DSP-Related Cardiomyopathy as a Distinct Clinical Entity? Emerging Evidence from an Italian Cohort.

Variants in desmoplakin gene (DSP MIM *125647) have been usually associated with Arrhythmogenic Cardiomyopathy (ACM), or Dilated Cardiomyopathy (DCM) inherited in an autosomal dominant manner. A cohort of 18 probands, characterized as heterozygotes for DSP variants by a target Next Generation Sequencing (NGS) cardiomyopathy panel, was analyzed. Cardiological, genetic data, and imaging features were retrospectively collected. A total of 16 DSP heterozygous pathogenic or likely pathogenic variants were identified, 75% (n = 12) truncating variants, n = 2 missense variants, n = 1 splicing variant, and n = 1 duplication variant. The mean age at diagnosis was 40.61 years (IQR 31-47.25), 61% of patients being asymptomatic (n = 11, New York Heart Association (NYHA) class I) and 39% mildly symptomatic (n = 7, NYHA class II). Notably, 39% of patients (n = 7) presented with a clinical history of presumed myocarditis episodes, characterized by chest pain, myocardial enzyme release, 12-lead electrocardiogram abnormalities with normal coronary arteries, which were recurrent in 57% of cases (n = 4). About half of the patients (55%, n = 10) presented with a varied degree of left ventricular enlargement (LVE), four showing biventricular involvement. Eleven patients (61%) underwent implantable cardioverter defibrillator (ICD) implantation, with a mean age of 46.81 years (IQR 36.00-64.00). Cardiac magnetic resonance imaging (CMRI) identified in all 18 patients a delayed enhancement (DE) area consistent with left ventricular (LV) myocardial fibrosis, with a larger localization and extent in patients presenting with recurrent episodes of myocardial injury. These clinical and genetic data confirm that DSP-related cardiomyopathy may represent a distinct clinical entity characterized by a high arrhythmic burden, variable degrees of LVE, Late Gadolinium Enhancement (LGE) with subepicardial distribution and episodes of myocarditis-like picture.

Genetic and Epigenetic Factors of Takotsubo Syndrome: A Systematic Review.

Takotsubo syndrome (TTS), recognized as stress's cardiomyopathy, or as left ventricular apical balloon syndrome in recent years, is a rare pathology, described for the first time by Japanese researchers in 1990. TTS is characterized by an interindividual heterogeneity in onset and progression, and by strong predominance in postmenopausal women. The clear causes of these TTS features are uncertain, given the limited understanding of this intriguing syndrome until now. However, the increasing frequency of TTS cases in recent years, and particularly correlated to the SARS-CoV-2 pandemic, leads us to the imperative necessity both of a complete knowledge of TTS pathophysiology for identifying biomarkers facilitating its management, and of targets for specific and effective treatments. The suspect of a genetic basis in TTS pathogenesis has been evidenced. Accordingly, familial forms of TTS have been described. However, a systematic and comprehensive characterization of the genetic or epigenetic factors significantly associated with TTS is lacking. Thus, we here conducted a systematic review of the literature before June 2021, to contribute to the identification of potential genetic and epigenetic factors associated with TTS. Interesting data were evidenced, but few in number and with diverse limitations. Consequently, we concluded that further work is needed to address the gaps discussed, and clear evidence may arrive by using multi-omics investigations.

Modelling the pathogenesis of Myotonic Dystrophy type 1 cardiac phenotype through human iPSC-derived cardiomyocytes.

Myotonic Dystrophy type 1 (DM1) is a multisystemic disease, autosomal dominant, caused by a CTG repeat expansion in DMPK gene. We assessed the appropriateness of patient-specific induced pluripotent stem cell-derived cardiomyocytes (CMs) as a model to recapitulate some aspects of the pathogenetic mechanism involving cardiac manifestations in DM1 patients. Once obtained in vitro, CMs have been characterized for their morphology and their functionality. CMs DM1 show intranuclear foci and transcript markers abnormally spliced respect to WT ones, as well as several irregularities in nuclear morphology, probably caused by an unbalanced lamin A/C ratio. Electrophysiological characterization evidences an abnormal profile only in CMs DM1 such that the administration of antiarrythmic drugs to these cells highlights even more the functional defect linked to the disease. Finally, Atomic Force Measurements reveal differences in the biomechanical behaviour of CMs DM1, in terms of frequencies and synchronicity of the beats. Altogether the complex phenotype described in this work, strongly reproduces some aspects of the human DM1 cardiac phenotype. Therefore, the present study provides an in vitro model suggesting novel insights into the mechanisms leading to the development of arrhythmogenesis and dilatative cardiomyopathy to consider when approaching to DM1 patients, especially for the risk assessment of sudden cardiac death (SCD). These data could be also useful in identifying novel biomarkers effective in clinical settings and patient-tailored therapies.

Next Generation Sequencing and Linkage Analysis for the Molecular Diagnosis of a Novel Overlapping Syndrome Characterized by Hypertrophic Cardiomyopathy and Typical Electrical Instability of Brugada Syndrome.

BACKGROUND: Familial hypertrophic cardiomyopathy (HCM) is an autosomal dominant inherited disorder; mutations in at least 20 genes have been associated. Brugada syndrome (BrS) is an autosomal dominant inherited disorder caused by mutations mainly in theSCN5Agene. A new clinical entity that consists of HCM, typical electrical instability of BrS and sudden death (SD), is described. METHODS AND RESULTS: The family was constituted by 7 members, 4 of who presented clinical features of HCM and electrical instability of BrS. The clinical presentation of proband was ventricular fibrillation. All members were clinically evaluated by physical examination, 12-lead electrocardiography, 2-dimensional echocardiography, stress test, electrocardiogram Holter, flecainide test, and electrophysiological study. An integrated linkage analysis and next generation sequencing (NGS) approach was used to identify the causative mutation. Linkage with the α-tropomyosin (TPM1) gene on chromosome 15q22 was identified. The NGS study identified a missense mutation within theTPM1gene (c.574G>A; p.E192K), exactly located in a binding domain with polycystin-2 protein. No other pathogenic mutations were identified. CONCLUSIONS: This is the first report of an association between HCM and BrS, and the first to use a combined approach of linkage and NGS to identify a causative mutation in SD. The present study expands the clinical spectrum of disorders associated with theTPM1gene and may be useful to report novel mechanisms of electrical instability in HCM and BrS.

The role of cardiac magnetic resonance in sports cardiology: results from a large cohort of athletes.

BACKGROUND: Cardiac magnetic resonance (CMR) provides information on morpho-functional abnormalities and myocardial tissue characterisation. Appropriate indications for CMR in athletes are uncertain. OBJECTIVE: To analyse the CMR performed at our Institute to evaluate variables associated with pathologic findings in a large cohort of athletes presenting with different clinical conditions. METHODS: All the CMR performed at our Institute in athletes aged > 14 years were recruited. CMR indications were investigated. CMR was categorised as "positive" or "negative" based on the presence of morphological and/or functional abnormalities and/or the presence of late gadolinium enhancement (excluding the right ventricular insertion point), fat infiltration, or oedema. Variables associated with "positive" CMR were explored. RESULTS: A total of 503 CMR were included in the analysis. "Negative" and "positive" CMR were 61% and 39%, respectively. Uncommon ventricular arrhythmias (VAs) were the most frequent indications for CMR, but the proportion of positive results was low (37%), and only polymorphic ventricular patterns were associated with positive CMR (p = 0.006). T-wave inversion at 12-lead ECG, particularly on lateral and inferolateral leads, was associated with positive CMR in 34% of athletes (p = 0.05). Echocardiography abnormalities resulted in a large proportion (58%) of positive CMR, mostly cardiomyopathies. CONCLUSION: CMR is more efficient in identifying a pathologic cardiac substrate in athletes in case of VAs (i.e., polymorphic beats), abnormal ECG repolarisation (negative T-waves in inferolateral leads), and borderline echocardiographic findings (LV hypertrophy, mildly depressed LV function). On the other hand, CMR is associated with a large proportion of negative results. Therefore, a careful clinical selection is needed to indicate CMR in athletes appropriately.

Acute myocardial infarction in a patient with MELAS syndrome: a possible link?

The mitochondrial encephalomyopathy, lactic acidosis, and stroke (MELAS) syndrome is a mitochondrial disorder, commonly caused by m.3243A>G mutation in the MT-TL1 gene. It encodes for the mitochondrial leucine transfer RNA (tRNA Leu [UUR]), implicated in the translation of proteins involved in the assembly and function of mitochondrial complexes in the electron transport chain. The m.3243A>G mutation determines complex I (CI) deficiency, ultimately leading to NADH accumulation, higher rates of glycolysis in order to compensate for the reduced ATP production and increase in lactates, the end-product of glycolysis. Disruption of the oxidative phosphorylation function with an inability to produce sufficient energy results in multi-organ dysfunction, with high energy demanding cells, such as myocytes and neurons, being the most affected ones. Therefore, MELAS syndrome is characterized by a heterogeneous clinical spectrum. Here we report on a case of a 55-year-old man affected by MELA syndrome with no cardiovascular risk factors. He was admitted to our department because of a non ST-segment elevation myocardial infarction (NSTEMI). A coronary angioplasty of the posterior descending artery and of the left anterior descending artery was realized. Transthoracic echocardiography showed inferior and anterior left ventricular wall hypokinesis together with a moderate left ventricle hypertrophy. Cardiac involvement is reported in about a third of the patients and left ventricular hypertrophy (LVH) is the most common phenotype, with possible dilated cardiomyopathy in end-stage disease; brady- arrhythmias and tachy-arrhythmias are also frequently reported as well as Wolff- Parkinson-White (WPW) syndrome. Organ impairment and clinical manifestations depend on the heteroplasmy level of mutant DNA in cells that can differ among individuals, explaining why some patients present a more severe disease. A clear relationship between MELAS syndrome and atherosclerosis has never been established, however recently advocated. In vitro studies in MELAS patients have shown that higher mitochondrial ROS levels and increased expression of oxidative stress-related genes, as a consequence of complex I deficiency and disrupted electron transport, allow circulating LDL to be promptly oxidized into ox-LDL, contributing to endothelial dysfunction and atherosclerosis plaque formation. In light of the recent evidence suggesting a possible link between mitochondrial disorders and atherosclerosis, we speculate that MELAS syndrome may have played a role in the pathogenesis of coronary artery disease in our patient. Further investigations are needed to confirm a pathogenetic link.

Spontaneous coronary artery dissection: review, case report and analysis of COVID-19-related cases.

Spontaneous coronary artery dissection (SCAD) accounts for 1-4% of all acute coronary syndromes (ACS). Since the first description in 1931, our understanding of the disease has evolved; however, its pathophysiology and management are still a matter of debate. SCAD typically occurs in a middle-aged woman with no or few traditional cardiovascular risk factors. Two hypotheses have been proposed to explain the pathophysiology depending on the primary event: an intimal tear in the "inside-out" hypothesis and a spontaneous hemorrhage from the vasa vasorum in the "outside-in" hypothesis. Etiology appears to be multifactorial: different predisposing and precipitating factors have been identified. Coronary angiography is the gold standard for the diagnosis of SCAD. Current recommendations on the treatment of SCAD patients are based on expert opinions: a conservative strategy is preferred in hemodynamically stable SCAD patients, while urgent revascularization should be considered in hemodynamically unstable patients. Eleven cases of SCAD in COVID-19 patients have already been described: although the exact pathophysiological mechanism remains unclear, COVID-19-related SCAD is considered a combination of significant systemic inflammatory response and localized vascular inflammation. We present a literature review of SCAD, and we report an unpublished case of SCAD in a COVID-19 patient.

Sport activity in patients with cardiomyopathies: a review.

Exercise has undisputable benefits and is an important therapy component for most cardiovascular diseases, with a proven role in reducing mortality. On the contrary, exercise may paradoxically trigger sudden cardiac arrest in patients with cardiomyopathies requiring refrain from competitive sports participation. The 2020 European guidelines for patients with cardiovascular disease provided indication for sports participation for patients with cardiac conditions, including cardiomyopathies. Although in some cases, the knowledge of the natural history of the disease and the risk of death during intensive exercise is more robust, in others, the evidence is scarce. Therefore, recommendations are not available for all possible scenarios with several uncertainties. In addition, many patients aspire to continue competitive sports or practise recreational activities after a diagnosis of cardiomyopathy. These aspects generate concern for the physician, who should make complex decisions, and confronts the request to design specific exercise programmes without specific indications. This article will review the available evidence on the sports-related risk of sudden cardiac death or cardiovascular events and the progression of the disease in cardiomyopathies.

Reversible Apical Hypertrophy in a Young Competitive Athlete with Familiar Hypertrophic Cardiomyopathy.

BACKGROUND Differential diagnosis between athlete's heart and hypertrophic cardiomyopathy is sometimes challenging in sport cardiology since endurance training can cause a distinct pattern of functional and structural changes of the cardiovascular system. It is of crucial importance to accurately diagnose it and stratify the arrhythmic risk since hypertrophic cardiomyopathy is one of the leading causes of sudden cardiac death in young athletes. Apical hypertrophic cardiomyopathy is a relatively rare form of hypertrophic cardiomyopathy that predominantly affects the apex of the left ventricle and usually has a nonobstructive physiology. Few data and studies are available on influence of aerobic training (and detraining) on morphological changes in athletes with apical hypertrophic cardiomyopathy. CASE REPORT We present the case of a 19-year-old male soccer athlete with family history for obstructive hypertrophic cardiomyopathy, with electrocardiographic and morphological left ventricular remodeling in association with sports activity. Intensive aerobic training led to marked T-wave inversion on 12-lead ECG and left ventricular hypertrophy compatible with apical hypertrophic cardiomyopathy. Genetic testing confirmed the presence of familial variant c853C>T, p.(Arg 285Cys) on TNNT2 gene. After 18 months detraining, we observed a complete regression of ECG abnormalities and a reverse remodeling of the left ventricular hypertrophy. No pharmacological therapy was indicated; periodic cardiological evaluations were advised. Monitoring devices or implantable cardioverter defibrillator were not recommended. CONCLUSIONS This case suggests that intensive aerobic training can affect the pathological hypertrophic cardiomyopathy substrate, facilitating the development of left ventricular hypertrophy and, more interesting, regression of structural changes after detraining.

Low prevalence of cardiac abnormalities in competitive athletes at return-to-play after COVID-19.

OBJECTIVE: to evaluate the prevalence of cardiac involvement after COVID-19 in competitive athletes at return-to-play (RTP) evaluation, following the recommended Italian protocol including cardiopulmonary exercise test (CPET) and 24-Hour Holter monitoring. DESIGN AND METHODS: this is a single centre observational, cross-sectional study. Since October 2020, all competitive athletes (age ≥ 14 years) evaluated in our Institute after COVID-19, prior RTP were enrolled. The protocol dictated by the Italian governing bodies included: 12­lead ECG, blood test, CPET, 24-h ECG monitoring, spirometry. Cardiovascular Magnetic Resonance (CMR) was performed based on clinical indication. RESULTS: 219 consecutive athletes were examined (59% male), age 23 years (IQR 19-27), 21% asymptomatic, 77% mildly symptomatic, 2% with previous pneumonia. The evaluation was performed after a median of 10 (6-17) days from negative SARS-CoV-2 swab. All athletes showed a good exercise capacity at CPET without cardiovascular and respiratory limitations. Uncommon premature ventricular contractions (PVCs) were found in 9.5% (n = 21) at CPET/Holter ECG monitoring. Two athletes (0.9%) were diagnosed with acute myocarditis (by CMR) and another one with new pericardial effusion. All the three athletes were temporally restricted from sport participation. CONCLUSIONS: Myocarditis in competitive athletes screened after COVID-19 resolution was detected in a low minority of the cases (0.9%). However, a non-negligible prevalence of uncommon PVCs (9%) was observed, either at CPET and/or Holter ECG monitoring, including all athletes with COVID-19 related cardiovascular abnormalities.

Periodic health evaluation in athletes competing in Tokyo 2020: from SARS-CoV-2 to Olympic medals.

Background: The Tokyo Olympic games were the only games postponed for a year in peacetime, which will be remembered as the COVID-19 Olympics. No data are currently available on the effect on athlete's performance. Aim: To examine the Italian Olympic athletes who have undergone the return to play (RTP) protocol after COVID-19 and their Olympic results. Methods: 642 Potential Olympics (PO) athletes competing in 19 summer sport disciplines were evaluated through a preparticipation screening protocol and, when necessary, with the RTP protocol. The protocol comprised blood tests, 12-lead resting ECG, transthoracic echocardiogram, cardiopulmonary exercise test, 24-hour Holter-ECG monitoring and cardiovascular MR based on clinical indication. Results: Of the 642 PO athletes evaluated, 384 participated at the Olympic Games, 254 being excluded for athletic reasons. 120 athletes of the total cohort of 642 PO were affected by COVID-19. They were evaluated with the RTP protocol before resuming physical activity after a mean detraining period of 30±13 days. Of them, 100 were selected for Olympic Games participation, 16 were excluded for athletic reasons and 4 were due to RTP results (2 for COVID-19-related myocarditis, 1 for pericarditis and 1 for complex ventricular arrhythmias). Among athletes with a history of COVID-19 allowed to resume physical activity after the RTP and selected for the Olympic Games, no one had abnormalities in cardiopulmonary exercise test parameters, and 28 became medal winners with 6 gold, 6 silver and 19 bronze medals. Conclusions: Among athletes with COVID-19, there is a low prevalence of cardiac sequelae. For those athletes allowed to resume physical activity after the RTP evaluation, the infection and the forced period of inactivity didn't have a negative impact on athletic performance.

The Diagnostic Value of the 12-Lead ECG in Arrhythmogenic Left Ventricular Cardiomyopathy: Novel ECG Signs.

BACKGROUND: Electrocardiographic (ECG) findings in arrhythmogenic left ventricular cardiomyopathy (ALVC) are limited to small case series. OBJECTIVES: This study aimed to analyze the ECG characteristics of ALVC patients and to correlate ECG with cardiac magnetic resonance and genotype data. METHODS: We reviewed data of 54 consecutive ALVC patients (32 men, age 39 ± 15 years) and compared them with 84 healthy controls with normal cardiac magnetic resonance. RESULTS: T-wave inversion was often noted (57.4%), particularly in the inferior and lateral leads. Low QRS voltages in limb leads were observed in 22.2% of patients. The following novel ECG findings were identified: left posterior fascicular block (LPFB) (20.4%), pathological Q waves (33.3%), and a prominent R-wave in V1 with a R/S ratio ≥0.5 (24.1%). The QRS voltages were lower in ALVC compared with controls, particularly in lead I and II. At receiver-operating characteristic analysis, the sum of the R-wave in I to II ≤8 mm (AUC: 0.909; P < 0.0001) and S-wave in V1 plus R-wave in V6 ≤12 mm (AUC: 0.784; P < 0.0001) effectively discriminated ALVC patients from controls. It is noteworthy that 4 of the 8 patients with an apparently normal ECG were recognized by these new signs. Transmural late gadolinium enhancement was associated to LPFB, a R/S ratio ≥0.5 in V1, and inferolateral T-wave inversion, and a ringlike pattern correlated to fragmented QRS, SV1+RV6 ≤12 mm, low QRS voltage, and desmoplakin alterations. CONCLUSIONS: Pathological Q waves, LPFB, and a prominent R-wave in V1 were common ECG signs in ALVC. An R-wave sum in I to II ≤8 mm and SV1+RV6 ≤12 mm were specific findings for ALVC phenotypes compared with controls.

Cholesterol-lowering drugs inhibit lectin-like oxidized low-density lipoprotein-1 receptor function by membrane raft disruption.

Lectin-like oxidized low-density lipoprotein (LOX-1), the primary receptor for oxidized low-density lipoprotein (ox-LDL) in endothelial cells, is up-regulated in atherosclerotic lesions. Statins are the principal therapeutic agents for cardiovascular diseases and are known to down-regulate LOX-1 expression. Whether the effect on the LOX-1 receptor is related to statin-mediated cholesterol-lowering activity is unknown. We investigate the requirement of cholesterol for LOX-1-mediated lipid particle internalization, trafficking, and processing and the role of statins as inhibitors of LOX-1 function. Disruption of cholesterol-rich membrane microdomains by acute exposure of cells to methyl-ß-cyclodextrin or chronic exposure to different statins (lovastatin and atorvastatin) led to a spatial disorganization of LOX-1 in plasma membranes and a marked loss of specific LOX-1 function in terms of ox-LDL binding and internalization. Subcellular fractionation and immunochemical studies indicate that LOX-1 is naturally present in caveolae-enriched lipid rafts and, by cholesterol reduction, the amount of LOX-1 in this fraction is highly decreased (≥60%). In contrast, isoprenylation inhibition had no effect on the distribution and function of LOX-1 receptors. Furthermore, in primary cultures from atherosclerotic human aorta lesions, we confirm the presence of LOX-1 in caveolae-enriched lipid rafts and demonstrate that lovastatin treatment led to down-regulation of LOX-1 in lipid rafts and rescue of the ox-LDL-induced apoptotic phenotype. Taken together, our data reveal a previously unrecognized essential role of membrane cholesterol for LOX-1 receptor activity and suggest that statins protect vascular endothelium against the adverse effect of ox-LDL by disruption of membrane rafts and impairment of LOX-1 receptor function.

Prevalence of inherited thrombophilia in patients with documented stent thrombosis.

BACKGROUND: Stent thrombosis (ST) is a multi-factorial process involving different mechanisms. The impact of inherited coagulation disorders in the genesis of ST has never been assessed. The aim of the present study was to evaluate the prevalence of G1691A Factor V Leiden mutation, G20210A Factor II (prothrombin) mutation and C677T homozygous methylenetetrahydrofolate reductase (MTHFR) polymorphism in patients with ST. METHODS AND RESULTS: The prevalence of the aforementioned gene variations was assessed in 127 patients: 50 admitted for ST and 77 previously treated with percutaneous coronary intervention not developing ST. A control cohort of 529 healthy volunteers was sampled from the same geographical area. Patients with ST were carriers of at least 1 gene variation in 28% of cases. The prevalence of G1691A Factor V Leiden mutation (odds ratio [OR]=0.64; 95% confidence interval [CI]: 0.04-10.5), G20210A Factor II mutation (OR=0.63; 95% CI: 0.12-3.28) and C677T MTHFR homozygous polymorphism (OR=1.13; 95% CI: 0.47-2.72) did not differ significantly among patients with or without ST. The logistic regression model did not show a significant association between gene variations and ST (OR=0.61; 95% CI: 0.24-1.60; P=0.32). CONCLUSIONS: A specific association between studied gene variations and ST has not been detected. The relatively high prevalence of at least 1 gene anomaly in such a rare subset of patients, and its consequences in term of secondary prevention therapy, suggests that screening for thrombophilia might be justifiable in cases of ST.

Systematic Cardiovascular Screening in Olympic Athletes before and after SARS-CoV-2 Infection.

Conflicting results on the cardiovascular involvement after SARS-CoV-2 infection generated concerns on the safety of return-to-play (RTP) in athletes. The aim of this study was to evaluate the prevalence of cardiac involvement after COVID-19 in Olympic athletes, who had previously been screened in our pre-participation program. Since November 2020, all consecutive Olympic athletes presented to our Institute after COVID-19 prior to RTP were enrolled. The protocol was dictated by the Italian governing bodies and comprised: 12-lead ECG, blood test, cardiopulmonary exercise test (CPET), 24-h ECG monitoring, and spirometry. Cardiovascular Magnetic Resonance (CMR) was also performed. All Athletes were previously screened in our Institute as part of their periodical pre-participation evaluation. Forty-seven Italian Olympic athletes were enrolled: 83% asymptomatic, 13% mildly asymptomatic, and 4% had pneumonia. Uncommon premature ventricular contractions (PVCs) were found in 13% athletes; however, only 6% (n = 3) were newly detected. All newly diagnosed uncommon PVCs were detected by CPET. One of these three athletes had evidence for acute myocarditis by CMR, along with Troponin raise; another had pericardial effusion. No one of the remaining athletes had abnormalities detected by CMR. Cardiac abnormalities in Olympic athletes screened after COVID-19 resolution were detected in a minority, and were associated with new ventricular arrhythmias. Only one had evidence for acute myocarditis (in the presence of symptoms and elevated biomarkers). Our data support the efficacy of the clinical assessment including exercise-ECG to raise suspicion for cardiovascular abnormalities after COVID-19. Instead, the routine use of CMR as a screening tool appears unjustified.

LOX-1/LOXIN: the yin/yang of atheroscleorosis.

Atherosclerosis is the first cause of death in industrialized countries. Together with traditional risk factors (male gender, hypercholesterolemia, hypertension, diabetes, smoking and age), non-traditional risk factors have also been described as predisposing to this disease. Among these, oxidized low density lipoproteins (OxLDL) have been described in correlation to many proatherogenic processes. Many of the effects of OxLDL are mediated by the lectin like oxidized low density lipoprotein receptor 1 (LOX-1), expressed on endothelial cells, macrophages, SMCs and platelets. LOX-1 is encoded by the lectin like oxidized low density lipoprotein receptor 1 (OLR1) gene, located in the p12.3-p13.2 region of human chromosome 12. Variations on this gene have been studied extensively both at the functional and epidemiological level. Despite the fact that functional roles for two variants have been demonstrated, the epidemiological studies have provided inconsistent and inconclusive results. Of particular interest, it has been demonstrated that a linkage disequilibirum block of SNPs located in the intronic sequence of the OLR1 gene modulates the alternative splicing of OLR1 mRNA, leading to different ratios of LOX-1 full receptor and LOXIN, an isoform lacking part of the functional domain. As demonstrated, LOXIN acts by blocking the negative effective of LOX-1 activation. Here we review the state of the art regarding LOX-1, LOXIN, and the functional effects that are associated with the interaction of these molecules.

Clinical Features of LMNA-Related Cardiomyopathy in 18 Patients and Characterization of Two Novel Variants.

Dilated cardiomyopathy (DCM) refers to a spectrum of heterogeneous myocardial disorders characterized by ventricular dilation and depressed myocardial performance in the absence of hypertension, valvular, congenital, or ischemic heart disease. Mutations in LMNA gene, encoding for lamin A/C, account for 10% of familial DCM. LMNA-related cardiomyopathies are characterized by heterogeneous clinical manifestations that vary from a predominantly structural heart disease, mainly mild-to-moderate left ventricular (LV) dilatation associated or not with conduction system abnormalities, to highly pro-arrhythmic profiles where sudden cardiac death (SCD) occurs as the first manifestation of disease in an apparently normal heart. In the present study, we select, among 77 DCM families referred to our center for genetic counselling and molecular screening, 15 patient heterozygotes for LMNA variants. Segregation analysis in the relatives evidences other eight heterozygous patients. A genotype-phenotype correlation has been performed for symptomatic subjects. Lastly, we perform in vitro functional characterization of two novel LMNA variants using dermal fibroblasts obtained from three heterozygous patients, evidencing significant differences in terms of lamin expression and nuclear morphology. Due to the high risk of SCD that characterizes patients with lamin A/C cardiomyopathy, genetic testing for LMNA gene variants is highly recommended when there is suspicion of laminopathy.

Variants in MHY7 Gene Cause Arrhythmogenic Cardiomyopathy.

BACKGROUND: Arrhythmogenic Cardiomyopathy (ACM) is a disease of the cardiac muscle, characterized by frequent ventricular arrhythmias and functional/ structural abnormalities, mainly of the right ventricle. To date, 20 different genes have been associated with ACM and the majority of them encode for desmosomal proteins. In this study, we describe the characterization of two novel variants in MHY7 gene, segregating in two ACM families. MYH7 encodes for myosin heavy chain ß (MHC-ß) isoform, involved in cardiac muscle contractility. METHOD AND RESULTS: In family A, the autopsy revealed ACM with biventricular involvement in both the proband and his father. In family B, the proband had been diagnosed as affected by ACM and implanted with implantable cardioverter defibrillator (ICD), due to ECG evidence of monomorphic ventricular tachycardia after syncope. After clinical evaluation, a molecular diagnosis was performed using a NGS custom panel. The two novel variants identified predicted damaging, located in a highly conserved domain: c. 2630T>C is not described while c.2609G>A has a frequency of 0.00000398. In silico analyses evaluated the docking characteristics between proteins using the Haddock2.2 webserver. CONCLUSIONS: Our results reveal two variants in sarcomeric genes to be the molecular cause of ACM, further increasing the genetic heterogeneity of the disease; in fact, sarcomeric variants are usually associated with HCM phenotype. Studies on the role of sarcomere genes in the pathogenesis of ACM are surely recommended in those ACM patients negative for desmosomal mutation screening.

Rotational atherectomy in resistant chronic total occlusions.

OBJECTIVES: To assess the application of rotational atherectomy to improving the success rate of percutaneous recanalization of chronic total occlusion (CTO). BACKGROUND: Although the inability to cross the occlusion with a guidewire is the reason for failure in the majority of cases, one of the most frustrating situations that may occur during a recanalization procedure is when a guidewire crosses successfully but it is impossible to advance any device over the wire through the occluded segment. METHODS: From January 2006 to October 2009, 45/648 (7%) consecutive patients with CTO resistant to recanalization by conventional techniques were treated by high-speed rotational atherectomy (Rotablator group). RESULTS: All but two lesions were successfully crossed by Rotablator and eventually treated by stent implantation. As compared to the 603 CTO treated by conventional techniques (Conventional group), the 45 patients in the Rotablator group were older, more often female, active smokers, with chronic kidney disease and higher rate of previous surgical revascularization. The CTO in the Rotablator group had a longer duration. Peri-procedural myocardial infarction was more frequent in the Rotablator group (35% vs. 22%; P = 0.044). Coronary perforation occurred only in three patients in the Conventional group and two of these patients needed urgent surgical intervention. No patient died from either group. CONCLUSIONS: The inability to cross a CTO with a balloon catheter occurs in approximately 7% of all CTOs that are successfully crossed with a guidewire. Rotational atherectomy is a safe and effective technique to overcome this frustrating situation.

Population differences in allele frequencies at the OLR1 locus may suggest geographic disparities in cardiovascular risk events.

BACKGROUND: Several studies have demonstrated a link between cardiovascular disease (CVD) susceptibility and the genetic background of populations. Endothelial activation and dysfunction induced by oxidized low-density lipoprotein (ox-LDL) is one of the key steps in the initiation of atherosclerosis. The oxidized low density lipoprotein (lectin-like) receptor 1 (OLR1) gene is the main receptor of ox-LDL. We have previously characterized two polymorphisms (rs3736235 and rs11053646) associated with the risk for coronary artery disease (CAD) and acute myocardial infarction (AMI). AIM: Given their clinical significance, it is of interest to know the distribution of these variants in populations from different continents. SUBJECTS AND METHODS: A total of 1229 individuals from 17 different African, Asian and European populations was genotyped for the two considered markers. RESULTS: The high frequencies of ancestral alleles in South-Saharan populations is concordant with the African origin of our species. The results highlight that African populations are closer to Asians, and clearly separated from the Europeans. CONCLUSION: The results confirm significant genetic structuring among populations and suggest a possible basis for varying susceptibility to CVD among groups correlated with the geographical location of populations linked with the migrations out of Africa, or with different lifestyle.