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Papers by jacob joseph

Paul Ehrlich, the discoverer of the mast cell, may have hada premonition of its biological power ... more Paul Ehrlich, the discoverer of the mast cell, may have hada premonition of its biological power when he named it mastzelle or “well-fed cell, ” a moniker he bestowed in recognition of the wealth of granular material discovered inside this cell.1 Though originally thought to be involved only in immune function and host defense, more than a century of research into the function of the mast cell has revealed a plethora of mast-cell-derived mediators and an important role for this cell in tissue homeostasis.2 Mast cells accumulate in cardiovascular tissue in most pathologies, including coronary artery disease, myocardial infarction, and cardiomyopathy.3–7 Although initially thought to be a delete-rious influence on cardiovascular biology,3–7 recent reports suggest that the mast cell is a “tunable effector cell”8 that can alter its phenotype and thereby have a beneficial9 or delete-rious role in tissue and organ function. In this issue of

Permissions: Requests for permissions to reproduce figures, tables, or portions of articles origi... more Permissions: Requests for permissions to reproduce figures, tables, or portions of articles originally published in Circulation Research can be obtained via RightsLink, a service of the Copyright Clearance Center, not the Editorial Office. Once the online version of the published article for which permission is being requested is located, click Request Permissions in the middle column of the Web page under Services. Further information about this process is available in the Permissions and Rights Question and Answer document. Reprints: Information about reprints can be found online at:

Nutrients, 2021

Selenium (Se) is a trace nutrient that promotes human health through its incorporation into selen... more Selenium (Se) is a trace nutrient that promotes human health through its incorporation into selenoproteins in the form of the redox-active amino acid selenocysteine (Sec). There are 25 selenoproteins in humans, and many of them play essential roles in the protection against oxidative stress. Selenoproteins, such as glutathione peroxidase and thioredoxin reductase, play an important role in the reduction of hydrogen and lipid hydroperoxides, and regulate the redox status of Cys in proteins. Emerging evidence suggests a role for endoplasmic reticulum selenoproteins, such as selenoproteins K, S, and T, in mediating redox homeostasis, protein modifications, and endoplasmic reticulum stress. Selenoprotein P, which functions as a carrier of Se to tissues, also participates in regulating cellular reactive oxygen species. Cellular reactive oxygen species are essential for regulating cell growth and proliferation, protein folding, and normal mitochondrial function, but their excess causes ce...

International Journal of Molecular Sciences, 2020

Sodium is an essential mineral and nutrient used in dietary practices across the world and is imp... more Sodium is an essential mineral and nutrient used in dietary practices across the world and is important to maintain proper blood volume and blood pressure. A high sodium diet is associated with increased expression of β—myosin heavy chain, decreased expression of α/β—myosin heavy chain, increased myocyte enhancer factor 2/nuclear factor of activated T cell transcriptional activity, and increased salt-inducible kinase 1 expression, which leads to alteration in myocardial mechanical performance. A high sodium diet is also associated with alterations in various proteins responsible for calcium homeostasis and myocardial contractility. Excessive sodium intake is associated with the development of a variety of comorbidities including hypertension, chronic kidney disease, stroke, and cardiovascular diseases. While the American College of Cardiology/American Heart Association/Heart Failure Society of America guidelines recommend limiting sodium intake to both prevent and manage heart failu...

Current atherosclerosis reports, 2015

In addition to the interaction of nutrition and genetic variation on the genesis and natural hist... more In addition to the interaction of nutrition and genetic variation on the genesis and natural history of cardiovascular disease, recent studies have revealed an entire new genome that resides in the trillions of microbes that exist in various human habitats, predominantly in the gut, that may also contribute to the pathogenesis of cardiovascular disease. This microbial genome and the proteins for which it codes have important functions in homeostatic adaptations to the past and present changes in diet and environment accompanying human civilization. Both preclinical and clinical investigations suggest the role of commensal microbiota in promoting adverse cardiovascular risk. Specifically, microbial metabolism of methylated amines leads to direct pro-atherogenic effects in humans. Further investigations are needed to understand the complex relationships among nutritional status, genetic variation, and the microbial genome, which may explain the recent negative results of clinical tria...

World journal of cardiology, Jan 26, 2011

Inhibition of the renin angiotensin system has beneficial effects in cardiovascular prevention an... more Inhibition of the renin angiotensin system has beneficial effects in cardiovascular prevention and treatment. The advent of orally active direct renin inhibitors adds a novel approach to antagonism of the renin-angiotensin system. Inhibition of the first and rate-limiting step of the renin angiotensin cascade offers theoretical advantages over downstream blockade. However, the recent discovery of the (pro)renin receptor which binds both renin and prorenin, and which can not only augment catalytic activity of both renin and prorenin in converting angiotensinogen to angiotensin I, but also signal intracellularly via various pathways to modulate gene expression, adds a significant level of complexity to the field. In this review, we will examine the basic and clinical data on renin and its inhibition in the context of cardiovascular pathophysiology.

American journal of physiology. Heart and circulatory physiology, 2002

Hyperhomocysteinemia (Hhe), linked to cardiovascular disease by epidemiological studies, may be a... more Hyperhomocysteinemia (Hhe), linked to cardiovascular disease by epidemiological studies, may be an important factor in adverse cardiac remodeling in hypertension. Specifically, convergence of myocardial and vascular alterations promoted by Hhe and hypertension may exacerbate cardiac remodeling and myocardial dysfunction. We studied male spontaneously hypertensive rats fed one of three diets: control, intermediate Hhe inducing, or severe Hhe inducing. After 10 wk of dietary intervention, cardiac function was assessed in vitro, and cardiac and coronary arteriolar remodeling were monitored by histomorphometric, immunohistochemical, and biochemical techniques. Results showed that Hhe induced diastolic dysfunction, as characterized by the diastolic pressure-volume curve, without significant changes in baseline systolic function. Perivascular collagen levels were increased by Hhe, and there was an increase in left ventricular hydroxyproline levels. Myocyte size was not affected. Coronary ...

Cancer research, Jan 15, 2005

Radiation-induced heart disease (RIHD), characterized by accelerated atherosclerosis and adverse ... more Radiation-induced heart disease (RIHD), characterized by accelerated atherosclerosis and adverse tissue remodeling, is a serious sequelae after radiotherapy of thoracic and chest wall tumors. Adverse cardiac remodeling in RIHD and other cardiac disorders is frequently accompanied by mast cell hyperplasia, suggesting that mast cells may affect the development of cardiac fibrosis. This study used a mast cell-deficient rat model to define the role of mast cells in RIHD. Mast cell-deficient rats (Ws/Ws) and mast cell-competent littermate controls (+/+) were exposed to 18 Gy localized single-dose irradiation of the heart. Six months after irradiation, cardiac function was examined by echocardiography and Langendorff-perfused isolated heart preparation, whereas structural changes were assessed using quantitative histology and immunohistochemical analysis. Mast cell-deficient rats exhibited more severe postradiation changes than mast cell-competent littermates. Hence, mast cell-deficient r...

American journal of physiology. Heart and circulatory physiology, 2003

A recent report indicated that hyperhomocysteinemia (Hhe), in addition to its atherothrombotic ef... more A recent report indicated that hyperhomocysteinemia (Hhe), in addition to its atherothrombotic effects, exacerbates the adverse cardiac remodeling seen in response to hypertension, a powerful stimulus for pathological ventricular hypertrophy. The present study was undertaken to determine whether Hhe has a direct effect on ventricular remodeling and function in the absence of other hypertrophic stimuli. Male Wistar-Kyoto rats were fed either an amino acid-defined control diet or an intermediate Hhe-inducing diet. After 10 wk of dietary treatment, rats were subjected to echocardiographic assessment of left ventricular (LV) dimensions and systolic function. Subsequently, blood was collected for plasma homocysteine measurements, and the rats were killed for histomorphometric and biochemical assessment of cardiac remodeling and for in vitro cardiac function studies. Significant LV hypertrophy was detected by echocardiographic measurements, and in vitro results showed hypertrophy with sig...

Background-Exercise-induced increase in peroxisome proliferator-activated receptor-γ coactivator-... more Background-Exercise-induced increase in peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) expression has been shown to increase the expression of the fibronectin type III domain containing 5 (FNDC5) gene and thereby its product, irisin, in mice. Given that exercise intolerance is a hallmark characteristic of heart failure (HF), and because PGC-1α and irisin promote exercise benefits in animals, we hypothesized that expression of these genes relates to aerobic performance in patients with HF. Methods and Results-Systolic HF (left ventricular ejection fraction ≤40%) patients underwent cardiopulmonary exercise testing to evaluate aerobic performance. High versus low aerobic performance was assessed using oxygen consumption (peak Vo 2 [>14 versus ≤14 mL O 2 •kg −1 •min −1 ]) and ventilatory efficiency (VE/Vco 2 slope [<34 versus ≥34]). Muscle biopsies of the vastus lateralis and real-time polymerase chain reaction were used to quantify muscle gene expression.. Twenty-four patients were studied. FNDC5 (5.7±3.5 versus 3.1±1.2, P<0.05) and PGC-1α (9.9±5.9 versus 4.5±1.9, P<0.01) gene expressions were greater in the high-peak Vo 2 group; correlation between FNDC5 and PGC-1α was significant (r=0.56, P<0.05) only in the high-peak Vo 2 group. Similarly, FNDC5 and PGC-1α gene expression was greater in the high-performance group based on lower VE/Vco 2 slopes (5.8±3.6 versus 3.3±1.4, P<0.05 and 9.7±6 versus 5.3±3.4, P<0.05); FNDC5 also correlated with PGC-1α (r=0.55, P<0.05) only in the low VE/Vco 2 slope group. Conclusions-This is the first study to show that FNDC5 expression relates to functional capacity in a human HF population. Lower FNDC5 expression may underlie reduced aerobic performance in HF patients.

Background: Experiments were designed to determine whether hyperhomocysteinemia (Hhe) affects car... more Background: Experiments were designed to determine whether hyperhomocysteinemia (Hhe) affects cardiovascular function when monitored in conscious unrestrained animals. Methods: Adult, male Sprague-Dawley rats were fed a homocystine-supplemented diet for 6 months. Blood pressure (BP), heart rate, and pulse pressure were monitored continuously, 24 h a day, using biotelemetry techniques. Results: The resulting intermediate level of Hhe was not associated with significant changes in heart rate, diastolic BP, systolic BP, or the circadian variation in heart rate. In spite of the lack of significant changes in systolic and diastolic BP, there was a slight but statistically significant increase in pulse pressure after 4 months of treatment that returned toward control levels after 6 months. Conclusions: Current results indicate that Hhe alone does not have significant effects on BP. Furthermore, they suggest that the previously reported Hhe-induced adverse cardiac remodeling and diastolic dysfunction in this animal model are not the result of pressure overload.

European journal of preventive cardiology, 2013

While cardiopulmonary exercise testing (CPX) assessment is generally regarded as an optimal means... more While cardiopulmonary exercise testing (CPX) assessment is generally regarded as an optimal means to assess functional capacity in heart failure (HF) patients, strength parameters are omitted. CPX indices collected in recovery may provide additional insight regarding function, including strength. We performed a cross-sectional controlled study. Systolic HF patients (aged ≥ 50 years) and age-matched controls were assessed using CPX and strength evaluations. Standard CPX indices were assessed during exercise (peak oxygen consumption [VO2], first ventilatory threshold [1stVT], and ventilatory efficiency [VE/VCO2 slope]) as well as indices at 1-minute recovery (1 min VO2, 1 min VE/VCO2, and 1 min heart rate recovery [HRR]) and differences between peak and 1-minute recovery (ΔVO₂ and ΔVE/VCO₂). Lower extremity strength was evaluated using the 1-repetition maximum (1RM) and power. Seventy adults (31 HF; 39 controls), mean age 66.2 ± 9.7 years were evaluated. Peak VO2 (15.4 ± 4.2 versus 23...

PLoS ONE, 2013

Myocardial fibrosis, a major pathophysiologic substrate of heart failure with preserved ejection ... more Myocardial fibrosis, a major pathophysiologic substrate of heart failure with preserved ejection fraction (HFPEF), is modulated by multiple pathways including the renin-angiotensin system. Direct renin inhibition is a promising anti-fibrotic therapy since it attenuates the pro-fibrotic effects of renin in addition to that of other effectors of the renin-angiotensin cascade. Here we show that the oral renin inhibitor aliskiren has direct effects on collagen metabolism in cardiac fibroblasts and prevented myocardial collagen deposition in a non-hypertrophic mouse model of myocardial fibrosis. Adult mice were fed hyperhomocysteinemia-inducing diet to induce myocardial fibrosis and treated concomitantly with either vehicle or aliskiren for 12 weeks. Blood pressure and plasma angiotensin II levels were normal in control and hyperhomocysteinemic mice and reduced to levels lower than observed in the control group in the groups treated with aliskiren. Homocysteineinduced myocardial matrix gene expression and fibrosis were also prevented by aliskiren. In vitro studies using adult rat cardiac fibroblasts also showed that aliskiren attenuated the pro-fibrotic pattern of matrix gene and protein expression induced by D,L, homocysteine. Both in vivo and in vitro studies demonstrated that the Akt pathway was activated by homocysteine, and that treatment with aliskiren attenuated Akt activation. In conclusion, aliskiren as mono-therapy has potent and direct effects on myocardial matrix turnover and beneficial effects on diastolic function.

Nutrients, 2013

Although selenium metabolism is intricately linked to cardiovascular biology and function, and de... more Although selenium metabolism is intricately linked to cardiovascular biology and function, and deficiency of selenium is associated with cardiac pathology, utilization of selenium in the prevention and treatment of cardiovascular disease remains an elusive goal. From a reductionist standpoint, the major function of selenium in vivo is antioxidant defense via its incorporation as selenocysteine into enzyme families such as glutathione peroxidases and thioredoxin reductases. In addition, selenium compounds are heterogeneous and have complex metabolic fates resulting in effects that are not entirely dependent on selenoprotein expression. This complex biology of selenium in vivo may underlie the fact that beneficial effects of selenium supplementation demonstrated in preclinical studies using models of oxidant stress-induced cardiovascular dysfunction, such as ischemia-reperfusion injury and myocardial infarction, have not been consistently observed in clinical trials. In fact, recent studies have yielded data that suggest that unselective supplementation of selenium may, indeed, be harmful. Interesting biologic actions of selenium are its simultaneous effects on redox balance and methylation status, a combination that may influence gene expression. These combined actions may explain some of the biphasic effects seen with low and high doses of selenium, the potentially harmful effects seen in normal individuals, and the beneficial effects noted in preclinical studies of disease. Given the complexity of selenium biology, systems biology approaches may be necessary to reach the goal of optimization of selenium status to promote health and prevent disease.

Modern Pathology, 2005

Cardiac nonamyloidotic immunoglobulin (Ig) deposition disease (CIDD) is a rare disorder character... more Cardiac nonamyloidotic immunoglobulin (Ig) deposition disease (CIDD) is a rare disorder characterized by Ig deposition in the myocardium associated with plasma cell dyscrasias. A retrospective review of cardiac biopsies performed at two different institutions identified eight patients with CIDD. All patients had plasma cell dyscrasias with monoclonal gammopathy. Three had IgG k, two had IgG j, one had IgD j and one each had free j and free k light chain. Four patients had concurrent amyloidosis involving other organs. One had amyloidosis of kidney alone, one had amyloidosis of kidney and abdominal fat pad and two others had amyloidosis of bone marrow vasculature. Three patients had dialysis-dependent renal insufficiency. None of the patients had symptoms of heart failure. Six patients had echocardiographically demonstrable concentric left ventricular hypertrophy with diastolic dysfunction. Two patients had significant cardiac arrhythmias requiring medical intervention. On endomyocardial biopsy, all eight had normal appearing myocardium on light microscopy with negative Congo Red and Thioflavin T stains. On immunofluorescent staining of the cardiac biopsies, all eight stained positive for interstitial Ig deposition. Electron microscopy (EM) confirmed the presence of granular deposits of Igs in the myocardium in five of the eight patients. EM studies were not available in one patient and two others had normal EM studies. In conclusion, CIDD should be considered in the spectrum of cardiovascular pathology in patients with plasma cell dyscrasias. They often, but not always, have left ventricular hypertrophy. These patients may be at risk for developing arrhythmias as well as diastolic dysfunction. Unless immunofluorescent and EM studies are performed routinely in biopsy material, this entity may be missed in the absence of amyloidosis. Concurrent amyloidosis in other organs sheds a unique perspective into the role of local microenvironment in the pathogenesis of systemic Ig deposition disease and amyloidosis.

Journal of the American College of Cardiology, 2003

used by 40%/42% of placebo-lvardenafil-treated patients. The mean change from pretreatment standi... more used by 40%/42% of placebo-lvardenafil-treated patients. The mean change from pretreatment standing SBP/DBP (mmHg). and HR (bpm) in the subgroup having post-dose data is summarized below.

Journal of the American College of Cardiology, 2002

S-Hypertension, Vascular Disease, and Prevention 253A Results: Basal blood pressure, heart rate, ... more S-Hypertension, Vascular Disease, and Prevention 253A Results: Basal blood pressure, heart rate, basal forearm blood flow, NTG% and body weight were similar between groups. FMD was greater in group A (72.9±7.6%) than in groups B (43.7+/-5.1%, p<0.05) or C (53.4+/-7.1%, p<0.05). No significant difference of FMD was observed between groups B (43.7±5.1%) and C (53.4±7.1%, p=NS). Ejection fraction was greater in group A (51±3.1%) than in groups B (26.0±0.93%, p<0.001) and C (24.1±1.0%, p<0.001), but no difference was observed in ejection fraction between groups B and C (p=NS). Conclusions: There is no significant difference in endothelial function between patients with ischemic and dilated cardiomyopathy. These findings indicate that undedying atherosclerosis plays a minor role in endothelial dysfunction in patients with heart failure.

Journal of the American College of Cardiology, 2004

Background: Chromogranin A (CgA) is widely distributed throughout the neurendocrine system and ma... more Background: Chromogranin A (CgA) is widely distributed throughout the neurendocrine system and may, due to its long in vivo and in vitro half-life, be an attractive candidate for assessment of neuroendocrine activity in congestive heart failure (CHF). Recently, increased plasma levels of CgA have been found in patients with CHF and related to the severity of symptoms and prognosis. The effect of physical exercise on circulating CgA levels in patients with CHF is unknown. Moreover, the relation between CgA levels and invasive hemodynamic indices remains to be established. Methods: 22 patients with chronic CHF (NYHA class II-IV) performed supine bicycle testing with breath-to-breath analysis for assessment of peak oxygen uptake (VO 2 max). Venous blood samples for CgA analysis were drawn at baseline, at peak exercise, and 1 hour post-exercise. Plasma levels of CgA were determined by radioimmunoassay. Echocardiography and left-and right cardiac catheterization were performed in all patients. 10 healthy age-and sex matched volunteers served as controls. Results: CHF patients had reduced peak VO 2 compared to controls (13.6 ± 5.4 vs 31.5 ± 10.0 ml/kg/min, p<0.001). The baseline level of CgA was elevated in patients compared to controls (24.3 ± 14.4 vs. 18.7 ± 1.5 ng/ml, p< 0.05). Baseline levels of CgA correlated positively with arteriovenous O 2 difference (r = 0.62, p = 0.02) and negatively with LVEF (r =-0.70, p< 0.001). CgA did not correlate significantly with pulmonary capillary wedge pressure, right atrial pressure, stroke volume, cardiac index or peak VO 2. Whereas CgA levels increased significantly from baseline to peak exercise in control subjects (from 18.7 ± 1.5 to 22.0 ± 3.6 ng/ml, p< 0.05), the CgA response to exercise was blunted in CHF patients (from 24.3 ± 14.4 to 24.4 ± 15.6 ng/ml, p = ns). Conclusion: CgA levels are elevated in patients with CHF and are related to left ventricular systolic function and arteriovenous O 2-difference. The CgA response to exercise is blunted in CHF, suggesting widespread baseline neuroendocrine activation in CHF. In contrast to catecholamines, circulating CgA concentrations are not affected by physical activity in patients with CHF.

Journal of Molecular and Cellular Cardiology, 2012

Elevated plasma homocysteine (Hcy) is a risk factor for cardiovascular disease. While Hcy has bee... more Elevated plasma homocysteine (Hcy) is a risk factor for cardiovascular disease. While Hcy has been shown to promote endothelial dysfunction by decreasing the bioavailability of nitric oxide and increasing oxidative stress in the vasculature, the effects of Hcy on cardiomyocytes remain less understood. In this study we explored the effects of hyperhomocysteinemia (HHcy) on myocardial function ex vivo and examined the direct effects of Hcy on cardiomyocyte function and survival in vitro. Studies with isolated hearts from wild type and HHcy mice (heterozygous cystathionine-beta synthase deficient mice) demonstrated that HHcy mouse hearts had more severely impaired cardiac relaxation and contractile function and increased cell death following ischemia reperfusion (I/R). In isolated cultured adult rat ventricular myocytes, exposure to Hcy for 24 hours impaired cardiomyocyte contractility in a concentration-dependent manner, and promoted apoptosis as revealed by terminal dUTP nick-end labeling and cleaved caspase-3 immunoblotting. These effects were associated with activation of p38 MAPK, decreased expression of thioredoxin (TRX) protein, and increased production of reactive oxygen species (ROS). Inhibition of p38 MAPK by the selective inhibitor SB203580 (5 µM) prevented all of these Hcy-induced changes. Furthermore, adenovirus-mediated overexpression of TRX in cardiomyocytes significantly attenuated Hcy-induced ROS generation, apoptosis, and impairment of myocyte contractility. Thus, Hcy may increase the risk for CVD not only by causing endothelial dysfunction, but also by directly exerting detrimental effects on cardiomyocytes.

European Heart Journal Supplements, 2008

Mobilizing haematopoietic progenitor cells (HPC) to repair the failing heart is a promising inter... more Mobilizing haematopoietic progenitor cells (HPC) to repair the failing heart is a promising intervention to halt the progression of this deadly disease. We postulated that low doses of granulocyte colony stimulating factor (GCSF) could successfully mobilize HPC in advanced systolic heart failure and lead to beneficial effects. In a pilot study involving patients with advanced systolic heart failure, we established that a low dose (5 mg/kg/day for 5 days) of GCSF was sufficient to mobilize HPC into the peripheral blood in adequate numbers (.10 cells/mL) in spite of advanced heart failure and subject age. A striking observation was the significant elevation of plasma interleukin-10 levels in response to GCSF, without any change in tumour necrosis factor-a or interferon-g levels. Left ventricular function improved significantly in subjects with ischaemic cardiomyopathy at 9 months after a single 5-day cycle of GCSF. Our results suggest the potential for improving left ventricular function in advanced systolic heart failure utilizing GCSF.