E-noise: An increasingly relevant health risk.

This article briefly reviews and discusses the current status of major non-communicable diseases (mNCDs), definition of e-noise, its possible link as a risk factor for cardiovascular diseases and other mNCDs, and proposes possible mechanisms and hypotheses on that link, and how to control e-noise in the future. E-noise is defined as signal from electronic products and instruments that emit radiation and electromagnetic fields. It includes not only the acoustic but also non-acoustic noise. Just like road traffic and aircraft noises, e-noise may not only lead to hearing loss and health problems such as fatigue, stress, irritability, headache, and insomnia, but may also endanger cardiovascular health and result in hypertension, ischemic heart disease (myocardial infarction), arrhythmia (atrial fibrillation) and stroke; brain and metabolic problems such as obesity and diabetes; mental and cognitive impairment; as well as changing of humans' long-evolved cortisol and circadian rhythms after long-term exposure. Even short-term exposure to excessive e-noise may lead to heightened stress responses and low quality of life. In conclusion, e-noise is a potential danger in our world, and further studies are needed of its effects on mechanisms of aging, disease, and human health.

Treatment of chronic heart failure in the 21st century: A new era of biomedical engineering has come.

Chronic heart failure (CHF) is a challenging burden on public health. Therapeutic strategies for CHF have developed rapidly in the past decades from conventional medical therapy, which mainly includes administration of angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, beta-blockers, and aldosterone antagonists, to biomedical engineering methods, which include interventional engineering, such as percutaneous balloon mitral valvotomy, percutaneous coronary intervention, catheter ablation, biventricular pacing or cardiac resynchronization therapy (CRT) and CRT-defibrillator use, and implantable cardioverter defibrillator use; mechanical engineering, such as left ventricular assistant device use, internal artery balloon counterpulsation, cardiac support device use, and total artificial heart implantation; surgical engineering, such as coronary artery bypass graft, valve replacement or repair of rheumatic or congenital heart diseases, and heart transplantation (HT); regenerate engineering, which includes gene therapy, stem cell transplantation, and tissue engineering; and rehabilitating engineering, which includes exercise training, low-salt diet, nursing, psychological interventions, health education, and external counterpulsation/enhanced external counterpulsation in the outpatient department. These biomedical engineering therapies have greatly improved the symptoms of CHF and life expectancy. To date, pharmacotherapy, which is based on evidence-based medicine, large-scale, multi-center, randomized controlled clinical trials, is still a major treatment option for CHF; the current interventional and mechanical device engineering treatment for advanced CHF is not enough owing to its individual status. In place of HT or the use of a total artificial heart, stem cell technology and gene therapy in regenerate engineering for CHF are very promising. However, each therapy has its advantages and disadvantages, and it is currently possible to select better therapeutic strategies for patients with CHF according to cost-efficacy analyses of these therapies. Taken together, we think that a new era of biomedical engineering for CHF has begun.

Novel strategies halt cardiovascular, diabetes, and cancer strips.

In this article, we introduce briefly several strategies for preventing atherosclerotic cardiovascular disease and promoting healthcare for non-communicable diseases (NCDs). These novel strategies include four core elements of health - sleep, emotion, exercise, and diet - and consist of SEED intervention (SEEDi) and E(e)SEEDi due to supplementation of the environment as a core element, and Hu's healthy lifestyles intervention (HHLi) which originates from E(e)SEED-BasED healthy lifestyles. They are suitable for the early evaluation of risk factors, and play a key role in the prevention and management of human NCDs when combined with the RT-ABCDEF strategy and the Grade 210 prevention, which include obesity-OSA-hypertension syndrome and C-type hypertension, especially in halting cardiovascular, diabetes and cancer (CDC) strips we first discovered. After successful clinical practice, we may expect our novel strategies for controlling these chronic diseases according to the conception of mass prevention and treatment.

SEEDi1.0-3.0 strategies for major noncommunicable diseases in China.

The purpose of this article is to briefly introduce the status and challenges of major noncommunicable diseases (mNCDs), which include cardiovascular disease, diabetes and cancer, as well as related risk factors, such as environmental pollution, smoking, obesity and sleep disorders. "S-E-E-D" rules or the strategies of "S-E-E-D" intervention (SEEDi) consist of four core healthy elements: sleep, emotion, exercise and diet. The history of SEEDi1.0-3.0 is also introduced, which includes versions 1.0, 1.5, 2.0 and 3.0 of the program. These guidelines are suitable for prevention and control of mNCDs. Not only the "Healthy China" initiated in China's "13th Five-year Plan," but also the "Healthy World" philosophy needs SEEDi1.0-3.0 strategies for control of mNCDs.

A novel management program for hypertension.

In this article, we describe a comprehensive management program for hypertension (HTN), based on the experience of leading cardiovascular centers in China. This comprehensive approach, adhering to a number of core principles, includes diagnosis and therapeutic interventions. Therapeutic management includes lifestyle changes, risk factor management and pharmacological intervention and should allow reliable lowering blood pressure (BP). Additional paragraphs discuss the relationship between paroxysmal atrial fibrillation (PAF), and HTN.

Tidal volume and minute ventilation parameters derived from pacemaker impedance measurements can predict experimental heart failure development.

BACKGROUND: Specific respiratory patterns and periodic breathing have been associated with heart failure. Less is known regarding changes in tidal volume (TV) and minute ventilation (MV) as a result of early heart failure (HF) decompensation. METHODS AND RESULTS: Twelve adult Yucatan minipigs were implanted with a biventricular pacemaker and a left ventricular pressure sensor. HF was induced using high-rate pacing at 240 paces per minute for 2-4 weeks, followed by 2 weeks of recovery. Left ventricular pressure measurements and weekly echocardiograms verified the development of HF. The right and left ventricular intrathoracic impedance (RVITI and LVITI, respectively) signals were used to determine the respiratory parameters of rate, TV, and MV. Compared to baseline (BL), during HF, the TV dropped 68% for RVITI and 61% for LVITI (P < 0.0001 for both). Correspondingly, MV dropped 34% for RVITI and 27% for LVITI (P < 0.0001 for both). The daily medians of the respiratory rate (RR) and the longest breath interval (LBI) did not change significantly from BL to HF and recovery. However, circadian variation of the RR and the LBI became blunted during HF development. All derived respiratory parameters showed the reverse trend during the recovery period. CONCLUSION: TV and MV change independently from the RR in early HF decompensation. Tracking the changes of TV and MV with an implantable device may provide an additional method for early HF detection and assessment of the response to therapy.

Autologous transplantation of endothelial progenitor cells genetically modified by adeno-associated viral vector delivering insulin-like growth factor-1 gene after myocardial infarction.

The regenerative potential of bone marrow-derived endothelial progenitor cells (EPCs) has been adapted for the treatment of myocardial and limb ischemia via ex vivo expansion. We sought to enhance EPC function by the efficient genetic modification of EPCs in a rat model of myocardial infarction. Peripheral blood EPCs were expanded and transduced, using adeno-associated virus (AAV). AAV-mediated EPC transduction efficacy was 23 ± 1.2%, which was improved by 4.0- to 7.2-fold after pretreatment with the tyrosine kinase inhibitor genistein. Adult rats (n = 7 in each group) underwent myocardial infarction by left anterior descending coronary artery occlusion, and received autologous EPCs transduced by AAV-IGF-1 or AAV-lacZ into the periinfarct area. Echocardiography demonstrated that cardiac function in the IGF-1-EPC group was significantly improved compared with the lacZ-EPC control group 12 weeks after myocardial infarction. In addition, IGF-1-expressing EPCs led to reduced cardiac apoptosis, increased cardiomyocyte proliferation, and increased numbers of capillaries in the periinfarct area. AAV expression was limited to the targeted heart region only. Pretreatment with genistein markedly improved AAV transduction of EPCs. IGF-1-expressing EPCs exhibit favorable cell-protective effects with tissue-limited expression in rat heart postinfarction.

Sonic hedgehog myocardial gene therapy: tissue repair through transient reconstitution of embryonic signaling.

Sonic hedgehog (Shh) is a crucial regulator of organ development during embryogenesis. We investigated whether intramyocardial gene transfer of naked DNA encoding human Shh (phShh) could promote a favorable effect on recovery from acute and chronic myocardial ischemia in adult animals, not only by promoting neovascularization, but by broader effects, consistent with the role of this morphogen in embryogenesis. After Shh gene transfer, the hedgehog pathway was upregulated in mammalian fibroblasts and cardiomyocytes. This resulted in preservation of left ventricular function in both acute and chronic myocardial ischemia by enhanced neovascularization, and reduced fibrosis and cardiac apoptosis. Shh gene transfer also enhanced the contribution of bone marrow-derived endothelial progenitor cells to myocardial neovascularization. These data suggest that Shh gene therapy may have considerable therapeutic potential in individuals with acute and chronic myocardial ischemia by triggering expression of multiple trophic factors and engendering tissue repair in the adult heart.

Clonally expanded novel multipotent stem cells from human bone marrow regenerate myocardium after myocardial infarction.

We have identified a subpopulation of stem cells within adult human BM, isolated at the single-cell level, that self-renew without loss of multipotency for more than 140 population doublings and exhibit the capacity for differentiation into cells of all 3 germ layers. Based on surface marker expression, these clonally expanded human BM-derived multipotent stem cells (hBMSCs) do not appear to belong to any previously described BM-derived stem cell population. Intramyocardial transplantation of hBMSCs after myocardial infarction resulted in robust engraftment of transplanted cells, which exhibited colocalization with markers of cardiomyocyte (CMC), EC, and smooth muscle cell (SMC) identity, consistent with differentiation of hBMSCs into multiple lineages in vivo. Furthermore, upregulation of paracrine factors including angiogenic cytokines and antiapoptotic factors, and proliferation of host ECs and CMCs, were observed in the hBMSC-transplanted hearts. Coculture of hBMSCs with CMCs, ECs, or SMCs revealed that phenotypic changes of hBMSCs result from both differentiation and fusion. Collectively, the favorable effect of hBMSC transplantation after myocardial infarction appears to be due to augmentation of proliferation and preservation of host myocardial tissues as well as differentiation of hBMSCs for tissue regeneration and repair. To our knowledge, this is the first demonstration that a specific population of multipotent human BM-derived stem cells can induce both therapeutic neovascularization and endogenous and exogenous cardiomyogenesis.

Synergistic effect of bone marrow mobilization and vascular endothelial growth factor-2 gene therapy in myocardial ischemia.

BACKGROUND: We performed a series of investigations to test the hypothesis that combining angiogenic gene therapy and cytokine (CK)-induced endothelial progenitor cell mobilization would be superior to either strategy alone for treatment of chronic myocardial ischemia. METHODS AND RESULTS: A swine model of chronic myocardial ischemia and a murine model of acute myocardial infarction were used in this study. In both models, animals were randomly assigned to 1 of 4 treatment groups: Combo group, intramyocardial vascular endothelial growth factor (VEGF)-2 gene transfer plus subcutaneous injection of CKs; VEGF-2, VEGF-2 gene transfer plus saline subcutaneously injected; CK, empty vector transfer plus CKs; and control, empty vector plus subcutaneous saline. Acute myocardial infarction was also induced in wild-type mice 4 weeks after bone marrow transplantation from enhanced green fluorescent protein transgenic mice to permit observation of bone marrow-derived cells in the myocardium after acute myocardial infarction. In chronic myocardial ischemia, combination therapy resulted in superior improvement in all indexes of perfusion and function compared with all other treatment groups. In the bone marrow transplant mice, double immunofluorescent staining revealed that the combination of CK-induced mobilization and local VEGF-2 gene transfer resulted in a significant increase in the number of bone marrow-derived cells incorporating into the neovasculature, indicating that recruitment and/or retention of bone marrow-derived progenitors was enhanced by mobilization and that local VEGF-2 gene transfer can provide signals for recruitment or incorporation of circulating progenitor cells. CONCLUSIONS: Mobilization of endothelial progenitor cells with cytokines potentiates VEGF-2 gene therapy for myocardial ischemia and enhances bone marrow cell incorporation into ischemic myocardium.

Unexpected severe calcification after transplantation of bone marrow cells in acute myocardial infarction.

BACKGROUND: There has been a rapid increase in the number of clinical trials using unselected bone marrow (BM) cells or the mononuclear fraction of BM cells for treating ischemic heart diseases. Thus far, no significant deleterious effects or complications have been reported in any studies using BM-derived cells for treatment of various cardiac diseases. METHODS AND RESULTS: Seven-week-old female Fisher-344 rats underwent surgery to induce acute myocardial infarction and were randomized into 3 groups of 16 rats, each receiving intramyocardial injection of either 7x10(5) DiI-labeled total BM cells (TBMCs), the same number of DiI-labeled, clonally expanded BM multipotent stem cells, or the same volume of phosphate-buffered saline in the peri-infarct area. Echocardiography 2 weeks after cell transplantation indicated intramyocardial calcification in 4 of 14 surviving rats (28.5%) in the TBMC group. Histological examination with hematoxylin and eosin staining and von Kossa staining confirmed the presence of extensive intramyocardial calcification. Alkaline phosphatase staining revealed strong positivity surrounding the calcified area suggestive of ongoing osteogenic activity. Fluorescent microscopic examination revealed that acellular calcific areas were surrounded by DiI-labeled TBMCs, suggesting the direct involvement of transplanted TBMCs in myocardial calcification. In contrast, in hearts receiving equal volumes of saline or BM multipotent stem cells delivered in the same manner, there was no evidence of calcification. CONCLUSIONS: These results demonstrate that direct transplantation of unselected BM cells into the acutely infarcted myocardium may induce significant intramyocardial calcification.

VEGF-C gene therapy augments postnatal lymphangiogenesis and ameliorates secondary lymphedema.

Although lymphedema is a common clinical condition, treatment for this disabling condition remains limited and largely ineffective. Recently, it has been reported that overexpression of VEGF-C correlates with increased lymphatic vessel growth (lymphangiogenesis). However, the effect of VEGF-C-induced lymphangiogenesis on lymphedema has yet to be demonstrated. Here we investigated the impact of local transfer of naked plasmid DNA encoding human VEGF-C (phVEGF-C) on two animal models of lymphedema: one in the rabbit ear and the other in the mouse tail. In a rabbit model, following local phVEGF-C gene transfer, VEGFR-3 expression was significantly increased. This gene transfer led to a decrease in thickness and volume of lymphedema, improvement of lymphatic function demonstrated by serial lymphoscintigraphy, and finally, attenuation of the fibrofatty changes of the skin, the final consequences of lymphedema. The favorable effect of phVEGF-C on lymphedema was reconfirmed in a mouse tail model. Immunohistochemical analysis using lymphatic-specific markers: VEGFR-3, lymphatic endothelial hyaluronan receptor-1, together with the proliferation marker Ki-67 Ab revealed that phVEGF-C transfection potently induced new lymphatic vessel growth. This study, we believe for the first time, documents that gene transfer of phVEGF-C resolves lymphedema through direct augmentation of lymphangiogenesis. This novel therapeutic strategy may merit clinical investigation in patients with lymphedema.