Mechanisms of cardiac dysfunction in diabetic cardiomyopathy: molecular abnormalities and phenotypical variants.

Diabetic cardiomyopathy (DCM) is a diabetes mellitus-induced pathophysiological condition characterized by cardiac structural, functional, and metabolic changes that can result in heart failure (HF), in the absence of coronary artery disease, hypertension, and valvular heart disease. Metabolic alterations such as hyperglycemia, insulin resistance, hyperinsulinemia, and increased metabolism of free fatty acids result in oxidative stress, inflammation, advanced glycation end products formation, abnormalities in calcium homeostasis, and apoptosis that are responsible for structural remodeling. Cardiac stiffness, hypertrophy, and fibrosis eventually lead to dysfunction and HF with preserved ejection fraction and/or HF with reduced ejection fraction. In this review, we analyzed in detail the cellular and molecular mechanisms and the metabolic pathways involved in the pathophysiology of DCM. Different phenotypes are observed in DCM, and it is not clear yet if the restrictive and the dilated phenotypes are distinct or represent an evolution of the same disease. Phenotypic differences can be observed between T1DM and T2DM DCM, possibly explained by the different myocardial insulin action. Further studies are needed in order to better understand the underlying mechanisms of DCM and to identify appropriate therapeutic targets and novel strategies to prevent and reverse the progression toward heart failure in diabetic patients.

Prognostic value of left ventricular global longitudinal strain in mitral regurgitation: a systematic review.

Conventional echocardiographic assessment may overestimate the left ventricular (LV) function in mitral regurgitation (MR). LV global longitudinal strain (GLS) is more sensitive marker to detect subclinical LV dysfunction. Multiple studies have investigated the prognostic value of LV-GLS in MR to examine its potential to determine the timing and indication of intervention. This systematic review aimed to assess the prognostic value of LV-GLS in patients with mitral regurgitation (MR) to define its clinical applicability. PUBMED and EMBASE were queried through July 2021 to identify studies investigating the prognostic value of LV-GLS in MR. A total of 24 observational studies with 5267 patients were identified. Sixteen studies investigated for primary MR, 7 studies for secondary MR, and 1 study for both. Most studies included patients who underwent intervention. There was significant heterogeneity in patient population, intervention status, follow-up period, LV-GLS cutoff value, outcomes, and statistical methods among the studies. Meta-analysis was not performed considering the significant variability. With exception to 1 study, all studies demonstrated significant association between impaired LV-GLS and worse clinical and echocardiographic outcomes in primary MR. Prognostic value of LV-GLS in secondary MR was less certain due to inconsistent findings and limited reporting. LV-GLS is a promising parameter of prognostication in primary MR and can be considered as alternative to determine the timing of intervention. However, the optimal cutoff value remains unclear. The prognostic value of LV-GLS in secondary MR is less clear. Further large-scale prospective study is warranted before its routine clinical application.

Downregulation of Circulating Hsa-miR-200c-3p Correlates with Dyslipidemia in Patients with Stable Coronary Artery Disease.

Coronary heart disease (CHD), one of the leading causes of disability and death worldwide, is a multifactorial disease whose early diagnosis is demanding. Thus, biomarkers predicting the occurrence of this pathology are of great importance from a clinical and therapeutic standpoint. By means of a pilot study on peripheral blood cells (PBMCs) of subjects with no coronary lesions (CTR; n = 2) and patients with stable CAD (CAD; n = 2), we revealed 61 differentially methylated regions (DMRs) (18 promoter regions, 24 genes and 19 CpG islands) and 14.997 differentially methylated single CpG sites (DMCs) in CAD patients. MiRNA-seq results displayed a peculiar miRNAs profile in CAD patients with 18 upregulated and 32 downregulated miRNAs (FC ≥ ±1.5, p ≤ 0.05). An integrated analysis of genome-wide DNA methylation and miRNA-seq results indicated a significant downregulation of hsa-miR-200c-3p (FCCAD = −2.97, p ≤ 0.05) associated to the hypermethylation of two sites (genomic coordinates: chr12:7073122-7073122 and chr12:7072599-7072599) located intragenic to the miR-200c/141 genomic locus (encoding hsa-miR-200c-3p) (p-value = 0.009) in CAD patients. We extended the hsa-miR-200c-3p expression study in a larger cohort (CAD = 72, CTR = 24), confirming its reduced expression level in CAD patients (FCCAD = −2; p = 0.02). However, when we analyzed the methylation status of the two CpG sites in the same cohort, we failed to identify significant differences. A ROC curve analysis showed good performance of hsa-miR-200c-3p expression level (AUC = 0.65; p = 0.02) in distinguishing CAD from CTR. Moreover, we found a significant positive correlation between hsa-miR-200c-3p expression and creatinine clearance (R2 = 0.212, p < 0.005, Pearson r = 0.461) in CAD patients. Finally, a phenotypic correlation performed in the CAD group revealed lower hsa-miR-200c-3p expression levels in CAD patients affected by dyslipidemia (+DLP, n = 58) (p < 0.01). These results indicate hsa-miR-200c-3p as potential epi-biomarker for the diagnosis and clinical progression of CAD and highlight the importance of deeper studies on the expression of this miRNA to understand its functional role in coronary artery disease development.

Gut Microbiota Composition and Cardiovascular Disease: A Potential New Therapeutic Target?

A great deal of evidence has revealed an important link between gut microbiota and the heart. In particular, the gut microbiota plays a key role in the onset of cardiovascular (CV) disease, including heart failure (HF). In HF, splanchnic hypoperfusion causes intestinal ischemia resulting in the translocation of bacteria and their metabolites into the blood circulation. Among these metabolites, the most important is Trimethylamine N-Oxide (TMAO), which is responsible, through various mechanisms, for pathological processes in different organs and tissues. In this review, we summarise the complex interaction between gut microbiota and CV disease, particularly with respect to HF, and the possible strategies for influencing its composition and function. Finally, we highlight the potential role of TMAO as a novel prognostic marker and a new therapeutic target for HF.

Epigenetic Modifications and Non-Coding RNA in Diabetes-Mellitus-Induced Coronary Artery Disease: Pathophysiological Link and New Therapeutic Frontiers.

Diabetes mellitus (DM) is a glucose metabolism disorder characterized by chronic hyperglycemia resulting from a deficit of insulin production and/or action. DM affects more than 1 in 10 adults, and it is associated with an increased risk of cardiovascular morbidity and mortality. Cardiovascular disease (CVD) accounts for two thirds of the overall deaths in diabetic patients, with coronary artery disease (CAD) and ischemic cardiomyopathy as the main contributors. Hyperglycemic damage on vascular endothelial cells leading to endothelial dysfunction represents the main initiating factor in the pathogenesis of diabetic vascular complications; however, the underlying pathophysiological mechanisms are still not entirely understood. This review addresses the current knowledge on the pathophysiological links between DM and CAD with a focus on the role of epigenetic modifications, including DNA methylation, histone modifications and noncoding RNA control. Increased knowledge of epigenetic mechanisms has contributed to the development of new pharmacological treatments ("epidrugs") with epigenetic targets, although these approaches present several challenges. Specific epigenetic biomarkers may also be used to predict or detect the development and progression of diabetes complications. Further studies on diabetes and CAD epigenetics are needed in order to identify possible new therapeutic targets and advance personalized medicine with the prediction of individual drug responses and minimization of adverse effects.

Treatment of HFpEF beyond the SGLT2-Is: Does the Addition of GLP-1 RA Improve Cardiometabolic Risk and Outcomes in Diabetic Patients?

Heart failure with preserved ejection fraction (HFpEF) is a common clinical syndrome frequently seen in elderly patients, the incidence of which is steadily increasing due to an ageing population and the increasing incidence of diseases, such as diabetes, hypertension, obesity, chronic renal failure, and so on. It is a multifactorial disease with different phenotypic aspects that share left ventricular diastolic dysfunction, and is the cause of about 50% of hospitalizations for heart failure in the Western world. Due to the complexity of the disease, no specific therapies have been identified for a long time. Sodium-Glucose Co-Transporter 2 Inhibitors (SGLT2-Is) and Glucagon-Like Peptide Receptor Agonists (GLP-1 RAs) are antidiabetic drugs that have been shown to positively affect heart and kidney diseases. For SGLT2-Is, there are precise data on their potential benefits in heart failure with reduced ejection fraction (HFrEF) as well as in HFpEF; however, insufficient evidence is available for GLP-1 RAs. This review addresses the current knowledge on the cardiac effects and potential benefits of combined therapy with SGLT2-Is and GLP-1RAs in patients with HFpEF.

Echo HALT: do we really need a cardiac CT?

Leaflet thrombosis is usually an incidental finding and Cardiac CT is the gold standard for its diagnosis, but the classic features of hypoattenuation leaflet thickening (HALT) and hypoattenuation affecting motion (HAM) can also be seen on echocardiography and more specifically on trans-esophageal echocardiography. We describe a case of transcatheter aortic valve thrombosis where both the diagnosis and treatment were based exclusively on the echocardiographic evaluation, without the need of cardiac CT, with good outcome for the patient.

Transcatheter aortic valve replacement outcomes in patients with low-flow very low-gradient aortic stenosis.

AIMS: In patients with severe aortic stenosis (AS), low-flow low-gradient (LG) is a known predictor of worse outcomes. However, very LG may represent a distinct population with further cardiac dysfunction. It is unknown whether this population benefits from transcatheter aortic valve replacement (TAVR). We aimed to describe the patient characteristics and clinical outcomes of low-flow very LG severe AS. METHODS AND RESULTS: This single-centre study included all patients with low-flow severe AS between 2019 and 2021. Patients were divided into groups with very LG [mean pressure gradient (MPG) ≤ 20 mmHg], LG (20 < MPG < 40 mmHg), and high-gradient (HG) (MPG ≥ 40 mmHg). Composite endpoint of all-cause mortality and heart failure rehospitalization was compared. A total of 662 patients [very LG 130 (20%); LG 339 (51%); HG 193 (29%)] were included. Median follow-up was 12 months. Very LG cohort had a higher prevalence of comorbid conditions with lower left ventricular ejection fraction (45% vs. 57% vs. 60%; P < 0.001). There was a graded increase in the risk of composite endpoint in the lower MPG strata (P < 0.001). Among those who underwent TAVR, very LG was an independent predictor of the composite endpoint (adjusted HR 2.42 [1.29-4.55]). While LG and HG cohorts had decreased risk of composite endpoint after TAVR compared with conservative management, very LG was not associated with risk reduction (adjusted HR 0.69 [0.35-1.34]). CONCLUSION: Low-flow very LG severe AS represents a distinct population with significant comorbidities and worse outcomes. Further studies are needed to evaluate the short- and long-term benefits of TAVR in this population.

Do we still need intra-procedural TTE during Transcatheter aortic valve replacement? A high volume, single center experience.

BACKGROUND: Transcatheter aortic valve implantation (TAVI) has undergone significant advances in recent years, with the development of improved pre-planning tools and devices. These advances have led to a reduction in the rate of paravalvular leak (PVL), a complication that is associated with poor outcomes even when mild. As some centers around the world are moving to solely fluoroscopy-focused implantation, we aimed to describe the clinical impact of intra-procedural transthoracic echocardiography (TTE) during TAVI in a high volume hospital. METHODS: Observational study during a 3-month period. A limited TTE examination was performed immediately after deployment to assess the existence of PVL and grade its severity. Complete TTE was performed a day after the procedure. In case of ≥mild PVL after valve deployment, a decision was made according to the severity of the PVL, patient anatomy and extent of annular calcification to preform balloon post-dilation. If done, an additional limited TTE was performed to assess possible complication and the degree of PVL post dilatation. RESULTS: 115 patient were included in the study. Intra-procedural TTE identified 16 patients (14 %) with at least mild PVL, three of them with moderate (3 %). Post balloon dilatation was performed in 10 patients (9 % of the cohort) with significant improvement in the degree of PVL. CONCLUSION: Intra-procedural TTE immediately after TAVI deployment can accurately identify PVL, allowing operators to perform post balloon dilatation with improvement in early echocardiographic results. Our findings support the routine use of TTE during procedures, without relying solely on fluoroscopy.

Management of Systemic Inflammatory Response Syndrome After Cardiovascular Interventions. Diagnostic, Prognostic, and Therapeutic Implications.

A substantial number of patients may experience systemic inflammatory response syndrome (SIRS) and related adverse events after transcatheter aortic valve implantation and endovascular aortic aneurysm repair. Although a clear etiology has not been established, endothelial disruption and tissue-ischemic response secondary to the foreign material may represent the trigger events. A latency period (0 to 48 hours) may occur between the initial injury and onset of symptoms mirroring an initial local response followed by a systemic response. Clinical presentation can be mild or severe depending on external triggers and characteristics of the patient. Diagnosis is challenging because it simulates an infection, but lack of response to antibiotics, negative cultures are supportive of SIRS. Increased in-hospital stay, readmissions, major cardiovascular events, and reduced durability of the device used are the main complications. Treatment includes non-steroidal anti-inflammatory drugs or corticosteroids. In conclusion, further studies are warranted to fully explore pathophysiologic mechanisms underpinning SIRS and the possibility of enhancing device material immune compatibility to reduce the inflammatory reaction of the host tissue.

Severe functional mitral regurgitation and cardiogenic shock after transcatheter aortic valve replacement.

An 83-year-old woman with symptomatic severe aortic stenosis was referred for transcatheter aortic valve replacement. Diagnostic left heart catheterization documented diffuse 3-vessel coronary artery disease.

Novel 3D Echocardiographic Technique for Mitral Calcium Mapping.

Mitral annular calcification (MAC) is a common chronic degenerative process of the mitral valve fibrous support ring. MAC increases the risk of mitral valve dysfunction, all-cause and cardiovascular mortality, and worse outcomes in cardiac interventions. Echocardiography represents the first imaging modality for MAC assessment, but it has low specificity compared to cardiac CT in terms of distinguishing between calcium and dense collagen. Novel three-dimensional transesophageal maximal intensity projection (MIP) mapping allows for the real-time MAC distribution and depth visualization of the cardiac anatomy and represents a useful and promising tool for pre-procedural assessment and intra-procedural guidance of cardiac interventions.

Beyond the Cardiovascular Effects of Glucagon-like Peptide-1 Receptor Agonists: Body Slimming and Plaque Stabilization. Are New Statins Born?

Atherosclerosis is a chronic inflammatory disease characterized by lipid and inflammatory cell deposits in the inner layer of large- and medium-sized elastic and muscular arteries. Diabetes mellitus (DM) significantly increases the risk of cardiovascular diseases and the overall and cardiovascular mortality, and it is a pro-atherogenic factor that induces atherosclerosis development and/or accelerates its progression through a multifactorial process. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are a new class of drugs, belonging to the armamentarium to fight type 2 DM, that have shown robust reductions in atherosclerotic events and all-cause mortality in all studies. Preclinical studies have shown that GLP-1RAs play a role in the immunomodulation of atherosclerosis, affecting multiple pathways involved in plaque development and progression. In this review, we wanted to explore the translational power of such preclinical studies by analyzing the most recent clinical trials investigating the atheroprotective effect of GLP-1RAs.

Coronary Obstruction during Valve-in-Valve Transcatheter Aortic Valve Replacement: Pre-Procedural Risk Evaluation, Intra-Procedural Monitoring, and Follow-Up.

Valve-in-valve (ViV) transcatheter aortic valve replacement (TAVR) is emerging as an effective treatment for patients with symptomatically failing bioprosthetic valves and a high prohibitive surgical risk; a longer life expectancy has led to a higher demand for these valve reinterventions due to the increased possibilities of outliving the bioprosthetic valve's durability. Coronary obstruction is the most feared complication of valve-in-valve (ViV) TAVR; it is a rare but life-threatening complication and occurs most frequently at the left coronary artery ostium. Accurate pre-procedural planning, mainly based on cardiac computed tomography, is crucial to determining the feasibility of a ViV TAVR and to assessing the anticipated risk of a coronary obstruction and the eventual need for coronary protection measures. Intraprocedurally, the aortic root and a selective coronary angiography are useful for evaluating the anatomic relationship between the aortic valve and coronary ostia; transesophageal echocardiographic real-time monitoring of the coronary flow with a color Doppler and pulsed-wave Doppler is a valuable tool that allows for a determination of real-time coronary patency and the detection of asymptomatic coronary obstructions. Because of the risk of developing a delayed coronary obstruction, the close postprocedural monitoring of patients at a high risk of developing coronary obstructions is advisable. CT simulations of ViV TAVR, 3D printing models, and fusion imaging represent the future directions that may help provide a personalized lifetime strategy and tailored approach for each patient, potentially minimizing complications and improving outcomes.

Advances in Imaging for Tricuspid Transcatheter Edge-to-Edge Repair: Lessons Learned and Future Perspectives.

Severe tricuspid valve (TV) regurgitation (TR) has been associated with adverse long-term outcomes in several natural history studies, but isolated TV surgery presents high mortality and morbidity rates. Transcatheter tricuspid valve interventions (TTVI) therefore represent a promising field and may currently be considered in patients with severe secondary TR that have a prohibitive surgical risk. Tricuspid transcatheter edge-to-edge repair (T-TEER) represents one of the most frequently used TTVI options. Accurate imaging of the tricuspid valve (TV) apparatus is crucial for T-TEER preprocedural planning, in order to select the right candidates, and is also fundamental for intraprocedural guidance and post-procedural follow-up. Although transesophageal echocardiography represents the main imaging modality, we describe the utility and additional value of other imaging modalities such as cardiac CT and MRI, intracardiac echocardiography, fluoroscopy, and fusion imaging to assist T-TEER. Developments in the field of 3D printing, computational models, and artificial intelligence hold great promise in improving the assessment and management of patients with valvular heart disease.

Case report: Paravalvular regurgitation post transcatheter aortic valve replacement: When in doubt choose cardiac magnetic resonance.

Paravalvular leak (PVL) is a common complication following transcatheter aortic valve replacement (TAVR). Significant PVL is associated with adverse prognosis, but may be challenging to assess accurately. We report the case of an 81-year-old man with shortness of breath 5 months post TAVR. Echocardiography classified PVL as either moderate or severe depending on the parameter utilized, while angiography found only mild PVL. Cardiac magnetic resonance allowed an exact quantification of regurgitant flow volume, classified as clinically and hemodynamically significant. This case highlights the role of multimodality imaging assessment including cardiac magnetic resonance for a more accurate assessment of PVL severity, especially when other imaging modalities show discordant results.

Concurrent cardiac and central nervous system complications of acute infective endocarditis: case report.

Background: Cerebral mycotic aneurysms represent a rare but life-threatening complication of infective endocarditis (IE), with high mortality rate when ruptured. Due to the lack of randomized controlled trials, management of infectious aneurysms complicating endocarditis remains a controversial topic. Case summary: We describe a case of Streptococcus salivarius bicuspid aortic and mitral valve endocarditis with concurrent spontaneous mycotic aneurysm rupture and acute subarachnoid haemorrhage (SAH). A 40-year-old man with history of intravenous drug abuse presented to our emergency department with altered mental status and dyspnoea. Echocardiography documented large vegetations on a bicuspid aortic valve and on the mitral valve, causing acute severe aortic and mitral regurgitation. Brain computed tomography imaging documented a ruptured fusiform aneurysm in a distal branch of the right middle cerebral artery causing acute SAH and acute obstructive hydrocephalus. An external ventricular drain was emergently placed and endovascular embolization of the aneurysm was achieved with deployment of six coils. Blood cultures grew S. salivarius and antibiotic therapy according to microbiological sensitivities was administered. Hospital stay was complicated by acute heart failure, ST-elevation myocardial infarction, conduction disturbances, cerebral vasospasm, recurrent mycotic aneurysm rupture, and death. Discussion: Clinicians should be mindful of the rare, potentially severe complication of IE with cerebral mycotic aneurysms to enable prompt treatment. Generally, central nervous system procedures are performed prior to cardiac surgical management of IE, since cardiopulmonary bypass may exacerbate cerebral haemorrhage, ischaemic damage, and oedema in areas of blood-brain barrier disruption. A multidisciplinary collaboration is crucial for optimal patient management.

Protective Biomolecular Mechanisms of Glutathione Sodium Salt in Ischemia-Reperfusion Injury in Patients with Acute Coronary Syndrome-ST-Elevation Myocardial Infarction.

Ischemia-Reperfusion Injury (IRI) is responsible for adverse outcomes in patients with ST-Elevation Myocardial Infarction (STEMI). Oxidative stress, resulting from the production of Reactive Oxygen Species (ROS) and low availability of Glutathione (GSH), are the two main mediators of IRI. The effectiveness of exogenous antioxidant therapy in this scenario is still debated, since the encouraging results obtained in animal models have not been fully reproduced in clinical studies. In this review we focus on the role of GSH, specifically on the biomolecular mechanisms that preserve myocardial cells from damage due to reperfusion. In this regard, we provide an extensive discussion about GSH intrinsic antioxidant properties, its current applications in clinical practice, and the future perspectives.

Biomolecular Mechanisms of Cardiorenal Protection with Sodium-Glucose Co-Transporter 2 Inhibitors.

Diabetes mellitus (DM) is a metabolic disorder characterized by chronic hyperglycemia and associated with an increased risk of morbidity and mortality, primarily from cardiovascular and renal diseases. Sodium-glucose cotransporter 2 inhibitors (SGLT2-Is) are novel drugs for the treatment of type 2 DM and heart failure (HF). SGLT2-Is mediate protective effects on both the renal and cardiovascular systems. This review addresses the current knowledge on the biomolecular mechanisms of the cardiorenal protective effects of SGLT2-Is, which appear to act mainly through non-glucose-mediated pathways. Cardiorenal protection mechanisms lead to reduced chronic renal disease progression and improved myocardial and coronary endothelial function. Concomitantly, it is possible to observe reflected changes in biomarkers linked with diabetic kidney disease and HF.

The Transaxillary Route as a Second Access Option in TAVI Procedures: Experience of a Single Centre.

Background: The aim of our study was to determine the feasibility and efficacy of transaxillary (TAX) TAVI in patients not eligible for the transfemoral route. Methods: This is a retrospective study of a single center. We analysed 262 patients treated with TAVI. In 17 patients (6.5%), the procedure was performed with the TAX approach. Procedural and hospital data, 30-day safety, and clinical efficacy were assessed and compared between the transfemoral and TAX groups. Results: In the TAX groups, we found a higher prevalence of men (p = 0.001), smokers (p = 0.033), and previous strokes (p = 0.02). The EUROSCORE II was higher in the TAX group (p = 0.014). The success rate of the device was 100%. TAX was associated with a longer procedure time (p = 0.001) and shorter median device time (p = 0.034) in minutes. Patients treated with TAX had a longer hospital stay (p = 0.005) and higher overall bleeding rate (p = 0.001). Peripheral neurological complications were more frequent with TAX (p = 0.001), which almost completely resolved by 30 days. Conclusions: TAX TAVI is safe and effective and should be considered as a second choice when transfemoral TAVI is not feasible due to severe comorbidities.