Global Cardiology Science and Practice - Volume 2014, Issue 4

Diabetic patients have higher risk of stroke when compared to non-diabetics and in 25% of patients the cause of stroke is unknown. Marfella et al hypothesized that subclinical episodes of atrial fibrillation may be a common etiologic factor. 464 type-2 diabetic patients were compared to 240 health controls and were followed-up for 37 months. Silent cerebral infarcts at baseline were more common among diabetic patients with silent AF (176 patients) when compared to non-silent AF group (288 patients) (61% vs. 29%; p < 0.001) and was associated with higher number of stroke at follow-up.

A landmark study by Habashi et al¹ in 2006 documented for the first time both the prevention and reversal of structural changes in the aorta associated with Marfan syndrome, via pharmacological means. This study, carried out in a rat model, concluded that such results were due to an inhibitor effect by the drug losartan on TGB-β1 (Figure 1).Figure 1.  Homo dimer of TGF-β 1. Courtesy of Poornima Rao, QCRC.

Habashi's paper prompted some physicians, in the absence of human trials, to begin the clinical off-label use of losartan on Marfan patients, arguing that this was justified due to the drug's excellent safety profile. This has caused some controversy.

Two significant randomized human trials of losartan in Marfan patients have since been conducted, which contribute different but valuable elements to the debate; the COMPARE trial demonstrated a significantly lower increase in aortic root diameter among study subjects receiving losartan compared with a placebo group after 3 years, although no significant differences were observed in aortic diameter beyond the root itself. A more recently concluded trial by Lacro et al² from the Paediatric Heart Network, comparing losartan with atenolol (and no placebo group), appeared to show no comparative benefit with respect to the rate of aortic dilatation over three years among the losartan users compared with study patients given atenolol, with both groups of patients experiencing a similar decrease in the rate of dilatation over the 3 year follow-up.

Both studies suggest a positive impact of losartan on aortic dilation in humans with Marfan, but they also highlight a number of important questions that remain unanswered. Further trials are clearly needed in order to assess optimal dosing and to guide timing of therapy, and also to further assess the potential and comparative effectiveness of both losartan and β-blockers, individually and in combination, as therapeutic treatments for aortic protection of different groups of patients with Marfan syndrome.

Prostacyclin is a powerful cardioprotective hormone released by the endothelium of all blood vessels. Prostacyclin exists in equilibrium with other vasoactive hormones and a disturbance in the balance of these factors leads to cardiovascular disease including pulmonary arterial hypertension. Since it's discovery in the 1970s concerted efforts have been made to make the best therapeutic utility of prostacyclin, particularly in the treatment of pulmonary arterial hypertension. This has centred on working out the detailed pharmacology of prostacyclin and then synthesising new molecules based on its structure that are more stable or more easily tolerated. In addition, newer molecules have been developed that are not analogues of prostacyclin but that target the receptors that prostacyclin activates. Prostacyclin and related drugs have without doubt revolutionised the treatment and management of pulmonary arterial hypertension but are seriously limited by side effects within the systemic circulation. With the dawn of nanomedicine and targeted drug or stem cell delivery systems it will, in the very near future, be possible to make new formulations of prostacyclin that can evade the systemic circulation allowing for safe delivery to the pulmonary vessels. In this way, the full therapeutic potential of prostacyclin can be realised opening the possibility that pulmonary arterial hypertension will become, if not curable, a chronic manageable disease that is no longer fatal. This review discusses these and other issues relating to prostacyclin and its use in pulmonary arterial hypertension.

Genetic disorders are not equally distributed over the geography of the Arab region. While a number of disorders have a wide geographical presence encompassing 10 or more Arab countries, almost half of these disorders occur in a single Arab country or population. Nearly, one-third of the genetic disorders in Arabs result from congenital malformations and chromosomal abnormalities, which are also responsible for a significant proportion of neonatal and perinatal deaths in Arab populations. Strikingly, about two-thirds of these diseases in Arab patients follow an autosomal recessive mode of inheritance. High fertility rates together with increased consanguineous marriages, generally noticed in Arab populations, tend to increase the rates of genetic and congenital abnormalities. Many of the nearly 500 genes studied in Arab people revealed striking spectra of heterogeneity with many novel and rare mutations causing large arrays of clinical outcomes. In this review we provided an overview of Arab gene geography, and various genetic abnormalities in Arab populations, including disorders of blood, metabolic, circulatory and neoplasm, and also discussed their associated molecules or genes responsible for the cause of these disorders. Although studying Arab-specific genetic disorders resulted in a high value knowledge base, approximately 35% of genetic diseases in Arabs do not have a defined molecular etiology. This is a clear indication that comprehensive research is required in this area to understand the molecular pathologies causing diseases in Arab populations.

Innovations in drug-eluting stents (DES) have substantially reduced rates of in-segment restenosis and early stent thrombosis, improving clinical outcomes following percutaneous coronary interventions (PCI). However a fixed metallic implant in a vessel wall with restored patency and residual disease remains a precipitating factor for sustained local inflammation, in-stent neo-atherosclerosis and impaired vasomotor function increasing the risk for late complications attributed to late or very late stent thrombosis and late target lesion revascularization (TLR) (late catch-up).

The quest for optimal coronary stenting continues by further innovations in stent design and by using biocompatible materials other than cobalt chromium, platinum chromium or stainless steel for engineering coronary implants. Bioresorbable scaffolds made of biodegradable polymers or biocorrodible metals with properties of transient vessel scaffolding, local drug-elution and future restoration of vessel anatomy, physiology and local hemodynamics have been recently developed. These devices have been utilized in selected clinical applications so far providing preliminary evidence of safety showing comparable performance with current generation drug-eluting stents (DES).

Herein we provide a comprehensive overview of the current status of these technologies, we elaborate on the potential benefits of transient coronary scaffolds over permanent stents in the context of vascular reparation therapy, and we further focus on the evolving challenges these devices have to overcome to compete with current generation DES. Condensed Abstract:: The quest for optimizing percutaneous coronary interventions continues by iterative innovations in device materials beyond cobalt chromium, platinum chromium or stainless steel for engineering coronary implants. Bioresorbable scaffolds made of biodegradable polymers or biocorrodible metals with properties of transient vessel scaffolding; local drug-elution and future restoration of vessel anatomy, physiology and local hemodynamics were recently developed. These devices have been utilized in selected clinical applications providing preliminary evidence of safety showing comparable intermediate term clinical outcomes with current generation drug-eluting stents.

Background: Three-dimensional design simulations of coronary metallic stents utilizing mathematical and computational algorithms have emerged as important tools for understanding biomechanical stent properties, predicting the interaction of the implanted platform with the adjacent tissue, and informing stent design enhancements. Herein, we demonstrate the hemodynamic implications following virtual implantation of bioresorbable scaffolds using finite element methods and advanced computational fluid dynamics (CFD) simulations to visualize the device-flow interaction immediately after implantation and following scaffold resorption over time. Methods and Results: CFD simulations with time averaged wall shear stress (WSS) quantification following virtual bioresorbable scaffold deployment in idealized straight and curved geometries were performed. WSS was calculated at the inflow, endoluminal surface (top surface of the strut), and outflow of each strut surface post-procedure (stage I) and at a time point when 33% of scaffold resorption has occurred (stage II). The average WSS at stage I over the inflow and outflow surfaces was 3.2 and 3.1 dynes/cm² respectively and 87.5 dynes/cm² over endoluminal strut surface in the straight vessel. From stage I to stage II, WSS increased by 100% and 142% over the inflow and outflow surfaces, respectively, and decreased by 27% over the endoluminal strut surface. In a curved vessel, WSS change became more evident in the inner curvature with an increase of 63% over the inflow and 66% over the outflow strut surfaces. Similar analysis at the proximal and distal edges demonstrated a large increase of 486% at the lateral outflow surface of the proximal scaffold edge. Conclusions: The implementation of CFD simulations over virtually deployed bioresorbable scaffolds demonstrates the transient nature of device/flow interactions as the bioresorption process progresses over time. Such hemodynamic device modeling is expected to guide future bioresorbable scaffold design.

The use of radiation in medicine is now pervasive and routine. From their crude beginnings 100 years ago, diagnostic radiology, nuclear medicine and radiation therapy have all evolved into advanced techniques, and are regarded as essential tools across all branches and specialties of medicine.

The inherent properties of ionizing radiation provide many benefits, but can also cause potential harm. Its use within medical practice thus involves an informed judgment regarding the risk/benefit ratio. This judgment requires not only medical knowledge, but also an understanding of radiation itself.

This work provides a global perspective on radiation risks, exposure and mitigation strategies.

Mammalian species express nine functional voltage-gated Na⁺ channels. Three of them, the cardiac-specific isoform Nav1.5 and the neuronal isoforms Nav1.8 and Nav1.9, are relatively resistant to the neurotoxin tetrodotoxin (TTX; IC50 ≥ 1 μM). The other six isoforms are highly sensitive to TTX with IC50 values in the nanomolar range. These isoforms are expressed in the central nervous system (Nav1.1, Nav1.2, Nav1.3, Nav1.6), in the skeletal muscle (Nav1.4), and in the peripheral nervous system (Nav1.6, Nav1.7). The isoform Nav1.5, encoded by the SCN5A gene, is responsible for the upstroke of the action potential in the heart. Mutations in SCN5A are associated with a variety of life-threatening arrhythmias, like long QT syndrome type 3 (LQT3), Brugada syndrome (BrS) or cardiac conduction disease (CCD). Previous immunohistochemical and electrophysiological assays demonstrated the cardiac expression of neuronal and skeletal muscle Na⁺ channels in the heart of various mammals, which led to far-reaching speculations on their function. However, when comparing the Na⁺ channel mRNA patterns in the heart of various mammalian species, only minute quantities of transcripts for TTX-sensitive Na⁺ channels were detectable in whole pig and human hearts, suggesting that these channels are not involved in cardiac excitation phenomena in higher mammals. This conclusion is strongly supported by the fact that mutations in TTX-sensitive Na⁺ channels were associated with epilepsy or skeletal muscle diseases, rather than with a pathological cardiac phenotype. Moreover, previous data from TTX-intoxicated animals and from cases of human tetrodotoxication showed that low TTX dosages caused at most little alterations of both the cardiac output and the electrocardiogram. Recently, genome-wide association studies identified SCN10A, the gene encoding Nav1.8, as a determinant of cardiac conduction parameters, and mutations in SCN10A have been associated with BrS. These novel findings opened a fascinating new research area in the cardiac ion channel field, and the on-going debate on how SCN10A/Nav1.8 affects cardiac conduction is very exciting.

Background: The reason why some individuals but not others are susceptible to rheumatic fever and chronic rheumatic heart disease is not understood. Because of the substantial evidence that poverty is an important determinant of the disease and must operate in early life, we have investigated the role of the early environment in an ecological study using 20^th century mortality as an index of disease prevalence. Methods: We analysed 37,321 deaths from rheumatic heart disease in England and Wales during 1968–78. We compared the geographical distribution of deaths with previous infant mortality records from 1911 onwards. These records included details of mortality at different ages and from different causes. They also included data on housing and population density. Results: Mortality from rheumatic heart disease showed a strong correlation with past infant mortality that was consistently stronger with postneonatal mortality (deaths from one month to one year) than with neonatal mortality (deaths during the first month of life). Areas with high infant mortality from diarrhoea or bronchitis had the highest subsequent mortality from rheumatic heart disease. Although rheumatic heart disease was linked with early overcrowding, regression analyses suggested that overcrowding could not per se explain the infant mortality associations. Conclusions: Chronic rheumatic heart disease may have its origins in early infancy. Our findings raise the possibility that susceptibility to rheumatic fever and rheumatic heart disease may be linked with infection in the postneonatal period. Alternatively, they may be explained by the operation of environmental factors that both predispose to infection in infancy and the subsequent liability to heart disease.

Background: Endomyocardial fibrosis (EMF) is the most common form of restrictive cardiomyopathy worldwide. It has been linked to poverty and various environmental factors, but—for unknown reasons—only some people who live in similar conditions develop the disease. EMF cases cluster within both families and ethnic groups, suggesting a role for a genetic factor in host susceptibility. The human leukocyte antigen (HLA) system is associated with predisposition to various diseases. This two-center study was designed to investigate variation in the HLA system between EMF patients and unaffected controls. We provide the first genetic investigation of patients with EMF, as well as a comprehensive review of the literature. Methods: HLA class I (HLA-A, -B, -C) and class II (DRB1, DQB1) types were determined in 71 patients with severe EMF and 137 controls from Uganda and Mozambique. Chi Square analysis was used to identify any significant difference in frequency of class I and class II HLA types between cases and controls. Results: Compared to ethnically matched controls, HLA-B*58 occurred more frequently in Mozambique patients with EMF and HLA-A*02:02 occurred more frequently in Ugandan patients with EMF. Conclusions: Ample subjective evidence in the historical literature suggests the importance of a genetically susceptible host in EMF development. In this first formal genetic study, we found HLA alleles associated with cases of EMF in two populations from sub-Saharan Africa, with EMF patients being more likely than controls to have the HLA-B*58 allele in Mozambique (p-0.03) and the HLA-A*02:02 in Uganda (p = 0.005). Further investigations are needed to more fully understand the role of genetics in EMF development.