Macro- and micronutrients in patients with congestive heart failure, particularly African-Americans

Not all patients with heart failure, defined as a reduced ejection fraction, will have an activation of the RAAS, salt and water retention, or the congestive heart failure (CHF) syndrome. Beyond this cardiorenal perspective, CHF is accompanied by a systemic illness that includes oxidative stress, a proinflammatory phenotype, and a wasting of soft tissues and bone. A dyshomeostasis of calcium, magnesium, zinc, selenium, and vitamin D contribute to the appearance of oxidative stress and to compromised endogenous defenses that combat it. A propensity for hypovitaminosis D, given that melanin is a natural sunscreen, and for secondary hyperparathyroidism in African-Americans make them more susceptible to these systemic manifestations of CHF—a situation which is further threatened by the calcium and magnesium wasting that accompanies the secondary aldosteronism of CHF and the use of loop diuretics

Diuretics and Bone Loss in Rats With Aldosteronism

ObjectivesWe hypothesized that the increased urinary Ca2+and Mg2+excretion and bone loss that accompanies aldosteronism is aggravated with furosemide and is attenuated by spironolactone.BackgroundFurosemide, a loop diuretic, is commonly used in patients with congestive heart failure (CHF), in which chronic, inappropriate (dietary Na+) elevations in plasma aldosterone (ALDO) and a catabolic state that includes bone wasting are expected.MethodsIn age- and gender-matched, untreated controls, four weeks of aldosterone/salt treatment (ALDO/salt, 0.75 μg/h + 1% NaCl/0.4% KCl in drinking water), four weeks of ALDO/salt + furosemide (40 mg/kg in prepared food), and four weeks of ALDO/salt + furosemide + spironolactone (200 mg/kg/day in divided doses by twice-daily gavage), we monitored: 24-h urinary Ca2+and Mg2+excretion; plasma-ionized [Ca2+]o and [Mg2+]o, K+, and parathyroid hormone (PTH); and bone mineral density (BMD) in the femur.ResultsThe ALDO/salt increased (p < 0.05) urinary Ca2+and Mg2+excretion (4,969 ± 1,078 and 3,856 ± 440 μg/24 h, respectively) compared with controls (896 ± 138 and 970 ± 137 μg/24 h, respectively); furosemide co-treatment further increased (p < 0.05) urinary Ca2+and Mg2+excretion (6,976 ± 648 and 6,199 ± 759 μg/24 h, respectively), whereas spironolactone co-treatment attenuated (p < 0.05) these incremental losses (4,003 ± 515 and 3,915 ± 972 μg/24 h). Plasma [Ca2+]o was reduced (p < 0.05) at week 4 ALDO/salt + furosemide and was accompanied by hypokalemia (<3.4 mmol/l) that were rescued by spironolactone. Plasma PTH was increased (p < 0.05) compared with controls (30 ± 4 vs. 11 ± 3 pg/ml, respectively), whereas BMD was decreased (p < 0.05) with ALDO/salt and ALDO/salt + furosemide, but not with spironolactone co-treatment.ConclusionsIn aldosteronism, hypercalciuria and hypermagnesuria and accompanying decrease in plasma-ionized [Ca2+]o and [Mg2+]o lead to hyperparathyroidism that accounts for bone wasting. Furosemide exaggerates these losses, whereas its combination with spironolactone attenuates these responses to prevent bone loss

Congestive Heart Failure is a Systemic Illness: A Role for Minerals and Micronutrients

Congestive heart failure (CHF) is a clinical syndrome that features a failing heart together with signs and symptoms arising from renal retention of salt and water, mediated by attendant neurohormonal activation, and which prominently includes the renin-angiotensin-aldosterone system. More than this cardiorenal perspective, CHF is accompanied by a systemic illness whose features include an altered redox state in diverse tissues and blood, an immunostimulatory state with proinflammatory cytokines and activated lymphocytes and monocytes, and a wasting of tissues that includes muscle and bone. Based on experimental studies of aldosteronism and clinical findings in patients with CHF, there is an emerging body of evidence that secondary hyperparathyroidism is a covariant of CHF. The aldosteronism of CHF predisposes patients to secondary hyperparathyroidism because of a chronic increase in Ca2+ and Mg2+ losses in urine and feces, with a fall in their serum ionized levels and consequent secretion of parathyroid hormone. Secondary hyperparathyroidism accounts for bone resorption and contributes to a fall in bone strength that can lead to nontraumatic fractures.The long-term use of a loop diuretic with its attendant urinary wasting of Ca2+ and Mg2+ further predisposes patients to secondary hyperparathyroidism and attendant bone loss. Aberrations in minerals and micronutrient homeostasis that includes Ca2+, Mg2+, vitamin D, zinc and selenium appear to be an integral component of pathophysiologic expressions of CHF that contributes to its systemic and progressive nature. This broader perspective of CHF, which focuses on the importance of secondary hyperparathyroidism and minerals and micronutrients, raises the prospect that dietary supplements could prove remedial in combination with the current standard of care

A Murine Hypertrophic Cardiomyopathy Model: The DBA/2J Strain.

Familial hypertrophic cardiomyopathy (HCM) is attributed to mutations in genes that encode for the sarcomere proteins, especially Mybpc3 and Myh7. Genotype-phenotype correlation studies show significant variability in HCM phenotypes among affected individuals with identical causal mutations. Morphological changes and clinical expression of HCM are the result of interactions with modifier genes. With the exceptions of angiotensin converting enzyme, these modifiers have not been identified. Although mouse models have been used to investigate the genetics of many complex diseases, natural murine models for HCM are still lacking. In this study we show that the DBA/2J (D2) strain of mouse has sequence variants in Mybpc3 and Myh7, relative to widely used C57BL/6J (B6) reference strain and the key features of human HCM. Four-month-old of male D2 mice exhibit hallmarks of HCM including increased heart weight and cardiomyocyte size relative to B6 mice, as well as elevated markers for cardiac hypertrophy including β-myosin heavy chain (MHC), atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), and skeletal muscle alpha actin (α1-actin). Furthermore, cardiac interstitial fibrosis, another feature of HCM, is also evident in the D2 strain, and is accompanied by up-regulation of type I collagen and α-smooth muscle actin (SMA)-markers of fibrosis. Of great interest, blood pressure and cardiac function are within the normal range in the D2 strain, demonstrating that cardiac hypertrophy and fibrosis are not secondary to hypertension, myocardial infarction, or heart failure. Because D2 and B6 strains have been used to generate a large family of recombinant inbred strains, the BXD cohort, the D2 model can be effectively exploited for in-depth genetic analysis of HCM susceptibility and modifier screens

Mitochondrial Role in Oncogenesis and Potential Chemotherapeutic Strategy of Mitochondrial Infusion in Breast Cancer

Triple negative breast cancer (TNBC) is one of the most aggressive cancers diagnosed amongst women with a high rate of treatment failure and a poor prognosis. Mitochondria have been found to be key players in oncogenesis and tumor progression by mechanisms such as altered metabolism, reactive oxygen species (ROS) production and evasion of apoptosis. Therefore, mitochondrial infusion is an area of interest for cancer treatment. Studies in vitro and in vivo demonstrate mitochondrial-mediated reduction in glycolysis, enhancement of oxidative phosphorylation (OXPHOS), reduction in proliferation, and an enhancement of apoptosis as effective anti-tumor therapies. This review focuses on mitochondrial dysregulation and infusion in malignancies, such as TNBC

Temporal responses to intrinsically coupled calcium and zinc dyshomeostasis in cardiac myocytes and mitochondria during aldosteronism

Intracellular Ca2+ overloading, coupled to induction of oxidative stress, is present at 4-wk aldosterone/salt treatment (ALDOST). This prooxidant reaction in cardiac myocytes and mitochondria accounts for necrotic cell death and subsequent myocardial scarring. It is intrinsically linked to increased intracellular zinc concentration ([Zn2+]i) serving as an antioxidant. Herein, we addressed the temporal responses in coupled Ca2+ and Zn2+ dyshomeostasis, reflecting the prooxidant-antioxidant equilibrium, by examining preclinical (week 1) and pathological (week 4) stages of ALDOST to determine whether endogenous antioxidant defenses would be ultimately overwhelmed to account for this delay in cardiac remodeling. We compared responses in cardiomyocyte free [Ca2+]i and [Zn2+]i and mitochondrial total [Ca2+]m and [Zn2+]m, together with biomarkers of oxidative stress and antioxidant defenses, during 1- and 4-wk ALDOST. At week 1 and compared with controls, we found: 1) elevations in [Ca2+]i and [Ca2+]m were coupled with [Zn2+]i and [Zn2+]m; 2) increased mitochondrial H2O2 production, cardiomyocyte xanthine oxidase activity, and cardiac and mitochondrial 8-isoprostane levels, counterbalanced by increased activity of antioxidant proteins, enzymes, and the nonenzymatic antioxidants that can be considered as cumulative antioxidant capacity; some of these enzymes and proteins (e.g., metallothionein-1, Cu/Zn-superoxide, glutathione synthase) are regulated by metal-responsive transcription factor-1; and 3) although these augmented antioxidant defenses were sustained at week 4, they fell short in combating the persistent intracellular Ca2+ overloading and marked rise in cardiac tissue 8-isoprostane and mitochondrial transition pore opening. Thus a coupled Ca2+ and Zn2+ dyshomeostasis occurs early during ALDOST in cardiac myocytes and mitochondria that regulate redox equilibrium until week 4 when ongoing intracellular Ca2+ overloading and prooxidants overwhelm antioxidant defenses