Increased Mobilization of Mesenchymal Stem Cells in Patients With Essential Hypertension: The Effect of Left Ventricular Hypertrophy

Stem cells have great clinical significance in many cardiovascular diseases. However, there are limited data regarding the involvement of mesenchymal stem cells (MSCs) in the pathophysiology of arterial hypertension. The aim of this study was to investigate the circulation of MSCs in patients with essential hypertension. The authors included 24 patients with untreated essential hypertension and 19 healthy individuals. Using flow cytometry, MSCs in peripheral blood, as a population of CD45−/CD34−/CD90+ cells and also as a population of CD45−/CD34−/CD105+ cells, were measured. The resulting counts were translated into the percentage of MSCs in the total cells. Hypertensive patients were shown to have increased circulating CD45−/CD34−/CD90+ compared with controls (0.0069%±0.012% compared with 0.00085%±0.0015%, respectively; P=.039). No significant difference in circulating CD45−/CD34−/CD105+ cells was found between hypertensive patients'' and normotensive patients'' peripheral blood (0.018%±0.013% compared with 0.015%±0.014%, respectively; P=.53). Notably, CD45−/CD34−/CD90+ circulating cells were positively correlated with left ventricular mass index (LVMI) (r=0.516, P<.001). Patients with essential hypertension have increased circulating MSCs compared with normotensive patients, and the number of MSCs is correlated with LVMI. These findings contribute to the understanding of the pathophysiology of hypertension and might suggest a future therapeutic target.

In recent years there has been growing interest in the role of adult stem cells in the pathophysiology of cardiovascular diseases. Although it used to be believed that mammalian cardiomyocytes cease replication soon after birth and that the subsequent growth of the heart was attributable only to cardiomyocyte hypertrophy, newer studies have demonstrated a small degree of cardiogenesis and cardiomyocyte turnover that occurs throughout life.¹, ² These findings led to further research into the contribution of stem cells to the pathophysiology of cardiovascular disorders that has raised the hope of developing new therapeutic approaches. Stem cells have the potential for self‐renewal and differentiation and are the origin cells of various mature cells.Mesenchymal stem cells (MSCs) are also known to have a highly plastic differentiation potential that includes not only adipogenesis, osteogenesis, and chondrogenesis, but also endothelial, cardiovascular,³ and neovascular differentiation.⁴, ⁵, ⁶ Although present in only very small numbers in peripheral blood, in recent years stem and progenitor cells have been implicated in ventricular remodeling and are thought to be of great clinical significance in the pathophysiology of heart failure and atheromatosis. Previous studies have indicated that MSCs derived from peripheral blood, apart from their multilineage potential, can also be used for cellular and gene therapies.⁷ Human MSCs isolated from adult bone marrow provide a model for the development of stem cell therapeutics and could find application in the cardiovascular system—although this is still under investigation.⁸ Under normal conditions, endogenous cardiac progenitor cells are responsible for homeostasis in the heart.⁹ However, it appears that under conditions of stress, this may change, with stem cells from extra‐cardiac sources also playing a role. An interesting experimental study has shown that an increase in preload results in the mobilization of progenitor cells from the bone marrow for use in neovascularization, which plays an important role in cardiac hypertrophy.¹⁰ There are indications that the recruitment of bone marrow–derived cells is involved in cardiac myocyte hypertrophy and maintenance of function in response to pressure overload.¹¹ A recent study from our department has shown increased expression of myocardin and GATA4 genes in the peripheral blood mononuclear cell fraction of hypertensive patients, implying the presence of mesenchymal progenitor cells in the peripheral blood that could possibly be intended to differentiate into cells of the cardiac series.¹² Interestingly, in the patients in that study, myocardin and GATA4 expression was associated with both blood pressure (BP) levels and left ventricular hypertrophy (LVH).To date, most published reports concerning the cardiovascular applications of stem cells have focused on their role in myocardial infarction and in heart failure. Very little work has been done on arterial hypertension, and most has concerned endothelial progenitor cells. The role and behavior of MSCs in patients with essential hypertension is unknown. In a recent animal study, it was shown that the degree to which angiotensin II increased neointima formation was statistically correlated with the increased incorporation of fluorescent bone marrow–derived smooth muscle cells, and that this was inhibited by angiotensin‐1 receptor antagonism.¹³ Based on the hypothesis that MSCs participate in pathophysiological processes that contribute to hypertension, and on the assumption that the behavior of MSCs is altered in hypertensive patients, we carried out the first flow cytometric analysis of CD45−/CD34−/CD90+ and CD45−/CD34−/CD105+ in the peripheral blood of those patients compared with healthy individuals.     

STK11 Domain XI Mutations: Candidate Genetic Drivers Leading to the Development of Dysplastic Polyps in Peutz–Jeghers Syndrome

Peutz–Jeghers syndrome (PJS) is a rare hereditary disorder resulting from mutations in serine/threonine kinase 11 (STK11) and characterized by gastrointestinal (GI) hamartomatous polyps, mucocutaneous pigmentation, and an increased risk for specific cancers. Little is known about the genetic implications of specific STK11 mutations with regard to their role in dysplastic and malignant transformation of GI polyps. Peripheral blood genomic DNA samples from 116 Chinese PJS patients from 52 unrelated families were investigated for STK11 mutations. Genotype–phenotype correlations were investigated. The mutation detection rate was 67.3% (51.9% point mutations, 15.4% large deletions). Fourteen out of the 25 point mutations identified were novel. Nearly one‐third of all mutations, 8/27 (29.6%), were in exon 7, the shortest out of the nine exons. Strikingly, mutations affecting protein kinase domain XI, encoded in part by exon 7, correlated with a 90% (9/10) incidence of GI polyp dysplasia. In contrast, only two out of 17 (11.8%) nondomain XI mutations were linked to polyp dysplasia (P = 0.0001). The extent of the association between dysplasia and the development of GI‐related cancers is currently unknown but our results highlight a novel STK11 genotype–phenotype association as the basis for future genetic counseling and basic research studies.     

Follow-up with exercise test of effort-induced ventricular arrhythmias linked to ryanodine receptor type 2 gene mutations

The aim of this study was to assess exercise test results and efficacy of therapy with a β blocker (acebutolol) in ryanodine receptor type 2 (RyR2) mutation carriers with documented ventricular arrhythmias (VAs) and long-term follow-up. Twenty RyR2 mutation carriers belonging to 8 families and regularly followed at our center were analyzed using a study protocol involving electrocardiography, exercise tests off and on β-blocker therapy, 2-dimensional echocardiography, and signal-averaged electrocardiography. Off-therapy exercise testing triggered the onset of VAs at different heart rates (mean 132 ± 13 beats/min) with various patterns that worsened while exercising and disappeared immediately after stopping. The most severe VAs detected were nonsustained ventricular tachycardia in 35% and ventricular couplets in 35%. In the remaining subjects single ventricular premature beats were recorded. In 15% of patients single monomorphic ventricular premature beats were detected and identified to be linked to RyR2 mutations owing to the presence of sudden deaths of their family members and subsequent family screening. Acebutolol made the VAs disappear completely in 20% of subjects and decreased their complexity in 50%, whereas it did not change VAs appreciably in 30% of patients with less complex VAs. After 11 ± 8 years of follow-up 2 patients developed syncope. In conclusion, exercise testing was a fundamental tool for assessing the clinical phenotype and efficacy of therapy in RyR2 mutation carriers and therapy with acebutolol led in most subjects to a decreased complexity of the arrhythmic pattern or to complete suppression.     

Phenotype and genotype frequency of β-thalassemia and sickle cell disease carriers in Halkidiki, Northern Greece

A decade of screening (years 2000 to 2010) for hemoglobinopathies in 3,931 patients was performed at the General Hospital of Poligiros, Halkidiki, Northern Greece. Among the patients examined, 10.8% heterozygotes for β-thalassemia (β-thal) were found, as well as 4.1% with sickle cell disease and 1.2% with double β-thal/Hb S [β6(A3)Glu→Val] heterozygosity. Iron deficiency was observed in 23.4%. The geographical distribution in the region revealed a substantial incidence of hemoglobinopathies even in mountainous areas. This pattern did not follow the typical distribution according to the malaria hypothesis, as incidence did not dovetail with swamp locations recorded in the past. The HBB gene mutations for 85 patients were also analyzed. Most prevalent in Halkidiki, Northern Greece, was the codon 39 (C>T) mutation (27.1%) followed by the IVS-I-110 (G>A) mutation (22.4%); this was in direct contrast to the current distribution of the same mutations seen in the rest of Greece (Greek National Genetic Database, GNGD). This frequency inversion was statistically significant, with the difference from the GNGD being 20.6% for the IVS-I-110 mutation (p <0.0005) and 7.6% for the codon 39 mutation (p = 0.0238). The history of Halkidiki, denoting a clear example of geographical isolation from the rest of the country, may possibly account for a potentially diverse genetical identity of the disease in this region.     

A national registry of haemoglobinopathies in Greece: deducted demographics, trends in mortality and affected births

Haemoglobinopathies are the most common hereditary disorders in Greece. Although there is a successful national prevention program, established 35 years ago, there is lack of an official registry and collection of epidemiological data for haemoglobinopathies. This paper reports the results of the first National Registry for Haemoglobinopathies in Greece (NRHG), recently organized by the Greek Society of Haematology. NRHG records all patients affected by thalassaemia major (TM), thalassaemia intermedia (TI), "H" Haemoglobinopathy (HH) and sickle cell disease (SCD). Moreover, data about the annual rate of new affected births along with deaths, between 2000 and 2010, are reported. A total of 4,506 patients are registered all over the country while the number of affected newborns was significantly decreased during the last 3 years. Main causes for still having affected births are: (1) lack of medical care due to financial reasons or low educational level; (2) unawareness of time limitations for prenatal diagnosis (PD); due either to obstetricians' malpractice or to delayed demand of medical care of couples at risk; and (3) religious, social or bioethical reasons. Cardiac and liver disorders consist main causes for deaths while life expectancy of patients lengthened after 2005 (p < 0.01). The NRHG of patients affected by haemoglobinopathies in Greece provides useful data about the haemoglobinopathies in the Greek population and confirms the efficacy of the National Thalassaemia Prevention Program on impressively decreasing the incidence of TM and sickle cell syndromes.     

Endoscopic third ventriculostomy in the treatment of idiopathic normal pressure hydrocephalus: a review study

Idiopathic normal pressure hydrocephalus is a hydrodynamic disorder whose etiology remains unclear. The diagnosis is mainly clinical and the traditional treatment is cerebrospinal fluid shunt diversion. With the introduction of modern management strategies, endoscopic third ventriculostomy has become a viable alternative to shunting and constitutes a well-established method of treatment for obstructive hydrocephalus. The new hydrodynamic concept of hydrocephalus suggests that endoscopic third ventriculostomy (ETV) may be an effective treatment for communicative hydrocephalus. In our current review, the authors focus on the up-to-date knowledge regarding the consideration of endoscopic third ventriculostomy as a safe surgical option in the management of idiopathic normal pressure hydrocephalus.