Advanced cell and gene therapies in cardiology.

We review the evidence for the presence of stem/progenitor cells in the heart and the preclinical and clinical data using diverse cell types for the therapy of cardiac diseases. We highlight the failure of adult stem/progenitor cells to ameliorate heart function in most cardiac diseases, with the possible exception of refractory angina. The use of pluripotent stem cell-derived cardiomyocytes is analysed as a viable alternative therapeutic option but still needs further research at preclinical and clinical stages. We also discuss the use of direct reprogramming of cardiac fibroblasts into cardiomyocytes and the use of extracellular vesicles as therapeutic agents in ischemic and non-ischemic cardiac diseases. Finally, gene therapies and genome editing for the treatment of hereditary cardiac diseases, ablation of genes responsible for atherosclerotic disease, or modulation of gene expression in the heart are discussed.

Molecular Mechanisms of Obesity-Linked Cardiac Dysfunction: An Up-Date on Current Knowledge.

Obesity is defined as excessive body fat accumulation, and worldwide obesity has nearly tripled since 1975. Excess of free fatty acids (FFAs) and triglycerides in obese individuals promote ectopic lipid accumulation in the liver, skeletal muscle tissue, and heart, among others, inducing insulin resistance, hypertension, metabolic syndrome, type 2 diabetes (T2D), atherosclerosis, and cardiovascular disease (CVD). These diseases are promoted by visceral white adipocyte tissue (WAT) dysfunction through an increase in pro-inflammatory adipokines, oxidative stress, activation of the renin-angiotensin-aldosterone system (RAAS), and adverse changes in the gut microbiome. In the heart, obesity and T2D induce changes in substrate utilization, tissue metabolism, oxidative stress, and inflammation, leading to myocardial fibrosis and ultimately cardiac dysfunction. Peroxisome proliferator-activated receptors (PPARs) are involved in the regulation of carbohydrate and lipid metabolism, also improve insulin sensitivity, triglyceride levels, inflammation, and oxidative stress. The purpose of this review is to provide an update on the molecular mechanisms involved in obesity-linked CVD pathophysiology, considering pro-inflammatory cytokines, adipokines, and hormones, as well as the role of oxidative stress, inflammation, and PPARs. In addition, cell lines and animal models, biomarkers, gut microbiota dysbiosis, epigenetic modifications, and current therapeutic treatments in CVD associated with obesity are outlined in this paper.

Cardiac pathology in mucopolysaccharidosis I mice: Losartan modifies ERK1/2 activation during cardiac remodeling.

Mucopolysaccharidosis type I (MPS I) is a lysosomal storage disorder caused by mutations in the IDUA gene, that codifies the alpha-L-iduronidase enzyme, which deficiency leads to storage of glycosaminoglycans, with multiple clinical manifestations. One of the leading causes of death in MPS I patients are cardiac complications such as cardiac valve thickening, conduction abnormalities, myocardial dysfunction, and cardiac hypertrophy. The mechanism leading to cardiac dysfunction in MPS I is not entirely understood. In a previous study, we have demonstrated that losartan and propranolol improved the cardiac function in MPS I mice. Thus, we aimed to investigate whether the pathways influenced by these drugs may modulate the cardiac remodeling process in MPS I mice. According to our previous observation, losartan and propranolol restore the heart function, without altering valve thickness. MPS I mice presented reduced activation of AKT and ERK1/2, increased activity of cathepsins, but no alteration in metalloproteinase activity was observed. Animals treated with losartan showed a reduction in cathepsin activity and restored ERK1/2 activation. While both losartan and propranolol improved heart function, no mechanistic evidence was found for propranolol so far. Our results suggest that losartan or propranolol could be used to ameliorate the cardiac disease in MPS I and could be considered as adjuvant treatment candidates for therapy optimization.

Inflammatory myopathy in the context of an unusual overlapping laminopathy.

Laminopathies are genetic disorders associated with alterations in nuclear envelope proteins, known as lamins. The LMNA gene encodes lamins A and C, and LMNA mutations have been linked to diseases involving fat (type 2 familial partial lipodystrophy [FPLD2]), muscle (type 2 Emery-Dreifuss muscular dystrophy [EDMD2], type 1B limb-girdle muscular dystrophy [LGMD1B], and dilated cardiomyopathy), nerves (type 2B1 Charcot-Marie-Tooth disease), and premature aging syndromes. Moreover, overlapping syndromes have been reported. This study aimed to determine the genetic basis of an overlapping syndrome in a patient with heart disease, myopathy, and features of lipodystrophy, combined with severe metabolic syndrome. We evaluated a 54-year-old woman with rheumatoid arthritis, chronic hypercortisolism (endogenous and exogenous), and a history of cured adrenal Cushing syndrome. The patient presented with a complex disorder, including metabolic syndrome associated with mild partial lipodystrophy (Köbberling-like); mild hypertrophic cardiomyopathy, with Wolff-Parkinson- White syndrome and atrial fibrillation; and limb-girdle inflammatory myopathy. Mutational analysis of the LMNA gene showed a heterozygous c.1634G>A (p.R545H) variant in exon 10 of LMNA. This variant has previously been independently associated with FPLD2, EDMD2, LGMD1B, and heart disease. We describe a new, LMNA-associated, complex overlapping syndrome in which fat, muscle, and cardiac disturbances are related to a p.R545H variant.

Inflammatory myopathy in the context of an unusual overlapping laminopathy

Summary Laminopathies are genetic disorders associated with alterations in nuclear envelope proteins, known as lamins. The LMNA gene encodes lamins A and C, and LMNA mutations have been linked to diseases involving fat (type 2 familial partial lipodystrophy [FPLD2]), muscle (type 2 Emery-Dreifuss muscular dystrophy [EDMD2], type 1B limb-girdle muscular dystrophy [LGMD1B], and dilated cardiomyopathy), nerves (type 2B1 Charcot-Marie-Tooth disease), and premature aging syndromes. Moreover, overlapping syndromes have been reported. This study aimed to determine the genetic basis of an overlapping syndrome in a patient with heart disease, myopathy, and features of lipodystrophy, combined with severe metabolic syndrome. We evaluated a 54-year-old woman with rheumatoid arthritis, chronic hypercortisolism (endogenous and exogenous), and a history of cured adrenal Cushing syndrome. The patient presented with a complex disorder, including metabolic syndrome associated with mild partial lipodystrophy (Köbberling-like); mild hypertrophic cardiomyopathy, with Wolff-Parkinson- White syndrome and atrial fibrillation; and limb-girdle inflammatory myopathy. Mutational analysis of the LMNA gene showed a heterozygous c.1634G>A (p.R545H) variant in exon 10 of LMNA. This variant has previously been independently associated with FPLD2, EDMD2, LGMD1B, and heart disease. We describe a new, LMNA-associated, complex overlapping syndrome in which fat, muscle, and cardiac disturbances are related to a p.R545H variant.

A Novel Missense GLA Mutation (p.G35V) Detected in Hemodialysis Screening Leads to Severe Systemic Manifestations of Fabry Disease in Men and Women.

BACKGROUND/AIMS: Fabry disease (FD), an X-linked lysosomal storage disorder, leads to accumulation of globotriaosylceramide. Screening in dialysis patients may identify genetic variants of unknown clinical significance. We aimed to characterize the pathogenicity of a novel GLA gene mutation identified during hemodialysis screening and the histologic findings of early Fabry nephropathy. METHODS: One out of 108 male hemodialysis patients screened for FD presented low α-galactosidase A activity. A novel missense mutation (p.G35V) in the GLA gene was detected. Family screening identified 11 additional cases (8 women). Clinical investigation was conducted in 10 patients (index case and 9 relatives). Pathogenicity of the new mutation was investigated by clinical and laboratory tests, cardiac and cranial magnetic resonance imaging, and kidney biopsy. RESULTS: Cardiac manifestations were detected in most patient from both genders, such as left ventricular hypertrophy and short PR interval. White matter lesion was present in 3 women. Pulvinar lesion of the thalamus and ischemic stroke were detected in male patients. Abnormal glomerular filtration rate (GFR) and/or albuminuria were present in 5 patients (3 women). Renal biopsies (n = 7) revealed globotriaosylceramide deposits in different cell types and foot processes effacement in all patients, including women with normal albuminuria. Despite a normal GFR, tubulointerstitial fibrosis ranging from 5 to 20% was present in young women and men with normal or high albuminuria, respectively. CONCLUSION: The novel missense mutation p.G35V leads to severe systemic manifestations of FD in men and women. Kidney histological changes, including tubulointerstitial fibrosis, may predate albuminuria and GFR changes in adult women. Novel non-invasive markers are required for early detection of Fabry nephropathy.

Targeting ß3-Adrenergic Receptors in the Heart: Selective Agonism and ß-Blockade.

Cardiac diseases, such as heart failure, remain leading causes of morbidity and mortality worldwide, with myocardial infarction as the most common etiology. HF is characterized by ß-adrenergic receptor (ßAR) dysregulation that is primarily due to the upregulation of G protein-coupled receptor kinases that leads to overdesensitization of ß1 and ß2ARs, and this clinically manifests as a loss of inotropic reserve. Interestingly, the "minor" ßAR isoform, the ß3AR, found in the heart, lacks G protein-coupled receptor kinases recognition sites, and is not subject to desensitization, and as a consequence of this, in human failing myocardium, the levels of this receptor remain unchanged or are even increased. In different preclinical studies, it has been shown that ß3ARs can activate different signaling pathways that can protect the heart. The clinical relevance of this is also supported by the effects of ß-blockers which are well known for their proangiogenic and cardioprotective effects, and data are emerging showing that these are mediated, at least in part, by enhancement of ß3AR activity. In this regard, targeting of ß3ARs could represent a novel potential strategy to improve cardiac metabolism, function, and remodeling.

Effects of paraoxonase 1 gene polymorphisms on heart diseases: Systematic review and meta-analysis of 64 case-control studies.

BACKGROUND: Associations between paraoxonase 1 (PON1) gene polymorphisms and heart diseases (HD) risk remain inconsistent. In order to obtain address this issue we performed a meta-analysis to assess the association between the L55M and Q192R polymorphisms of PON1 gene and heart diseases risk. METHODS: Relevant studies were enrolled by searching databases systematically. Odds ratios (ORs) with 95% confidence intervals (CIs) were used to calculate the strength of association. Subgroup analyses were conducted for diagnostic and ethnicity. The heterogeneity among each of the studies was calculated by using Cochran Qtest and the inconsistency index (I), and Begg's funnel plot and Egger's tests were performed to evaluate publication bias. RESULT: Sixty four studies involving a total of 19,715 cases and 33,397 controls were included in this meta-analysis. We found that the L55M polymorphism showed a significant association with heart diseases in Europeans (OR 1.44, 95%CI 1.33-1.56) and Asians (OR 1.18, 95%CI 1.03-1.35). This meta-analysis also showed a protective association of Q192R polymorphism with HD in Asian (OR 0.49, 95%CI 0.37-0.66) and African populations (OR 0.67, 95%CI 0.53-0.84). The 192R allele significantly decreased the risk of myocardial infarction (OR 0.75, 95%CI 0.57-0.99) and coronary artery disease (OR 0.91, 95%CI 0.84-0.98); however, individuals with 192Q allele had a markedly increased risk of coronary artery disease development (OR 1.38, 95%CI 1.22-1.56). CONCLUSION: This study demonstrated that the genetic risk for heart diseases is associated with the PON1 gene polymorphisms. L55M polymorphism is a risk factor and Q192R polymorphism is protective in certain populations. It is worth noting that the 192Q allele may be a risk factor to develop coronary artery disease.

Association between angiotensin-converting enzyme insertion/deletion polymorphisms and the risk of heart disease: an updated meta-analysis.

Insertion/deletion (I/D) polymorphisms of the gene encoding angiotensin converting enzyme (ACE) are a controversial risk factor for heart diseases (HDs). ACE I/D polymorphism has been reported to be associated with various cardiovascular diseases. However, some studies have presented conflicting results. In this study, we aim to explore the association between ACE I/D polymorphisms and the risk of coronary HD (CHD), coronary artery disease (CAD), and myocardial infarction (MI). A meta-analysis was conducted, which included 12,533 cases and 20,726 controls from 75 case-control studies. We performed overall analysis on the entire dataset and found that the D allele of ACE was significantly associated with increased risk of HDs in three different comparison models (dominant, recessive, and homozygote). We also performed analyses on subgroups based on ethnicity as well as disease type. Our results showed that the D allele of ACE was significantly associated with an increased risk of HDs in the Asian and European groups but not in the American group. In addition, in all three subgroups (CHD, CAD, and MI), the D allele of ACE was found to be significantly associated with increased risk of disease. Begg's funnel plots were generated to evaluate publication biases, but no obvious publication bias was found in the studies included in our meta-analysis. In conclusion, our meta-analysis demonstrated that the D allele of ACE was significantly associated with an increased risk of HDs.

More Than Tiny Sacks: Stem Cell Exosomes as Cell-Free Modality for Cardiac Repair.

Stem cell therapy provides immense hope for regenerating the pathological heart, yet has been marred by issues surrounding the effectiveness, unclear mechanisms, and survival of the donated cell population in the ischemic myocardial milieu. Poor survival and engraftment coupled to inadequate cardiac commitment of the adoptively transferred stem cells compromises the improvement in cardiac function. Various alternative approaches to enhance the efficacy of stem cell therapies and to overcome issues with cell therapy have been used with varied success. Cell-free components, such as exosomes enriched in proteins, messenger RNAs, and miRs characteristic of parental stem cells, represent a potential approach for treating cardiovascular diseases. Recently, exosomes from different kinds of stem cells have been effectively used to promote cardiac function in the pathological heart. The aim of this review is to summarize current research efforts on stem cell exosomes, including their potential benefits and limitations to develop a potentially viable therapy for cardiovascular problems.

8p23.1 Interstitial Deletion in a Patient with Congenital Cardiopathy, Neurobehavioral Disorders, and Minor Signs Suggesting 22q11.2 Deletion Syndrome.

Copy number variation studies of known disorders have the potential to improve the characterization of clinical phenotypes and may help identifying candidate genes and their pathways. The authors described a child with congenital heart disease, microcephaly, facial dysmorphisms, developmental delay, learning difficulties, and behavioral problems. There was initially a clinical suspicion of 22q11.2 deletion syndrome (22q11.2 DS), but molecular cytogenetic analysis (array genomic hybridization [aGH]) showed the presence of a de novo 3.6-Mb interstitial microdeletion in 8p23.1. The main features of 8p23.1 DS include congenital heart disease and behavioral problems, in addition to minor dysmorphisms and mental delay. Therefore, this article highlights the application of aGH to investigate 8p23.1 deletion in nonconfirmed 22q11.2 DS patients presenting neurobehavioral disorders, congenital cardiopathy, and minor dysmorphisms.

Cardiac genetic testing: a single-center pilot study of a Dominican population.

The impact of undergoing genetic testing in a Dominican population is not well understood. The objective of this investigation was to evaluate the psychological well-being and perceived cardiac risk among Dominicans who underwent genetic testing. Participants completed a qualitative interview and the Short Form-36 (SF-36) questionnaire after cardiac genetic testing. There were 31 subjects evaluated (mean age 42 ± 11 years). Participants revealed three common themes: (a) fear of dying prematurely, (b) guilt of possibly passing on a mutation to their children, and (c) fear of having an implantable cardioverter defibrillator (ICD) shock. Physical components of the SF-36 were within normal limits (46.2 ± 6.6) but elevated for mental components (59.9 ± 5.3). The quality of life and specific themes results determined in this investigation warrant further research in the Dominican population.

[Changing the paradigm of congenital heart disease: from the anatomy to the molecular etiology]. / Cambiando el paradigma en las cardiopatías congénitas: de la anatomía a la etiología molecular.

Heart development consists in a group of complex and specific morfogenetic interactions, that requires the proper activity of each factor implicated in this process. Congenital heart defects (CHD) are a group of multifactorial complex diseases with environmental and genetic factors playing important roles. There is not an exact relation between molecular mechanisms and morphological defects in CHD, because in most of the cases the proper development of an anatomical structure implies the adequate function of several pathways that may depend of the action of different genes. This review summarizes the genetic factors implied in the normal heart development and the most common gene mutations associated with CHD.

Presentación de un paciente con diagnóstico de miocardiopatía hipertrófica / Presentation of a Patient with Hypertrophic Cardiomyopathy

Se presentó una paciente femenina de 16 años con diagnóstico de miocardiopatía hipertrófica desde l os 12 días de nacida. La miocardiopatía hipertrófica es una enfermedad genética de herencia autosómica dominante, caracterizada por un incremento de la masa muscular y desorganización miofibrilar, con alto riesgo de muerte súbita, que no tiene predisposición racial o étnica. Tiene una prevalencia de 1/500 familias. Los pacientes afectados por lo general tienen las arterias coronarias intramurales anormales; la característica que más ha atraído la atención de esta enfermedad es el gradiente dinámico de presión a través del tracto de salida del ventrículo izquierdo. El grado de obstrucción varía de un paciente a otro(AU)

A ,16, year old female patient with hypertrophic cardiomyopathy diagnosed ,12, days after birth was presented in this paper. This is a genetic autosomal dominant inheritance disease characterized by increased muscle mass and myofibrillar disarray with high risk of sudden death, which has no racial or ethnic bias. It has a prevalence of, 1 / 500, families. Affected patients usually have abnormal intramural coronary arteries, and the dynamic pressure gradient across the outflow tract of the left ventricle is the most representative of this disease.The degree of obstruction varies from patient to patient(AU)

The emerging role of miR-208a in the heart.

MicroRNAs (miRNAs) are a class of regulatory small RNAs that have fundamentally transformed our understanding of how gene networks are regulated representing one of the most exciting areas of the modern cardiology research. Among all known miRNAs, miR-208a is one of the most important heart-enriched miRNA playing a crucial role in the heart health and disease. miR-208a is a member of a miRNA family that also included miR-208b and is encoded by an intronic region of the Myh6 gene. Within the heart, miR-208a and miR-208b are involved in the regulation of the myosin heavy chain isoformswitch during development and in pathophysiological conditions. miR-208a is sufficient to induce arrhythmias, cardiac remodeling, and to regulate the expression of hypertrophy pathway components and the cardiac conduction system. Recently, the identification of miR-208a in the bloodstream has led to a great clinical interest to use this molecule as a potential noninvasive biomarker of myocardial injuries.

Cardiovascular disease in Latin American women.

Cardiovascular disease is a leading cause of death and disability in adults in Latin America. Women are more affected by these diseases than by all forms of cancer. Latin American countries have experienced rapid and uneven socioeconomic changes with a significant effect on lifestyle, demographic and health-related indicators. Differences in methodological approaches make it difficult to compare studies and health statistics across countries in the region. According to available statistics, female population in Latin American countries have lower mortality rate from coronary heart disease and higher mortality rate from cerebrovascular disease than North America. Current rates of obesity and type 2 diabetes are alarming in female in some countries. The high prevalence of risk factors forecasts an increase in cardiovascular disease for the coming decades in this region of the world. More systematic and sustained efforts for research, education, surveillance, prevention, early detection and affordable treatment are required across all Latin American countries to improve health conditions for adult population and particularly for women, who are more affected by obesity and diabetes. This article reviews the available information on cardiovascular disease and related risk factors in Latin American countries with a focus on female and to provide a brief description of selected multinational and national efforts to study and prevent this threat.

Association of -308G/A polymorphism in the tumor necrosis factor-alpha gene promoter with susceptibility to development of hantavirus cardiopulmonary syndrome in the Ribeirão Preto region, Brazil.

Activation of the immune response in hantavirus cardiopulmonary syndrome (HCPS) leads to a high TNF production, probably contributing to the disease. The polymorphic TNF2 allele (TNF -308G/A) has been associated with increased cytokine production. We investigated the association of the TNF2 allele with the outcome of hantavirus infection in Brazilian patients. A total of 122 hantavirus-exposed individuals (26 presenting HCPS and 96 only hantavirus seroconversion) were studied. The TNF2 allele was more frequently found in HCPS patients than in individuals with positive serology for hantavirus but without a history of HCPS illness, suggesting that the TNF2 allele could represent a risk factor for developing HCPS.