALDI-MS has been exten-sively researched for clinical applications, and it is set for a breakthrough as a routine tool for clinical diagnostics.Content: This review reports on the principles of MALDI-MS and discusses current clinical applications and the future clinical prospects for MALDI-MS. Furthermore, the review assesses the limitations currently experienced in clinical assays, the advantages and the impact of MALDI-MS to transform clinical laboratories.Summary: MALDI-MS is widely used in clinical microbiol-ogy for the screening of microbial isolates; however, there is scope to apply MALDI-MS in the diagnosis, prognosis, therapeutic drug monitoring and biopsy imaging in many diseases.Outlook: There is considerable potential for MALDI-MS in clinic as a tool for screening, profiling and imaging because of its high sensitivity and specificity over alterna-tive techniques

Association of gut-related metabolites with outcome in acute heart failure

BackgroundTrimethylamine N-oxide (TMAO), a gut-related metabolite, is associated with heart failure (HF) outcomes. However, TMAO is the final product of a complex metabolic pathway (ie, choline/carnitine) that has never been entirely investigated in HF. The present study investigates a panel of metabolites involved in the TMAO-choline/carnitine metabolic pathway for their associations with outcome in acute HF patients.MethodsIn total, 806 plasma samples from acute HF patients were analyzed for TMAO, trimethyllysine, L-carnitine, acetyl-L-carnitine, γ-butyrobetaine, crotonobetaine, trimethylamine, betaine aldehyde, choline, and betaine using a developed liquid chromatography-tandem mass spectrometry method. Associations with outcome of all-cause mortality (death) and a composite of all-cause mortality and/or rehospitalization caused by HF (death/HF) at 30 days and 1 year were investigated.ResultsTMAO, trimethyllysine, L-carnitine, acetyl-L-carnitine, and γ-butyrobetaine were associated with death and death/HF at 30 days (short term; hazard ratio 1.30-1.49, P≤ .021) and at 1 year (long term; hazard ratio 1.15-1.25, P≤ .026) when adjusted for cardiac risk factors. L-carnitine and acetyl-L-carnitine were superior for short-term outcomes whereas TMAO was the superior metabolite for association with long-term outcomes. Furthermore, acetyl-L-carnitine and L-carnitine were superior for in-hospital mortality and improved risk stratification when combined with current clinical risk scores (ie, Acute Decompensated HEart Failure National REgistry, Organized Program To Initiate Lifesaving Treatment In Hospitalized Patients With Heart Failure, and Get With The Guidelines-Heart Failure; odds ratio (OR) ≥ 1.52, P≤ .020).ConclusionsCarnitine-related metabolites show associations with adverse outcomes in acute HF, in particular L-carnitine and acetyl-L-carnitine for short-term outcomes, and TMAO for long-term outcomes. Further studies are warranted to investigate the role and implications of carnitine metabolites including intervention in the pathogenesis of HF.</div

Right Side of the Heart Pulmonary Circulation Unit Involvement in Left-Sided Heart Failure br Diagnostic, Prognostic, and Therapeutic Implications From the Forgotten Chamber to the Chamber of Secrets

Although long neglected, the right side of the heart (RH) is now widely accepted as a pivotal player in heart failure (HF) either with reduced or preserved ejection fraction. The chronic overload of the pulmonary microcirculation results in an initial phase characterized by right ventricular (RV) hypertrophy, right atrial dilation, and diastolic dysfunction. This progresses to overt RH failure when RV dilation and systolic dysfunction lead to RV-pulmonary arterial (RV-PA) uncoupling with low RV output. In the context of its established relevance to progression of HF, clinicians should consider assessment of the RH with information from clinical assessment, biomarkers, and imaging. Notably, no single parameter can predict prognosis alone in HF. Assessments simultaneously should encompass RV systolic function, pulmonary pressures, an estimation of RV-PA coupling, and RH morphologic features. Despite a large volume of evidence indicating the relevance of RH function to the clinical syndrome of HF, evidence-based management strategies are lacking. Targeting RH dysfunction in HF should be an objective of future investigations, being an unmet need in the current management of HF

Biomarkers in acute myocarditis and chronic inflammatory cardiomyopathy: an updated review of the literature

Myocarditis is a disease caused by cardiac inflammation that can progress to dilated cardiomyopathy, heart failure, and eventually death. Several etiologies, including autoimmune, drug-induced, and infectious, lead to inflammation, which causes damage to the myocardium, followed by remodeling and fibrosis. Although there has been an increasing understanding of pathophysiology, early and accurate diagnosis, and effective treatment remain challenging due to the high heterogeneity. As a result, many patients have poor prognosis, with those surviving at risk of long-term sequelae. Current diagnostic methods, including imaging and endomyocardial biopsy, are, at times, expensive, invasive, and not always performed early enough to affect disease progression. Therefore, the identification of accurate, cost-effective, and prognostically informative biomarkers is critical for screening and treatment. The review then focuses on the biomarkers currently associated with these conditions, which have been extensively studied via blood tests and imaging techniques. The information within this review was retrieved through extensive literature research conducted on major publicly accessible databases and has been collated and revised by an international panel of experts. The biomarkers discussed in the article have shown great promise in clinical research studies and provide clinicians with essential tools for early diagnosis and improved outcomes.</p

Gut-related metabolites are associated with respiratory symptoms in COVID-19: a proof-of-concept study

Gut-related metabolites have been linked with respiratory disease. The crosstalk between the gut and lung suggests that gut health may be compromised in COVID-19. The aims of the present study were to analyse a panel of gut-related metabolites (acetyl-L-carnitine, betaine, choline, L-carnitine, trimethylamine and TMAO) in COVID-19 patients, matched with healthy subjects, and non-COVID-19 respiratory patients. As results, metabolites from this panel are impaired in COVID-19, associated with symptoms (breathlessness and temperature) and able to differentiate between COVID-19 and asthma. Preliminary results show lower levels of betaine appear to be associated with poor outcomes in COVID-19 patients suggesting betaine as a marker of gut microbiome health

Implications of serial measurements of natriuretic peptides in heart failure: insights from BIOSTAT-CHF

Natriuretic peptides [NP, including B-typenatriuretic peptide (BNP) and amino-terminalprohormone of BNP (NT-proBNP)] arethe gold-standard biomarkers in heart failure (HF) management,1 with NP levels atpresentation/admission routinely used fordiagnostic and prognostic purposes. NPlevels at discharge/follow-up also showassociation with outcomes, and NP levelsfollowing HF treatment add further value totailoring risk. However, the usefulness of NPserial measurements beyond conventionalHF treatment in clinical practice still remainsa matter of controversy. A cohort withcurrent HF guideline-based treatment wouldprovide an ideal setting to revisit usefulnessof NP serial measurements in risk stratification of HF patients, including the role ofrecently identified BNP molecular forms.The European multi-national BIOlogy Studyto TAilored Treatment in Chronic HeartFailure (BIOSTAT-CHF) provides an opportunity for the aforementioned analysis, beinga European cohort in which serial sampling ofNPs was done before and after titration of HFmedications according to current Europeanguidelines in a multi-centre, observational,real-world setting.</div

Ethnic differences in associations of outcomes with trimethylamine N-oxide in acute heart failure patients

Aims The aim of this study was to investigate whether ethnicity influences the associations between trimethylamine N-oxide (TMAO) levels and heart failure (HF) outcomes. Methods and results Trimethylamine N-oxide levels were measured in two cohorts with acute HF at two sites. The UK Leicester cohort consisted mainly of Caucasian (n = 842, 77%) and South Asian (n = 129, 12%) patients, whereas patients in the Japanese cohort (n = 116, 11%) were all Japanese. The primary endpoint was the measurement of all-cause mortality and/or HF rehospitalization within 1 year post-admission. Association of TMAO levels with outcome was compared in the entire population and between ethnic groups after adjustment for clinical parameters. TMAO levels were significantly higher in Japanese patients [median (interquartile range): 9.9 μM (5.2–22.8)] than in Caucasian [5.9 μM (3.6–10.8)] and South Asian [4.5 μM (3.1–8.4)] (P < 0.001) patients. There were no differences in the rate of mortality and/or HF rehospitalization between the ethnic groups (P = 0.096). Overall, higher TMAO levels showed associations with mortality and/or rehospitalization after adjustment for confounders ( P = 0.002). Despite no differences between ethnicity and association with mortality/HF after adjustment (P = 0.311), only in Caucasian patients were TMAO levels able to stratify for a mortality/HF event (P < 0.001). Conclusions Differences were observed in the association of mortality and/or rehospitalization based on circulating TMAO levels. Elevated TMAO levels in Caucasian patients showed increased association with adverse outcomes, but not in non-Caucasian patients.</div