Association of Pressure Wave Reflections With Left Ventricular Mass: a Systematic Review and Meta-Analysis.

BACKGROUND: Pressure wave reflections (PWRs) within the circulation are assessed at various arterial sites by various noninvasive methods. We aimed at reviewing the conflicting data regarding the hypothesis that higher PWRs are associated with higher left ventricular mass and tested whether this association stands for all available indices of PWRs, all (proximal or distal to the heart) sites of assessment, and is modified by sex, age and heart rate. METHODS: Based on a predefined protocol applying the Meta-Analysis of Observational Studies in Epidemiology (MOOSE) guidelines, we identified eligible for meta-analysis data regarding: augmentation index, augmentation pressure, backward pressure (Pb), reflection index, and their association with left ventricular mass index (19 studies, total population n=8686). RESULTS: We found statistically significant associations, independent from blood pressure level, for all indices of PWRs at all arterial sites (carotid augmentation index; odds ratio; standardized beta coefficient [ß]: 0.14 [95% CI, 0.07% to 0.21%], per SD increase), radial augmentation index (ß: 0.21; 0.11 to 0.31), central augmentation pressure (ß: 0.15; 0.03 to 0.27), central Pb (ß: 0.23; 0.05 to 0.42), and central reflection index (ß: 0.14; 0.06 to 0.22), except for aortic augmentation index as estimated by generalized transfer functions. Meta-regression analysis showed that the association between carotid augmentation index and left ventricular mass was higher among populations with higher heart rate (P=0.036, beta: 0.017 [95% CI, 0.001 to 0.033]) and tended to be higher in middle-aged (P=0.07, beta: -0.001; -0.021 to 0.001). CONCLUSIONS: A clinically meaningful association between PWRs and left ventricular mass, assessed at either central or peripheral arterial sites by most available methods was shown, suggesting that PWR reduction strategies might be useful. Based on the present evidence, such trials should target middle-aged populations with high normal heart rate.

Fabry Disease: Current and Novel Therapeutic Strategies. A Narrative Review.

BACKGROUND: Fabry disease (FD) is an inherited lysosomal storage disorder, leading to multisystemic manifestations and causing significant morbidity and mortality. OBJECTIVE: The aim of this narrative review is to present the current and novel therapeutic strategies in FD, including symptomatic and specific treatment options. METHODS: A systematic literature search was conducted to identify relevant studies, including completed and ongoing randomized-controlled clinical trials (RCTs), prospective or retrospective cohort studies, case series and case reports that provided clinical data regarding FD treatment. RESULTS: A multidisciplinary symptomatic treatment is recommended for FD patients, personalized according to disease manifestations and their severity. During the last two decades, FD-specific treatments, including two enzyme-replacement-therapies (agalsidase alfa and agalsidase beta) and chaperone treatment with migalastat have been approved for use and allowed for symptoms' stabilization or even disease burden reduction. More therapeutic agents are currently under investigation. Substrate reduction therapies, including lucerastat and venglustat, have shown promising results in RCTs and may be used either as monotherapy or as complementary therapy to established enzymereplacement- therapies. More stable enzyme-replacement-therapy molecules that are associated with less adverse events and lower likelihood of neutralizing antibodies formation have also been developed. Ex-vivo and in-vivo gene therapy is being tested in animal models and pilot human clinical trials, with preliminary results showing a favorable safety and efficacy profile. CONCLUSION: The therapeutic landscape in FD appears to be actively expanding with more treatment options expected to become available in the near future, allowing for a more personalized approach in FD patients.

The effect of atropine used in dobutamine stress echocardiography on pupil diameter.

BACKGROUND: The use of atropine during dobutamine stress echocardiography (DSE) is contraindicated in persons with narrow angle glaucoma though there is limited evidence that low doses of intravenous atropine do not cause pupillary dilation. OBJECTIVE: The aim of this study is to investigate whether atropine when administered in persons without glaucoma during dobutamine stress echocardiography causes pupillary dilation. METHODS AND RESULTS: Out of 144 patients without a history of glaucoma referred for DSE for clinical indications, 105 patients received intravenous atropine doses ranging from 0.1 mg to 1.25 mg (most patients received 0.25-0.75 mg). Pupil diameter of both eyes was measured under the same light conditions before and after the DSE using a CP-30 Optical Digital PD Ruler. For the total of 210 examined eyes pupil diameter remained unaltered after each DSE test (3.65 ± 0.799 mm before vs 3.63 ± 0.766 mm after, p = .737). Similarly, pupil diameter remained unchanged when left and right eyes were assessed separately (right eye: 3.770 ± 0.812 before vs 3.752 ± 0.745 mm after, p = .821 and left eye: 3.521 ± 0.770 before vs 3.499 ± 0.770 mm after, p = .806). Diameter of right and left pupil were also unaltered after grouping patients by sex and iris pigmentation. Age, weight, atropine dose and propranolol dose were not correlated with changes in pupil diameter. CONCLUSION: Intravenous atropine in usual doses administered in DSE does not cause mydriasis in adults without glaucoma. Future studies need to confirm our findings and expand the investigation regarding safety of atropine use during DSE in patients with narrow angle glaucoma.

Association of gut microbiota composition and their metabolites with subclinical atheromatosis: A systematic review.

Study objective: The present systematic review investigates the hypothesis that specific components of the intestinal microbiome and/or their metabolites are associated with early stages of subclinical arterial damage (SAD). Design: Based on the MOOSE criteria, we conducted a systematic review of the literature (Scopus, Medline) investigating the potential association between gut microbiota and the most widely applied arterial biomarkers of SAD. Participants: All studies included individuals without established cardiovascular disease, either with or without SAD. Intervention: No interventions were made. Main outcome measures: Association between exposure (components/metabolites of microbiota) and outcome (presence of SAD). Results: Fourteen articles met the predefined criteria. Due to the large heterogeneity, their meta-analysis was not possible. Our review revealed (a) two studies on endothelial dysfunction, out of which one found an inverse relation between plasma trimethylamine N-oxide levels and FMD and the other did not substantiate a statistically significant correlation with RHI. (b) Twelve studies on atheromatosis, assessed as intimal-medial thickness (IMT), coronary artery calcium (CAC) and arterial plaque, of which, seven studies showed statistically significant associations (negative or positive depending on the microorganism or microbiota metabolite) with IMT, one study revealed significant associations with coronary artery calcium, while one showed absence of correlation and four studies reported statistically significant correlations with arterial plaque. (c) Three studies on arterial stiffness (pulse wave velocity - PWV) with two of them concluding in statistically significant association while the third study did not. Some articles investigated multiple of the correlations described and therefore, belonged to more than one section. Conclusion: Evidence of both positive and inverse associations of gut microbiota composition and their metabolites with different types of SVD has been found. However the small number and heterogeneity of available studies cannot allow to confirm or disprove the hypothesis.

The Role of Genetics in Risk Stratification Strategy of Dilated Cardiomyopathy.

Dilated cardiomyopathy (DCM) is a heart disorder of diverse etiologies that affects millions of people worldwide, associated with increased mortality rate and high risk of sudden cardiac death. Patients with DCM are characterized by a wide range of clinical and pre-clinical phenotypes which are related with different outcomes. Dominant studies have failed to demonstrate the value of the left ventricular ejection fraction as the only indicator for patients' assessment and arrhythmic events prediction, thus making sudden cardiac death (SCD) risk stratification strategy improvement, more crucial than ever. The multifactorial two-step approach, examining non-invasive and invasive risk factors, represents an alternative process that enhances the accurate diagnosis and the individualization of patients' management. The role of genetic testing, regarding diagnosis and decision making, is of great importance, as pathogenic variants have been detected in several patients either they had a disease relative family history or not. At the same time there are specific genes mutations that have been associated with the prognosis of the disease. The aim of this review is to summarize the latest data regarding the genetic substrate of DCM and the value of genetic testing in patients' assessment and arrhythmic risk evaluation. Undoubtedly, the appropriate application of genetic testing and the thoughtful analysis of the results will contribute to the identification of patients who will receive major benefit from an implantable defibrillator as preventive treatment of SCD.

X-linked dilated cardiomyopathy: the important role of genetic tests and imaging in the early diagnosis and treatment.

Familial dilated cardiomyopathy predominantly affects younger adults and may cause advanced heart failure and sudden cardiac death. Therefore, detailed family history, family members screening, appropriate genetic testing and counselling may allow correct identification of cardiac remodeling etiology, as well as earlier disease detection. Accordingly, we present a case with an early diagnosis of an X-linked dilated cardiomyopathy guided by clinical features, cardiac MRI and genetic testing. The diagnostic workup was guided by the positive family history of cardiomyopathy and sudden cardiac deaths. Clinical implications including early management, better arrythmia risk stratification and the revealing of a potential endemic entity clustering in several male subjects of a community on Crete island are further discussed.

Biomarkers Associated with Bleeding Risk in the Setting of Atrial Fibrillation.

BACKGROUND: Prevention of thromboembolic disease, mainly stroke, with oral anticoagulants remains a major therapeutic goal in patients with atrial fibrillation. Unfortunately, despite the high efficacy, anticoagulant therapy is associated with a significant risk of, frequently catastrophic, and hemorrhagic complications. Among different clinical and laboratory parameters related to an increased risk of bleeding, several biological markers have been recognized and various risk scores for bleeding have been developed. OBJECTIVES/METHODS: The aim of the present study is to review current evidence regarding the different biomarkers associated with raised bleeding risk in atrial fibrillation. RESULTS: Data originating from large cohorts or the recent large-scale trials of atrial fibrillation have linked numerous individual biomarkers to an increased bleeding risk. Such a relation was revealed for markers of cardiac physiology, such as troponin, BNP and NT-proBNP, markers of renal function, such as GFR and Cystatin or hepatic function, markers involving the system of coagulation, such as D-dimer and Von Willebrand factor, hematologic markers, such as low haemoglobin or low platelets, inflammatory markers, such as interleukin-6, other factors such as GDF-15 and vitamin-E and finally genetic polymorphisms. Many such biomarkers are incorporated in the bleeding risk schemata developed for the prediction of the hemorrhagic risk. CONCLUSIONS: Biomarkers were introduced in clinical practice in order to better estimate the potential risk of haemorrhage in these patients and increase the prognostic impact of clinical risk scores. In the last years this concept is gaining significant importance.

Inflammatory Biomarkers in Atrial Fibrillation.

During the last few years, a significant number of studies have attempted to clarify the underlying mechanisms that lead to the presentation of atrial fibrillation (AF). Inflammation is a key component of the pathophysiological processes that lead to the development of AF; the amplification of inflammatory pathways triggers AF, and, in tandem, AF increases the inflammatory state. Indeed, the plasma levels of several inflammatory biomarkers are elevated in patients with AF. In addition, the levels of specific inflammatory biomarkers may provide information regarding to the AF duration. Several small studies have assessed the role of anti-inflammatory treatment in atrial fibrillation but the results have been contradictory. Large-scale studies are needed to evaluate the role of inflammation in AF and whether anti-inflammatory medications should be routinely administered to patients with AF.

Effects of Oral and Non-Insulin Injectable Antidiabetic Treatment in Hypertension: A Systematic Review.

BACKGROUND: Diabetes mellitus type 2 (T2DM) often co-exists with hypertension, and this aggregation of co-morbidities amplifies the risk for future cardiovascular events. Therefore, it appears crucial to understand the essence of choosing oral and non-insulin injectable anti-diabetic drugs (ADs) with a favorable hemodynamic impact that could partially attenuate the increased baseline cardiovascular risk. OBJECTIVE: We sought to evaluate the effect of ADs on blood pressure (BP) indices and to assess the potential role of certain ADs towards hypertension treatment. METHOD: We performed a systematic review of the literature searching MEDLINE via Pubmed for all human studies implementing ADs, either individually or in combinations. RESULTS: Metformin was found to reduce BP in small cohorts but failed to confirm its beneficial effect in a metaanalysis of 41 studies. Thiazolidinediones are associated with BP lowering but are contraindicated in patients with heart failure. Sulfonylureas, on the other hand, may increase BP, while a-glucosidase inhibitors, DPP-4 inhibitors, and SGLT2 inhibitors activate favorable pathophysiologic mechanisms serving as potential BP lowering agents. Relevant BP reduction was established for GLP-1 Ras in most clinical trials. CONCLUSION: The favorable hemodynamic impact of certain classes of ADs might provide synergistic or incremental therapeutic benefits in high-risk patients suffering from both T2DM and hypertension. Additional randomized trials designed under the hypothesis of the emerging beneficial hemodynamic effect of ADs are expected to provide more robust evidence and to guide the optimization of combined treatment strategies in this challenging group of patients.

Impact of income status on prognosis of acute coronary syndrome patients during Greek financial crisis.

BACKGROUND: The effect of income status on patient outcome merits investigation during periods of financial crisis. We evaluated the impact of income status on out-of-hospital prognosis in a cohort of acute coronary syndrome (ACS) patients, included in a countrywide study during a period of financial crisis. METHODS: The study is a secondary analysis of a prospective, multicenter, observational study-the PHAETHON study-enrolling consecutive ACS patients in 37 hospitals in Greece. Patients were classified as low or high income based on the reported net annual household income using as a cut-off point the relative poverty threshold for Greece of 12,000 Euros. The outcome measure was survival free of the primary composite endpoint (cardiovascular death, myocardial infarction, stroke/transient ischemic attack, urgent revascularization and urgent hospitalization due to cardiovascular causes). RESULTS: The study population included 794 patients. The administration rate of evidence-based medications was similar in the low- (n = 455) and high-income (n = 339) groups during hospitalization and upon discharge. In a median follow-up of 189 days (interquartile range: 180-212 days), low-income patients had 92 % higher risk of the combined endpoint as compared to high-income patients [Hazard ratio (HR):1.92, 95 % CI:1.25-2.94, p = 0.003]. The effect of low-income status on the combined outcome remained significant after adjustment for age, gender and depression (HR:1.59, 95 % CI:1.02-2.49; p = 0.043). CONCLUSIONS: In a period of financial crisis, low income is a significant and independent predictor of poor out-of-hospital outcome in ACS patients. This association has profound implications and should be taken into consideration by public health policy makers.

Sertoli cell tumor and gonadoblastoma in an untreated 29-year-old 46,XY phenotypic male with Frasier syndrome carrying a WT1 IVS9+4C>T mutation.

OBJECTIVE: Frasier syndrome (FS) phenotype in 46,XY patients usually consists of female external genitalia, gonadal dysgenesis, high risk of gonadoblastoma and the development of end stage renal failure usually in the second decade of life. FS is caused by heterozygous de novo intronic splice site mutations of the Wilms' tumor suppressor gene 1 (WT1), although a few cases with typical exonic WT1 Denys-Drash mutations that resemble an FS phenotype have been described. The aim of this study was to present further data on the spectrum of FS phenotypes through the evaluation of a 29-year-old patient with a predominantly male phenotype and coexistence of Sertoli cell tumor and gonadoblastoma. RESULTS: Genetic analysis using standard methods for DNA sequencing confirmed FS due to a WT1 gene mutation, IVS9+4C>T. CONCLUSIONS: This very rare case illustrates the natural course of FS over many years due to the neglect by the patient to address his need for follow-up, while adding further data on the spectrum of FS phenotypes associated with IVS9+4 C>T mutations. The coexistence of the rare Sertoli cell tumor and gonadoblastoma emphasizes that early clinical recognition and molecular identification facilitates appropriate patient management, especially with respect to the high risk of gonadal malignancy.