Abstract
Since it was first synthesized in 1935, testosterone (T) has been viewed as the mythical Fountain of Youth, promising rejuvenation, restoring sexual appetites, growing stronger muscles, and ...quicker thinking. T is endowed with direct effects on myocardial and vascular structure and function, as well as on risk factors for cardiovascular (CV) disease. Indeed, low serum T levels are a risk factor for diabetes, metabolic syndrome, inflammation, and dyslipidaemia. Moreover, many studies have shown that T deficiency per se is an independent risk factor of CV and all-cause mortality. On this background and due to direct-to-patient marketing by drug companies, we have witnessed to the widespread use of T replacement therapy without clear indications particularly in late-life onset hypogonadism. The current review will dwell upon current evidence and controversies surrounding the role of T in the pathophysiology of CV diseases, the link between circulating T levels and CV risk, and the use of replacing T as a possible adjuvant treatment in specific CV disorders. Specifically, recent findings suggest that heart failure and type 2 diabetes mellitus represent two potential targets of T therapy once that a state of hypogonadism is diagnosed. However, only if ongoing studies solve the CV safety issue the T orchid may eventually ‘bloom’.
To investigate the prevalence and prognostic impact of right heart failure and right ventricular-arterial uncoupling in Corona Virus Infectious Disease 2019 (COVID-19) complicated by an Acute ...Respiratory Distress Syndrome (ARDS).
Ninety-four consecutive patients (mean age 64 years) admitted for acute respiratory failure on COVID-19 were enrolled. Coupling of right ventricular function to the pulmonary circulation was evaluated by a comprehensive trans-thoracic echocardiography with focus on the tricuspid annular plane systolic excursion (TAPSE) to systolic pulmonary artery pressure (PASP) ratio RESULTS: The majority of patients needed ventilatory support, which was noninvasive in 22 and invasive in 37. There were 25 deaths, all in the invasively ventilated patients. Survivors were younger (62 ± 13 vs. 68 ± 12 years, p = 0.033), less often overweight or usual smokers, had lower NT-proBNP and interleukin-6, and higher arterial partial pressure of oxygen (PaO
)/fraction of inspired O
(FIO
) ratio (270 ± 104 vs. 117 ± 57 mmHg, p < 0.001). In the non-survivors, PASP was increased (42 ± 12 vs. 30 ± 7 mmHg, p < 0.001), while TAPSE was decreased (19 ± 4 vs. 25 ± 4 mm, p < 0.001). Accordingly, the TAPSE/PASP ratio was lower than in the survivors (0.51 ± 0.22 vs. 0.89 ± 0.29 mm/mmHg, p < 0.001). At univariate/multivariable analysis, the TAPSE/PASP (HR: 0.026; 95%CI 0.01-0.579; p: 0.019) and PaO
/FIO
(HR: 0.988; 95%CI 0.988-0.998; p: 0.018) ratios were the only independent predictors of mortality, with ROC-determined cutoff values of 159 mmHg and 0.635 mm/mmHg, respectively.
COVID-19 ARDS is associated with clinically relevant uncoupling of right ventricular function from the pulmonary circulation; bedside echocardiography of TAPSE/PASP adds to the prognostic relevance of PaO
/FIO
in ARDS on COVID-19.
The biological differences among male and female, based on distinctive expression of sex chromosomes, on varied gene-expression and on peculiar sexual hormones, lead to important differences in ...physiology and pathophysiology.
The aim of this work was to briefly review the relationships among genderrelated differences and clinical implications in antithrombotic therapy, that could be related to sex-differences in platelet biology and coagulation reactions.
The major clinical setting in which antithrombotic drugs are involved for the treatment are atrial fibrillation, venous thromboembolisn, coronary artery disease and peripheral artery diseases. Considering that a consistent body of evidences suggests that, on one hand, human platelet activity may be influenced by sex and sex hormones and, on the other hand, estrogens are likely to play a crucial role on the transcriptional regulation of coagulation protein genes, the real impact of gender-related differences is still unclear. Moreover, women and men present different responses to antithrombotic drugs, reflecting genderspecific variances in pharmacokinetic profile, along with the physiological characteristics of each gender. Thus, the efficacy and adverse effects of antithrombotic drugs may vary according to gender.
Several gender-related differences could be reported in haemostasis and thrombosis pathophysiological mechanisms. Moreover, several data documented relevant gender differences in antithrombotic management and clinical effectiveness. Further studies are still needed to completely elucidate these issues.
Klinefelter syndrome (KS) is the most frequently occurring sex chromosomal aberration in males, with an incidence of about 1 in 500–700 newborns. Data acquired from large registry-based studies ...revealed an increase in mortality rates among KS patients when compared with mortality rates among the general population. Among all causes of death, metabolic, cardiovascular, and hemostatic complication seem to play a pivotal role. KS is associated, as are other chromosomal pathologies and genetic diseases, with cardiac congenital anomalies that contribute to the increase in mortality. The aim of the current study was to systematically review the relationships between KS and the cardiovascular system and hemostatic balance. In , patients with KS display an increased cardiovascular risk profile, characterized by increased prevalence of metabolic abnormalities including Diabetes mellitus (DM), dyslipidemia, and alterations in biomarkers of cardiovascular disease. KS does not, however, appear to be associated with arterial hypertension. Moreover, KS patients are characterized by subclinical abnormalities in left ventricular (LV) systolic and diastolic function and endothelial function, which, when associated with chronotropic incompetence may led to reduced cardiopulmonary performance. KS patients appear to be at a higher risk for cardiovascular disease, attributing to an increased risk of thromboembolic events with a high prevalence of recurrent venous ulcers, venous insufficiency, recurrent venous and arterial thromboembolism with higher risk of deep venous thrombosis or pulmonary embolism. It appears that cardiovascular involvement in KS is mainly due to chromosomal abnormalities rather than solely on low serum testosterone levels. On the basis of evidence acquisition and authors’ own experience, a flowchart addressing the management of cardiovascular function and prognosis of KS patients has been developed for clinical use.
Introduction
Friedreich Ataxia (FRDA) is an autosomal recessive neurodegenerative disorder that causes gait and limb ataxia, dysarthria, and impaired vibratory sense, with cardiomyopathy being the ...predominant cause of death. There is no approved therapy, which results in the use of symptomatic treatments and the chronic support of physiotherapy. Dimethyl fumarate (DMF) is a fumaric acid ester used for the treatment of psoriasis and Multiple Sclerosis (MS). It induces Nrf2
in vitro
and
in vivo
, and it increases frataxin in FRDA patient lymphoblasts, in mouse models, and in MS treated patients.
Methods
The aim of our study is to investigate if DMF can increase the expression of the
FXN
gene and frataxin protein and ameliorate
in-vivo
detectable measures of mitochondrial dysfunction in FRDA. The study is composed of a screening visit and two sequential 12-week phases: a core phase and an extension phase. During the first phase (core), patients will be randomly assigned to either the DMF or a placebo group in a 1:1 ratio. During the first week, patients will receive a total daily dose of 240 mg of DMF or placebo; from the second week of treatment, the dose will be increased to two 120 mg tablets BID for a total daily dose of 480 mg. During the second phase (extension), all patients will be treated with DMF. EudraCT number 2021-006274-23.
Endpoints
The primary endpoint will be a change in
FXN
gene expression level after 12 weeks of treatment. Secondary endpoints will be frataxin protein level,
c
ardiopulmonary exercise test outputs, echocardiographic measures, Nrf2 pathway and mitochondrial biogenesis gene expression, safety, clinical scales, and quality of life scales.
Conclusions
This is the first study aimed at exploring the ability of DMF, an already available treatment for MS and psoriasis, to correct the biological deficits of FRDA and potentially improve mitochondrial respiration
in-vivo
.
1–3 Despite being classically identified as a ‘simple’ intestinal dysfunction, the main hypothesis is currently focused on the role of inflammation and oxidative stress as a consequence of the ...intestinal wall ischaemia and/or congestion induced by HF, determining a gut barrier dysfunction and resulting in an increased gut bacterial translocation. 1–3 With this in mind, two main mechanisms have been proposed to link gut dysfunction and HF; (i) metabolism dependent, via gut-derived metabolites entering the systemic circulation and exerting pro-atherogenic effects and pro-inflammatory effects and (ii) metabolism independent, via bacterial components (e.g. lipopolysaccharides and endotoxins) translocating in the systemic circulation and contributing to the systemic inflammatory state with its well-known negative effects on HF. 4 To date, most of the research has identified a choline and L-carnitine metabolic by-product, trimethylamine N-oxide (TMAO), derived by the gut microbiota from the precursor trimethylamine (TMA) and subsequent oxidation via the liver enzyme flavin-containing monooxygenase 3 (FMO3) (see Figure 1), as the key useful prognostic biomarker in several cardiovascular diseases (e.g. coronary artery disease, acute myocardial infarction, and HF), with an interesting role in risk stratification. 5,6 Notably, TMAO, produced through the anaerobic metabolism of choline and carnitine containing molecules, is widely considered as the possible missing link between the consumption of a Western diet and the well-known increased cardiovascular diseases risk observed in the Western population. 7 Indeed, TMAO is produced through the anaerobic metabolism of choline and L-carnitine, of which eggs and red meat are rich in the Western diet (i.e., based on high fat foods), and diet can be considered as one the of most important factors affecting the gut microbiota composition. 8 Figure 1. From a pathophysiological point of view, TMAO pathway affects HF in different ways. 1,3 First, TMAO increases the risk of conditions determining HF (i.e. cardiac ischemic diseases), through its pro-atherosclerotic effects mediated by an increase in the expression of macrophage scavenger receptors with development of foam cells in the arterial wall, increasing thrombosis, increasing platelet reactivity, and causing endothelial dysfunction. 1,3 Second, TMAO increases HF susceptibility, directly acting on myocardial remodelling and fibrosis; in addition, it has been speculated that TMAO, being an organic osmolyte, altered cellular osmosis; lastly, it has been showed that TMAO worsens cardiomyocyte contractility, by acting on calcium cellular fluxes. 1,3 Worthy to be mentioned is the relationship between TMAO and renal function, with a possible effect on renal fibrosis and tubular injury further aggravating HF clinic. 1,3 Table 1 Main reports for associations between trimethylamine N-oxide and outcome in heart failure patients First author; year of publication Location Study population Follow-up length Main findings Trimethylamine N-oxide levels (μmol/L) Tang WH 2014 9 USA CHF, N = 720 5 years TMAO levels are associated with all-cause mortality 5.0 (3.0–8.5) Tang WH 2015 10 USA CHF, N = 112 5 years TMAO levels are associated with all-cause mortality and heart transplantation 5.8 (3.6–12.1) Trøseid M 2015 11 Norway CHF N = 115 5.2 years TMAO levels are associated with all-cause mortality and heart transplantation 13.5 ± 18.5 (CAD), 7.1 ± 5.6 (DCM) Suzuki T 2016 12 UK AHF, N = 972 1 years TMAO levels are associated with all-cause mortality and a composite mortality/rehospitalization 5.6 (3.4–10.5) Schuett K 2017 22 Germany CHF (pEF and rEF), N = 823 9.7 years TMAO levels are associated with all-cause mortality and cardiovascular mortality 4.7 (3.4–6.8) rEF, 4.7 (3.2–6.9) pEF Hayashi T 2018 13 Japan Decomp HF, N = 22 Cross-sectional TMAO levels (during decompensation and during compensation phases) and gut microbiome composition were altered compared with control subjects 17.3 ± 11.7 (Decomp), 17.7 ± 12.6 (Comp) Salzano A 2019 23 UK CHF (pEF and rEF), pEF = 118 vs rEF = 38 vs C = 40, N = 196 5 years TMAO levels are associated with mortality in pEF Use of levels of TMAO for risk stratification of long-term mortality in pEF 6.6 (4.3–12.2) pEF, 8.4 (3.7–13.8) rEF Suzuki T 2019 14 11 European countries Worsening or new-onset HF, N = 2234 3 years TMAO levels are associated with all-cause mortality and a composite of mortality/rehospitalization 5.9 (3.6–10.8) Yazaki Y 2019 31 11 European countries Worsening or new-onset HF, N = 2234 2 years TMAO levels of HF patients differed by region TMAO levels associated with risk of mortality CE > NW/S 6.2 (4.8–7.8) CE, 7.2 (5.5–8.8) NW, 6.5 (5.0–8.2) S Zhou X 2020 16 China HFrEF after MI, N = 1208 4 years TMAO levels are associated with major adverse cardiac events (MACE): all-cause mortality, HF rehospitalization, or recurrent MI, and all-cause mortality 4.5 Yazaki Y 2020 28 UK AHF, N = 1087 1 year TMAO levels are associated with a composite of all-cause mortality and/or rehospitalization 5.2–22.8 (Japanese), 3.6–10.8 (Caucasian), 3.1–8.4 (South Asian) Guo F 2020 24 China HFpEF, N = 228 5 years TMAO levels are independent predictor of new onset HF TMAO levels are independent risk factor of renal dysfunction 12.65 (9.32–18.66) Emoto T 2021 25 CHF (pEF and rEF), CHF = 22 vs C = 11, N = 33 TMAO levels are increased in Japanese HF compared to Caucasian/South Asian HF abundance of cntA/B positively correlated with TMAO 4.5–34.5 Papandreou C 2021 17 Spain CHF (pEF and rEF), AF = 509 vs C = 618, CHF = 326 vs C = 426, N = 1879 10 years TMAO levels are not associated with AF and HF incidence 3.0–8.5 Kinugasa Y 2021 26 Japan HFpEF, N = 146 5 years TMAO levels are associated with a composite endpoint of cardiac mortality and hospitalization for HF 20.37 Israr MZ 2021 30 UK AHF, N = 806 1 years TMAO levels are associated with all-cause mortality and a composite of all-cause mortality and/or rehospitalization caused by HF 10.2 (5.8–18.7) Dong Z 2021 27 China HFpEF, CHF = 61 vs C = 57, N = 118 1 years TMAO levels are independent risk factor for HFpEF 6.84 Yuzefpolskaya M 2021 18 USA CHF, N = 341 2 years + 8 months TMAO levels increased with HF severity and were similarly elevated, long term after LVAD and HT. TMAO levels positively related to biomarkers of inflammation (TNF-α and ET-1), endotoxemia (sCD14), and oxidative stress 6.96 (HF), 5.81 (LVAD), 5.35 (HT) Mollar A 2021 19 Spain Decomp HF, N = 102 1 years TMAO related with recent HF Wargny M 2022 32 France AHF, AHF = 209 vs C = 1140, N = 1468 7.3 years TMAO is not associated with occurrence of HF requiring hospitalization (HFrH) and composite event HFrH and/or cardiovascular mortality and all-cause mortality. 8.8 (5.3–17.0) Li N 2022 29 China AMI and HF, N = 985 1 years TMAO levels independently correlated with poor prognosis (i.e.: MACE, and all-cause mortality) and recurrence of MI in patients with AMI complicated by HF, especially in those with higher hsCRP levels TMAO the difference for rehospitalization due to HF is not statistically significant 6.7 (4.0, 11.7) Wei H 2022 20 China HFrEF, N = 955 8 years TMAO levels are associated with the composite outcome of cardiovascular death or heart transplantation 2.52 (1.18–4.06) Israr MZ 2022 21 UK HFrEF, N = 1783 3 years TMAO levels are associated with the composite outcome of HF hospitalization or death at 3 years 6.4 (3.9–11.6) Abbreviations: AF, atrial fibrillation; AMI, acute myocardial infarction; AHF, acute heart failure; BUN, blood urea nitrogen; C, controls; CAD, coronary artery disease; CE, Central/Eastern group (Germany, Poland, Serbia, and Slovenia); CHF, chronic heart failure; cntA/B, carnitine oxygenase/reductase; Comp, compensated; DCM, dilated cardiomyopathy; Decomp, decompensated; ET-1, endothelin-1; HF, heart failure; HFpEF, heart failure with preserved ejection fraction; HFrEF, heart failure with reduced ejection fraction; hsCRP, high-sensitivity C-reactive protein; HT, heart transplant; LVAD, left ventricular assist device; MACE, major adverse cardiac events; MI, myocardial infarction; NT-proBNP, N-terminal pro-brain type natriuretic peptide; NYHA, New York Heart Association; NW, the Northern/Western group (France, Netherlands, Norway, Sweden, and United Kingdom); S, Southern group (Greece and Italy); sCD14, soluble CD14; TMAO, trimethylamine N-oxide; TNF-α, tumour necrosis factor alpha. From a clinical point of view, since the first investigations regarding the association between TMAO and HFrEF as of about 10 years ago, 9 several studies have demonstrated that TMAO levels were higher in CHF when compared with healthy controls showing associations between TMAO and clinical and biochemical parameters (i.e., renal function, age, comorbidities, and CRP), severity of disease (NYHA classes), 15,18 and clinical outcomes
Heart Failure (HF) is a major healthcare issue, given its high prevalence and incidence, the rate of comorbidities, the related high health-care costs and its poor outcome. In the last years mounting ...evidence revealed several differences between men and women affected by this clinical condition. Apart from the well-known difference in phenotype (HF with reduced ejection fraction (HFrEF) occurs more commonly in men, and HF with preserved ejection fraction (HFpEF) is more frequent in women) other relevant sex-related issues dwell upon epidemiology, presentation, risk stratification and management. These differences shed new lights on the possibility to consider HF as a prototype of the impact of gender/sex issue in cardiovascular medicine. A call for action and future strategies might help in the achievement of a cleaver patient-care.
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