Posted in Nutritional Supplements: Atherogenesis, lipid metabolism on November 19, 2013| Leave a Comment »
USPSTF: Evidence for Supplement Use Lacking
Reporter: Aviva Lev-Ari, PhD, RN
See on Scoop.it – Cardiovascular and vascular imaging
There still is not enough evidence to recommend for or against vitamin and mineral supplements for primary prevention of heart disease or cancer, a draft of updated recommendations from the U.S.
See on www.medpagetoday.com
Posted in Cardiomyopathy, Cell Biology, Signaling & Cell Circuits, Frontiers in Cardiology and Cardiovascular Disorders, Metabolomics, Myocardial metabolism, Myocardial ischemia, myocardial perfusion, Myocardial adenine nucleotide metabolism, Nutrition, Population Health Management, Genetics & Pharmaceutical, Population Health Management, Nutrition and Phytochemistry, Proteomics, Systemic Inflammatory Response Related Disorders, tagged heart, Hypertrophy, leptin, Obesity, Signal transduction, STAT3 on November 3, 2013| Leave a Comment »
Curators: Larry H Bernstein, MD, FCAP and Aviva Lev-Ari, PhD, RN
There has been a lot of interest in leptins and both insulin resistance and obesity for the last decade. The association between obesity and cardiac hypertrophy is also known, but what drives this association. We have covered heart disease from many aspects in a long series of articles. The next is a pleasure to take in.
1Department of Cardiology and Pulmonary Medicine, Heart Research Center, Georg August University Medicine Goettingen, Robert Koch Strasse 40, D-37075, Göttingen, Germany
2Current address: Department of Pediatric Kidney, Liver and Metabolic Diseases, Hannover Medical School, Hannover, Germany
3Current address: Clinic for Anesthesiology and Intensive Care Medicine, University Medicine Rostock, Rostock, Germany
4Department of Pharmacology, Georg August University Medicine Goettingen, Goettingen, Germany
5Current address: Center for Thrombosis and Hemostasis, University Medicine Mainz, Mainz, Germany
J Translational Medicine: Cardiovascular, Metabolic and Lipoprotein Translation. 2013; 11:170. http://www.translational-medicine.com/content/11/1/170
http://dx.doi.org/10.1186/1479-5876-11-170
This is an Open Access article distributed under the terms of the Creative Commons Attribution License
http://creativecommons.org/licenses/by/2.0
The adipokine leptin and its receptor are expressed in the heart, and
Obesity is associated with
However, the role of cardiac leptin signaling in mediating the cardiomyopathy associated with increased body weight is unclear, in particular, whether it develops subsequently to cardiac leptin resistance or overactivation of hypertrophic signaling pathways via elevated leptin levels.
The cardiac phenotype of high-fat diet (HFD)-induced obese wildtype (WT) mice was examined and compared to age-matched genetically obese leptin receptor (LepR)-deficient (LepRdb/db) or lean WT mice. To study the role of leptin-mediated STAT3 activation during obesity-induced cardiac remodeling,
Obesity was associated with hyperleptinemia and elevated cardiac leptin expression in both diet-induced and genetically obese mice.
Although echocardiography revealed signs of cardiac hypertrophy in all obese mice,
LepRS1138 mice also exhibited an increased activation of signaling proteins downstream of LepR, including Jak2 (1.8-fold), Src kinase (1.7-fold), protein kinase B (1.3-fold) or C (1.6-fold). Histological analysis of hearts revealed that the inability of leptin to activate STAT3 in LepRdb/db and LepRS1138 mice
Our findings suggest that hearts from obese mice continue to respond to elevated circulating or cardiac leptin, which
On the other hand, the presence of cardiac hypertrophy in obese mice with complete LepR signal disruption indicates that additional pathways also play a role.
Heart; Hypertrophy; Leptin; Obesity; Signal transduction; STAT3
Obesity is frequently associated with elevated circulating leptin levels [1] and an increased risk to develop cardiac hypertrophy [2,3] or heart failure [4]. Clinical studies demonstrated a positive correlation between serum leptin levels and left ventricular (LV) mass or wall thickness [5,6], independent of blood pressure levels, suggesting a direct role for leptin in the pathogenesis of obesity-associated cardiomyopathy. Furthermore, leptin was shown to promote hypertrophy of isolated rat or human ventricular cardiomyocytes [7,8], and
Cardiac hypertrophy also develops in obese rodents fed high-fat diet (HFD)[10,11], and
The effects of leptin on cell shortening and intracellular Ca2+ transients were abrogated in cardiomyocytes isolated from HFD-fed obese rats [14], but then others found
The leptin receptor (LepR) belongs to the family of cytokine type I receptors that signal via activation of
Analysis of cardiomyocytes ex vivo revealed leptin promotes hypertrophy via activation of p38 and p42/44 MAP kinases as well as protein kinase B (Akt) [19,20]. But it is unknown whether STAT-3 activation downstream of LepR is required to transmit the cardiac effects of leptin and whether it may be involved in mediating protective (i.e. anti-apoptotic, anti-fibrotic or pro-angiogenic) signals, as previously reported in mice with cardiomyocyte-specific STAT-3 deletion [21,22].
In this study, we examined the cardiac phenotype of diet-induced (i.e. with hypothalamic leptin resistance) and genetically obese (i.e. with systemic leptin receptor deficiency) hyperleptinemic mice, developing with age or after continuous β-adrenergic stimulation. Moreover, we determined
C57Bl6/J leptin receptor-deficient db/db (LepRdb/db; BKS.Cg Leprdb/Leprdb) mice and C57Bl6/J wildtype (WT) controls were obtained from Harlan Winkelmann, Germany. Mice heterozygous mutant for the LepRS1138 allele (on the congenic B6.129/J background; 98- > 99% homozygous for C57Bl/6; [23]) were obtained from Professor Martin Myers (University of Michigan Medical School, Ann Arbor, USA) and bred at the animal facility of the University of Goettingen, Germany, to generate homozygous mutant obese LepRS1138 mice. Age- and gender-matched WT (LepR+/+) and heterozygous (LepRS/+) littermates were used as controls. To induce obesity, 3 months-old mice were switched to high-fat diet (HFD; D12451) for 4 months, while controls were maintained on normal rodent chow (D12450B; both Research Diets Inc.). The composition of both diets is shown in Additional file 1: Table S1. To examine the cardiac response to hypertrophic stimuli other than leptin, osmotic minipumps (Alzet®; model 2002; Charles River Laboratories) were filled with isoprenaline hydrochloride (Sigma; 20 mg/kg body weight [BW] per day) and implanted for 14 days under the dorsal skinfold of 2 months-old, 2% isoflurane anesthetized mice. At the time of tissue harvest, mice were weighed followed by intraperitoneal anesthesia with a mixture of 2% xylazine (6 mg/kg BW) and 10% ketamine hydrochloride (100 mg/kg BW), and blood was drawn by cardiac puncture. Hearts were rapidly excised, the atria removed and ventricles immediately processed for protein isolation or cryoembedding, respectively. All animal care and experimental procedures had been approved by the institutional Animal Research Committee and complied with national guidelines for the care and use of laboratory animals.
Additional file 1: Table S1. Diet composition.
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Freshly drawn blood was allowed to clot at room temperature (RT) for 30 min, followed by centrifugation for 10 min at 3,000 rpm. The supernatant was stored at -80°C pending analysis of serum leptin levels using specific enzyme-linked immunoassays (ELISA; R&D Systems).
Echocardiography was performed by a blinded examiner at the day before tissue harvest in mice under 1.5% isoflurane anesthesia using the VisualSonics Vevo 2100 system (Visualsonics) equipped with a 30 MHz center frequency ultrasound transducer, as previously described [24]. M-mode echocardiographical recordings were used to determine the end-diastolic and end-systolic LV diameter (EDD and ESD, respectively) and the ventricular wall thickness (WTh), corresponding to the mean of the anterior and posterior WTh. LV mass was calculated using the formula: 1.055 × ([AWTh + EDD + PWTh]3 – EDD3). Fractional shortening (FS) was calculated as (EDD – ESD)/EDD × 100. B-mode echocardiography images were used to calculate the heart weight, using the equation: 1.05 × (5/6) × ((Episyst × (Lsyst + ((AWThsyst + PWThsyst)/2))) – (Areasyst × Lsyst)).
Histochemical analyses were performed on 5 μm-thick frozen cross sections through the LV. For each mouse, 4 sections (approx. 500 μm apart) and 4 randomly selected viewing fields (at 200-fold magnification) per section were analyzed and findings averaged. Cardiac fibrosis was determined after overnight incubation in Bouin’s fixative followed by Masson’s trichrome (MTC) stain. Monoclonal rat antibodies against mouse CD31 (Santa Cruz Biotechnology) were used to detect endothelial cells [24,25]. Their number was manually counted by a person blinded to the mouse genotype and expressed per mm2 or cardiomyocyte, respectively.
Single cardiomyocytes were visualized by incubation with fluorescein-labeled wheat germ agglutinin (WGA; Molecular Probes), followed by determination of the cardiomyocyte cross-sectional area (CSA) using image analysis software (Image ProPlus). Per cross section, at least 10 randomly selected cardiomyocytes were evaluated and results averaged. Apoptosis was analyzed using the ‘In Situ Cell Death Detection kit’ (Roche). Cell nuclei were visualized using 4′,6-diamidino-2-phenylindole (DAPI; Sigma).
Membranes were blocked in 1% bovine serum albumine (in TBS, containing 0.1% Tween-20) prior to incubation with antibodies against phosphorylated (p)-Akt (S473) and total Akt, p-Jak2 (Y1007/1008) and total Jak2, p-p38 (T180/Y182) and total p38, p-p42/44 (T202/Y204) and total p42/44, p-Src (Y416) and total Src, p-STAT3 (Y705) and total STAT3, or p-PKC (pan), respectively (all Cell Signaling Technologies), or against leptin (R&D Systems) and GAPDH (Biotrend), respectively. Protein bands were visualized using HRP-conjugated secondary antibodies (Amersham Biosciences), followed by detection with SuperSignal® West Pico Substrate (Pierce). For the analysis of LepR phosphorylation, 100 μg total heart tissue lysates were immunoprecipitated under rotation at 4°C with 2 μg anti-LepR antibody (against an internal domain present in the short and long isoforms of murine LepR; Santa Cruz Biotechnology) plus 50 μL nProtein A Sepharose™ 4 Fast Flow beads (GE Healthcare) followed by detection of phosphorylated tyrosines (p-Tyr [PY20]; Santa Cruz Biotechnology) or LepR. For the analysis of STAT3 phosphorylation in response to acute elevations of circulating leptin, mice were fasted overnight, injected with recombinant murine leptin (1 mg/kg BW i.p.) and hearts harvested 30 min later.
Quantitative data are presented as mean ± standard error of the mean (SEM). Normal data distribution was tested using the D’Agostino & Pearson omnibus normality test. When three or more groups were compared, ANOVA was employed, if samples were normally distributed, or Kruskal-Wallis test, if not. For post-hoc comparisons, ANOVA was followed by Bonferroni’s and Kruskal-Wallis by Dunn’s multiple comparison test. Differences before and after isoprenaline infusion were tested using Student’s t-test for paired means. Statistical significance was assumed when P reached a value less than 0.05. All statistical analyses were performed using GraphPad PRISM software, version 4.01 (GraphPad Software Inc).
Clinical and experimental studies revealed that obesity is associated with LV hypertrophy [10,11], an important risk factor for the development of heart failure. As shown in Tables 1 and 2, WT mice fed HFD for 4 months (WT + HFD; mean body weight [BW], 44±1.9 g) to induce obesity exhibited a non-significant trend towards an increased mean heart weight, LV mass and WTh compared to age-matched lean controls fed normal chow (BW, 29±1.0 g). Marked LV hypertrophy was observed in 7 months-old obese LepRdb/db mice (Table 1 and 2), consistent with a previous report [12]. Longitudinal sections through hearts of WT, WT + HFD and LepRdb/db mice are shown in Figure 1A, representative M-mode echocardiography recordings in Figure 1B and cardiac cross-sections after WGA staining to delineate cardiomyocyte borders in Figure 1C. Of note, adiposity in mice with LepR deficiency was more pronounced compared to age-matched WT + HFD mice (Table 1; P < 0.001), in which obesity develops as result of hypothalamic resistance to chronically elevated leptin levels[26].
Figure 1.Cardiac phenotype of lean and obese WT, WT + HFD, LepRS1138 and LepRdb/db mice.
(A)Representative H&E-stained longitudinal sections through hearts of 7 months-old mice are shown. Magnification, ×10.(B) Representative M-mode echocardiographic recordings.(C) Representative images of wheat germ agglutinin (WGA)-stained myocardial cross sections. The mean cardiomyocyte cross-sectional areas are given in Table 1.
Table 1.Body, visceral fat and heart weights in 7 months-old mice
Table 2.Echocardiographic parameter in 7 months-old mice
The presence of cardiac hypertrophy in LepR-deficient and, to a lesser extent also in diet-induced obese mice, suggests that it develops as a result of the heart’s inability to respond to elevated systemic (Table 1) and/or cardiac (Figure 2A) leptin levels. In this regard, Western blot analysis revealed increased levels of phosphorylated (p-) LepR (Figure 2B) and STAT-3 (Figure 2C) protein in hearts of HFD-induced obese mice (P < 0.05 vs. WT for both), whereas findings in LepRdb/db mice did not differ from those in lean controls or were reduced compared to those in WT + HFD mice (P < 0.05 for differences in LepR phosphorylation). Moreover, both lean and HFD-induced obese WT mice responded to a single i.p. injection of recombinant murine leptin with a significant increase in the cardiac STAT-3 phosphorylation (Figure 2D), suggesting a preserved cardiac leptin signal transduction in hyperleptinemic, diet-induced obese mice.
Figure 2.Cardiac leptin expression and signal transduction in lean and obese mice.
Protein was extracted from hearts of 7 months-old mice (n = 8 per group) and analyzed for the expression of (A) leptin, (B)phosphorylated LepR (using immunoprecipitation of LepR, followed by the detection of total phosphotyrosines and LepR) and (C) phosphorylated STAT3. (D) Cardiac STAT3 phosphorylation in response (30 min later) to a single injection of recombinant murine leptin (1 mg/kg BW i.p.) was examined in WT (n = 4) and WT + HFD (n = 6) mice. Results are expressed as -fold increase of controls (black bars) after normalization for total protein and GAPDH expression. The mean ± SEM as well as representative Western blot results are shown. *P < 0.05 and **P < 0.01 vs. WT mice; #P < 0.05 vs. WT + HFD mice.
To further study the role of leptin signaling in the development of cardiac hypertrophy and also to determine, whether the inability of leptin to activate STAT3 contributes to the cardiac maladaptation in obesity, we examined mice in which tyrosine (Tyr)1138 within LepR had been replaced by a serine (LepRS1138). In these mice, leptin cannot signal via STAT3, but continues to be able to activate Jak2 and SH2 domain-containing adapter proteins. Western blot analysis revealed that p-LepR (Figure 2B) and p-STAT3 (Figure 2C) levels in hearts of LepRS1138 mice did not significantly differ from those in WT and LepRdb/db mice. Similar to mice with complete LepR deficiency, lack of LepR-mediated STAT3 activation resulted in severe adiposity, although serum leptin levels were lower than those in LepRdb/db mice (P < 0.001; Table 1). Interestingly, obese LepRS1138 exhibited a more pronounced increase in mean heart weights not only compared to lean or diet-induced obese WT mice, but also compared to LepRdb/db mice (P < 0.001 for all comparisons; Table 1), and differences persisted after normalization for body weight (P < 0.001) or tibia length (P < 0.001). Echocardiography confirmed increased LV mass (P < 0.01) or heart weights (P < 0.001) in LepRS1138 mice compared to their LepRdb/dbcounterparts (Table 2; please also see Figure 1A-C). Moreover, hearts of LepRS1138 mice exhibited elevated levels of phosphorylated Jak2 (P < 0.001 vs. WT; Figure 3A), Src kinase (P < 0.05 vs. WT, WT + HFD and LepRdb/db; Figure 3B), Akt (P < 0.001 vs. LepRdb/db; Figure 3C), PKC (P < 0.05 vs. WT and LepRdb/db, P < 0.01 vs. WT + HFD; Figure 3D) and p38 MAPK (P < 0.01 vs. LepRdb/db; Figure 3E), suggesting that an intact, Tyr1138-independent LepR activation in the presence of elevated leptin levels may have contributed to the pronounced cardiac hypertrophy present in these mice. On the other hand, cardiac levels of p-p42/44 MAPK did not significantly differ between the mouse groups (Figure 3F).
Figure 3.Hypertrophic signal transduction in hearts of lean and obese mice. Protein was isolated from hearts of 7 months-old WT (n = 15), WT + HFD (n = 12), LepRS1138(n = 15) and LepRdb/db (n = 15) mice and analyzed for the expression of phosphorylated Jak2 (A), Src kinase (B), Akt (C), PKC (D), p38 (E) and p42/44 MAPK (F). Results are expressed as -fold increase of lean control mice (after normalization for total protein [with the exception of PKC] and GAPDH expression). The mean ± SEM as well as representative findings are shown. *P < 0.05, **P < 0.01 and ***P < 0.001 vs. WT mice; #P < 0.05 and ##P < 0.01 vs. WT + HFD mice; §P < 0.05, §§P < 0.01 and §§§P < 0.001 for the difference between LepRdb/db and LepRS1138 mice.
M-mode echocardiography also revealed significantly increased enddiastolic LV diameters in LepRS1138 mice (P < 0.01 vs. WT and LepRdb/db mice; Table 2; representative findings are shown in Figure 1B), suggesting that the observed (over-)activation of LepR signaling together with the inability to induce STAT3 may result in augmented hypertrophy and maladaptive cardiac remodeling. Of note, fractional shortening (FS) was not significantly altered in HFD-induced obese WT mice (P = n.s. vs. WT mice), but found to be increased in both LepRdb/db (P < 0.01 vs. WT and P < 0.001 vs. WT + HFD mice) and LepRS1138mice (P < 0.05 vs. WT and P < 0.001 vs. WT + HFD mice). Histological analyses revealed significantly reduced numbers of CD31-positive capillary endothelial cells in LepRdb/db, and to a lesser extent also in LepRS1138 mice (Figure 4A), whereas the number of TUNEL-positive apoptotic cells (Figure 4B) and the fibrotic tissue area (Figure 4C) were found to be significantly increased in hearts of both LepRS1138 and LepRdb/db mice compared to lean and diet-induced obese WT mice.
Figure 4.Histological analysis of angiogenesis, apoptosis and fibrosis in hearts of lean and obese mice.
Serial cross sections through the LV of WT, WT + HFD, LepRS1138 and LepRdb/db mice (n = 10 per group) were immunostained and the number of (A) CD31-positive endothelial cells and (B) TUNEL-positive apoptotic cell nuclei determined. Results are expressed per cardiomyocyte and/or mm2.(C) The degree of cardiac fibrosis was quantified after Masson’s trichrome (MTC) staining. Results are expressed as % of total tissue area (at 200-fold magnification). The mean ± SEM as well as representative findings are shown. **P < 0.01 and ***P < 0.001 vs. WT; #P < 0.05, ##P < 0.01 and ###P < 0.001 vs. WT + HFD mice.
Figure 4.Histological analysis (unable to post)
To examine the specificity of leptin’s hypertrophic action in obesity, the cardiac response of young, i.e. 2 months-old WT (n = 12; body weight, 22 ± 0.9 g), LepRS1138 (n = 9; 34 ± 1.1 g, P < 0.001 vs. WT) and LepRdb/db mice (n = 7; 40 ± 1.3 g; P < 0.001 vs. WT and P < 0.01 vs. LepRS1138) to chronic isoprenaline infusion (20 mg/kg BW per day) was examined. Under basal conditions, similar findings as those in 7 months-old mice were observed, i.e. LepRS1138 mice exhibited an increased heart weight (P < 0.05 vs. LepRdb/db; Figure 5A), LV mass (P < 0.01 vs. WT; Figure 5B) and mean WTh (P < 0.05 vs. WT; Figure 5C), whereas other changes, such as differences in fractional shortening (Figure 5D), ESD (Figure 5E) and EDD (Figure 5F) were not (yet) detected. On the other hand, all mouse groups responded to chronic β-adrenergic stimulation with significant cardiac hypertrophy, and no differences (with the exception of heart weight; Figure 5A) were observed between LepRS1138 and LepRdb/db mice. Representative M-mode echocardiography tracings are shown in Figure 6 and summarized in Additional file 2: Table S2.
Figure 5.Echocardiography findings in young lean and obese mice before and after chronic β-adrenergic stimulation.
Isoprenaline-filled osmotic minipumps were subcutaneously implanted into 2 months-old WT (n = 12), LepRS1138 (n = 9) and LepRdb/db (n = 7) mice to examine the cardiac response to a hypertrophic stimulus other than leptin. Echocardiography (A-F) was performed immediately before (open bars) as well as at the time of tissue harvest 14 days later (dotted bars). *P < 0.05, *P < 0.01 and ***P < 0.001 for differences vs. WT mice; §P < 0.05 for differences between LepRdb/db and LepRS1138 mice. Significance levels for differences before and after isoprenaline stimulation (as determined using Student’s t test for paired means) are indicated within the graph.
Figure 6.Representative M-mode echocardiography recordings.
Additional file 2: Table S2. Echocardiographic parameter in 2 months-old mice before and 14 days after isoprenaline infusion.
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The adipocytokine leptin may link obesity with cardiac hypertrophy, an important risk factor for the development of heart failure. Studies in humans [2,3] and rodents [10,11] have shown that obesity is associated with LV hypertrophy, and body mass index was identified as a strong and independent predictor of LV mass [2,3]. Importantly, cardiac hypertrophy is also observed in normotensive obese subjects [6], and plasma leptin levels are associated with increased myocardial wall thickness independent of BW or blood pressure elevations [5], suggesting a causal role for leptin in the pathogenesis of cardiac hypertrophy.
Although the major source of leptin is adipose tissue, cardiomyocytes are also capable of synthesizing leptin [27], and increased cardiac leptin levels have been reported in mice or rats following coronary ligation [13,18] or in patients with heart failure [28]. In this study, elevated circulating as well as cardiac leptin levels were detected in both diet-induced and genetically obese mice, which may have acted on cardiomyocytes as well as other, non-cardiomyocyte cells expressing leptin receptors [29]. Although leptin serum levels were higher than in previous publications [30], we explain this findings with the higher age of the mice, a factor previously found to be associated with increased circulating leptin levels [31]. Leptin has been shown to stimulate the hypertrophy of cardiomyocytes isolated from rats [7,20] or humans [8,19]. Moreover, chronic leptin infusion increased cardiac ANP expression after myocardial infarction (MI) in mice [32], whereas neutralizing LepR antibodies abrogated the hypertrophy of the surviving myocardium after coronary artery ligation in rats [33]. On the other hand and as confirmed in our analysis, cardiac hypertrophy also develops in leptin- and LepR-deficient mice and may be reversed by leptin substitution[12]. Caloric restriction experiments suggested that the anti-hypertrophic effects of leptin had occurred in addition to weight loss [12], which itself may preserve heart function and attenuate LV remodeling [34]. Thus, it is unclear whether the cardiac hypertrophy in obesity is the consequence of pro-hypertrophic effects of the adipokine or rather the result of a resistance towards leptin’s preventive effects on hypertrophic cardiac remodeling. Of note, since body weight is markedly elevated in the diet-induced and particularly, the genetically obese mice, the heart-to-body weight ratio decreases, even though the absolute heart weight is increased (but to a relatively lesser extent).
Obesity is associated with elevated circulating leptin levels and hypothalamic resistance to the weight-reducing effects of the adipokine, whereas the existence of a peripheral (e.g. cardiac) leptin resistance is controversial. For example, reduced cardiac LepR expression has been reported in HFD-fed rats[14], whereas others demonstrated unaltered cardiac STAT3 phosphorylation in diet-induced obese rodents following acute leptin administration [15–17]. Our findings also suggest that hearts from diet-induced obese mice continue to respond to leptin in the presence of chronically elevated leptin levels and that the observed elevation of serum and cardiac leptin may thus contribute to the development of cardiac hypertrophy in obesity. For example, hearts of hyperleptinemic obese WT mice (i.e. those with intact leptin receptors) exhibited signs of activated leptin signaling, including elevated levels of phosphorylated LepR and STAT3, while they were unchanged or reduced in mice with mutated or truncated forms of LepR (i.e. LepRS1138 or LepRdb/db mice). Moreover, both lean and obese WT mice responded to a single leptin injection with increased cardiac STAT3 phosphorylation. Of note, we could not spatially dissect the cardiac responsiveness to leptin, since whole heart homogenates were examined. Possible explanations underlying the discrepancy between the present and some previous studies include the animal species, as the absence of a response to leptin in obesity has been so far primarily observed in rats[14]. In addition, age, sex and feeding status of the animals or the time of recombinant leptin administration may have influenced the results. Of note, previous studies in humans have reported the existence of individuals (up to 40%) exhibiting a blunted response to leptin [35], although it is unknown, whether such phenomenon also occurs in rodents.
Interestingly, hearts from LepRS1138 mice exhibited a marked overactivation of STAT3-independent leptin signaling pathways, including Jak2, Src kinase, Akt or p38 MAPK, i.e. factors previously shown to mediate the pro-hypertrophic effects of the adipokine in cardiomyocytes [19,20]. Importantly, overactivation of leptin signaling in hearts of LepRS1138 mice was accompanied by a pronounced cardiac hypertrophy, both at the organ and the single cardiomyocyte level, despite similar adiposity. Although leptin levels were found to be lower in LepRS1138compared to LepRdb/db mice, as previously reported [23], leptin continues to be able to activate LepR signal transduction in these mice, for example via LepR-Tyr985. Similar echocardiographical findings were obtained in young (i.e. 2 months-old) and older (i.e. 7 months-old) mice, arguing against the development of cardiac hypertrophy secondary to hemodynamic or other metabolic changes associated with obesity, although we cannot exclude the possible contribution of a more pronounced hyperinsulinemia [23] to the development of cardiac hypertrophy in LepRS1138 mice. On the other hand, hypertension had not been observed in ob/ob mice [12], and heart weight increase and concentric LV hypertrophy in obese mice and humans also occurs without systolic and diastolic blood pressure elevations [5,6,36].
Although a predominant cardiac expression of the short (i.e. without STAT3 binding site) over the long LepR isoform has been reported [7,29], previous studies have shown that stimulation of neonatal rat cardiomyocytes with leptin increased STAT3 phosphorylation, nuclear translocation and DNA binding activity [32]. Also, cardiac STAT3 activation after MI was blunted in leptin-deficient mice [13]. The observation that increased cardiac STAT3 phosphorylation in hyperleptinemic, diet-induced obese mice was reduced or almost completely abolished in LepRS1138 or LepRdb/db mice suggests that cardiac STAT3 activation in obesity largely occurs downstream of elevated leptin levels and that other cytokines, also elevated in obesity and known to signal via Jak2-STAT3, may be of minor importance. On the other hand, the importance of leptin-mediated STAT3 activation in the heart and its contribution to cardioprotective signaling pathways in vivo have not been directly examined so far.
STAT3 has been implicated in cardioprotection after various injuries. For example, cardiomyocyte-specific STAT3 deletion results in dilatative cardiomyopathy, characterized by increased apoptosis and interstitial fibrosis as well as reduced myocardial capillary density [21,22]. Previous studies suggested that leptin may exert beneficial effects on the heart. For example, administration of leptin was associated with smaller infarct size after ischemia/reperfusion injury [37], whereas ischemic postconditioning failed to induce cardioprotection in mice lacking leptin or its receptor [38]. Also, leptin deficiency was associated with a worsened cardiac function and survival after coronary artery ligation, which could be improved by leptin repletion [13]. Regarding possible mechanisms, increased cardiac myocyte apoptosis was observed in hearts from leptin (receptor)-deficient mice [39,40]. Similar findings were obtained in vitro, showing that leptin protects cardiomyocytes against apoptotic cell death induced by serum starvation [41]. Our analyses also revealed significantly elevated numbers of apoptotic cells in hearts of obese LepRS1138 and LepRdb/dbmice, consistent with a reduced activation of STAT3-responsive anti-apoptotic genes [40]. Although findings in mice with systemic defects in leptin signal transduction may have been confounded by the concomitant presence of obesity and associated metabolic and inflammatory alterations, adverse cardiac remodeling after MI [42] or lethal heart failure [43] were recently reported in mice with cardiomyocyte-specific LepR deletion. On the other hand, the beneficial effects of leptin-mediated STAT3 activation may not be restricted to cardiomyocytes. For example, we and others have shown that leptin promotes the angiogenic properties of endothelial (progenitor) cells [25,44], and cardiac angiogenesis was reduced in LepRS1138 and LepRdb/db mice. In addition, hearts of obese LepRS1138 and LepRdb/db mice exhibited increased interstitial fibrosis, which may have occurred secondary to increased cardiomyocyte loss, although previous studies have shown that leptin may also directly influence myocardial matrix metabolism [45]. On the functional level, the enhanced activation of pro-hypertrophic signaling pathways in the absence of STAT3-mediated cardioprotection may have contributed to the echocardiographic finding of LV cavity dilation in LepRS1138 compared to LepRdb/db mice.
Taken together, our findings suggest that hearts from diet-induced obese mice continue to respond to chronically elevated leptin levels and that increased systemic and/or local leptin and enhanced cardiac LepR activation contribute the development of cardiac hypertrophy. On the other hand, chronic overactivation of hypertrophic signaling mediators together with an inabilitity to activate STAT3-dependent cardioprotective pathways may promote maladaptive cardiac remodeling. Of note, our findings also indicate that leptin signaling is not a prerequisite to develop cardiac hypertrophy in obesity and that additional pathways also contribute to the increase in LV mass associated with higher body weight.
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Posted in Metabolomics, Nutrigenomics, Nutrition, Nutritional Supplements: Atherogenesis, lipid metabolism, Population Health Management, Nutrition and Phytochemistry, tagged Adipose tissue, fructose, fructose metabolism, glyoxalase-1, glyoxalase-2, green tea extract, hepatic lipogenesis on October 14, 2013| Leave a Comment »
Reporter: Larry H Bernstein, MD, FCAP
Christopher Masterjohn 1,2
, Youngki Park 1, Jiyoung Lee 1, Sang K. Noh 3, Sung I. Koo 1 and Richard S. Bruno 1,4,*
1 Department of Nutritional Sciences, University of Connecticut, Storrs, CT 06269, USA 2 Department of Comparative Biosciences, University of Illinois, Urbana, IL 61801, USA 3 Department of Food and Nutrition, Changwon National University, Changwon 641-773, Korea 4 Human Nutrition Program, Department of Human Sciences, The Ohio State University, Columbus, OH 43210, USA
Nutrients 2013, 5(8), 3311-3328; http://dx.doi.org/10.3390/nu5083311
The objective of this study was to determine whether dietary fructose and green tea extract (GTE) differentially regulate methylglyoxal accumulation in liver and adipose, mediated by tissue-specific differences in the glyoxalase system.
We fed six week old male Sprague-Dawley rats a low-fructose diet (10% w/w) or a high-fructose diet (60% w/w) containing no GTE or GTE at 0.5% or 1.0% for nine weeks.
Fructose-fed rats had higher (P < 0.05) adipose methylglyoxal, but GTE had no effect. Plasma and hepatic methylglyoxal were unaffected by fructose and GTE. Fructose and GTE also had no effect on the expression or activity of glyoxalase-1 and glyoxalase-2 at liver or adipose.
Keywords: fructose; glyoxalase I; glyoxalase II; pyruvaldehyde; rats; Sprague-Dawley
Masterjohn C, Park Y, Lee J, Noh SK, Koo SI, Bruno RS. Dietary Fructose Feeding Increases Adipose Methylglyoxal Accumulation in Rats in Association with Low Expression and Activity of Glyoxalase-2. Nutrients. 2013; 5(8):3311-3328. EISSN 2072-6643 Published by MDPI AG, Basel, Switzerland
Posted in Atherogenic Processes & Pathology, Biomarkers & Medical Diagnostics, Calcium, Interviews with Scientific Leaders, Nutrition, Nutritional Supplements: Atherogenesis, lipid metabolism, Origins of Cardiovascular Disease, Population Health Management, Nutrition and Phytochemistry, Regulated Clinical Trials: Design, Methods, Components and IRB related issues, Statistical Methods for Research Evaluation, tagged American Society for Bone and Mineral Research, Calcium, Cardiovascular disease, Joshua Lewis, Mark Bolland, Stanford University, University of Western Australia on October 11, 2013| Leave a Comment »
Curator and Reporter: Larry H. Bernstein, MD, FCAP
Article ID #82: New Data Dispute Calcium Cardiovascular Risk in Both Sexes. Published on 10/11/2013
WordCloud Image Produced by Adam Tubman
Nancy A. Melville Oct 08, 2013
BALTIMORE — Two new studies contribute further to the debate over the cardiovascular risk associated with supplementary or dietary calcium, each decidedly coming down on the side of no significant risk — to men or women.
“[Based on these findings], clinicians should continue to evaluate calcium intake, encourage adequate dietary intake, and if necessary, use supplements to reach but not exceed recommended intakes,” Douglas C. Bauer, MD, from the University of California, San Francisco, the lead author of the first study, told Medscape Medical News.
Results of both studies were reported at the recent American Society for Bone and Mineral Research (ASBMR) 2013 Annual Meeting.
Dr. Bauer’s observational trial is one of few contemporary studies to evaluate the level of risk among men, who are often poorly represented in calcium studies, he noted. The results showed no association between calcium dietary intake or supplementation and total or cardiovascular mortality. The second study was an updated meta-analysis of calcium supplementation among women and similarly demonstrated no increased risk for ischemic heart disease (with adjudicated outcomes) or total mortality in elderly women. It did draw some criticism for potential bias and contamination, however.
Nevertheless, says Robert Marcus, MD, a retired Stanford University bone specialist, the 2 studies are “powerful. The one involving men had very elegant, accurate reports of death and validated diagnosis of myocardial infarction, and the [study involving women] was also excellent work,” he commented.
“This field has been the subject of an enormous amount of controversy, ambiguity, and confusion for the past several years, and I think the most important thing is to help us come up with what is true,” he said. The quality of data to suggest an adverse effect of calcium is “very poor,” and there is now compelling evidence that there is little to substantiate this, he noted. But despite these reassuring new findings, public anxiety over a potential risk with calcium is unlikely to go away, he believes.
In recommendations issued in 2010, the ASBMR said that most adults 19 years of age and older require about 600 to 800 IUs of vitamin D daily and 1000 to 1200 mg of calcium daily through food and with supplements, if needed.
The use of calcium supplements, predominantly with vitamin D, is an important therapy for the prevention of osteoporosis and its clinical consequences. But concerns about the cardiovascular safety of calcium have emerged periodically; in 2 alarming meta-analyses published in 2010 and 2011 by Dr. Mark Bolland and colleagues, for example, there was a 27% increase in MI among individuals allocated to calcium supplements in the first study and a 24% increased risk in the second.
More recently, a 40% increase in total mortality and up to a 50% increase in cardiovascular mortality was seen among women from a Swedish mammography cohort with a calcium intake exceeding 1400 mg per day. In that study, the effect on mortality appeared to be especially strong if a high dietary intake of calcium was combined with calcium supplements.
In their new study, Dr. Bauer and his colleagues set out to assess rates of dietary calcium intake, use of supplements, and mortality in a prospective cohort of 5967 men over the age of 65 years in the Osteoporotic Fractures in Men (MrOS) study.
The participants completed extensive surveys at baseline on their dietary calcium intake, and supplementation was verified by a review of pill bottles by trained staff.
Mean dietary calcium intake was 1142 ± 590 mg/day, with more than half — 65% — of participants reporting use of calcium supplements.
Over the 10-year follow-up, among 2022 men who died, 687 deaths were caused by cardiovascular disease. The highest mortality for CVD was seen in the quartile with the lowest intake from calcium supplementation.
And in models that adjusted for age, energy intake, and calcium use, men in the lowest quartile of total calcium intake (less than 621 mg per day) had higher total mortality compared with those in the highest quartile (more than 1565 mg of calcium per day).
Adjustment for additional confounding factors showed no association between calcium dietary intake and total or cardiovascular mortality (P for trend .51 and .79, respectfully). Likewise, there was no association between calcium supplementation and total or cardiovascular mortality.
The authors also conducted an additional analysis of calcium intake and adjudicated cardiovascular disease events in a subcohort of the study, MrOS Sleep, involving 3120 patients who took part in a 7-year follow-up, and again there was no higher risk for cardiovascular events associated with calcium intake.
The study did have is limitations, Dr. Bauer acknowledged, including the observational design, calcium intake being assessed with a food frequency questionnaire, and cause of death not being formally adjudicated. Nevertheless, the findings are important in demonstrating the level of risk among men in a contemporary setting, he pointed out.
“Contrary to the Swedish study of women, we found no evidence that calcium supplementation is harmful to men, even among those with the highest dietary calcium intake,” he concluded, recommending that future studies should include adjudicated outcomes.
In the second study reported at the ASBMR meeting, Joshua Lewis, MD, PhD, from the University of Western Australia, Perth, and colleagues reported a meta-analysis of 19 randomized controlled trials involving women over the age of 50 years who had received calcium supplementation for more than a year.
Importantly, the analysis included reports of adjudicated cardiovascular outcomes, which the researchers note is important because gastrointestinal events can be misreported as cardiac ones. They also assessed all-cause mortality.
Among 59,844 participants in the studies, there were 4646 deaths, and the relative risk for death among those randomized to calcium supplements was 0.96 (P = .18).
The relative risk for 3334 ischemic heart disease events among 46,843 participants was 1.02 (P = .053), and the risk for 1097 MI events among 49,048 participants was 1.09 (P =.21).
“The data from this meta-analysis does not support the concept that calcium supplementation with or without vitamin D increases the risk of ischemic heart disease or total mortality in elderly women,” concluded Dr. Lewis.
But bone specialist Ian Reid, MD, from the University of Auckland, New Zealand, who was a coauthor on some of the Bolland studies, said this analysis essentially repeats previous ones, but with the inclusion of 20,000 patients from the Women’s Health Initiative (WHI), many of whom continued to take their own calcium tablets, regardless of whether they were randomized to calcium or placebo.
These “contaminated” WHI data have the potential to mask the effect of calcium, he told Medscape Medical News. In addition, in a study from Denmark also included in the meta-analysis, subjects were not properly blinded to treatment assignment and the calcium and control groups were not comparable at baseline for cardiovascular risk, which introduced “major potential bias,” he added.
Regarding the results from the study in men by Dr. Bauer and colleagues, Dr. Reid said they were not surprising to him. “Generally, people who take calcium supplements have more health-conscious behaviors than those who do not and so have a lower baseline risk of heart disease” that can “obscure small adverse effects of drugs such as calcium,” he observed.
An effect has to be “very substantial” before it can be picked up in an observational study, because of the many confounders that can obscure such an effect, he concluded.
Dr. Bauer, Dr. Lewis, Dr. Reid, and Dr. Marcus have reported no financial relationships. MrOS is supported by funding from the National Institutes of Health.
American Society for Bone and Mineral Research 2013 Annual Meeting. Abstracts 1001 and 1002, presented October 4, 2013.
Calcium (Ca) supplementation (>1400 mg/day): Higher Death Rates from all Causes and Cardiovascular Disease in Women
Aviva Lev-Ari, PhD. RN
http://pharmaceuticalintelligence.com/2013/02/19/calcium-ca-supplementation-1400-mgday-higher-death-rates-from-all-causes-and-cardiovascular-disease-in-women/
Posted in Accountable Care Organizations, Affordable Care Act, Ecosystems & Industrial Concentration in the Medical Device Sector, Federal Budget Appropriations, Health Economics and Outcomes Research, Health Law & Patient Safety, Healthcare costs and reimbursement, HealthCare IT, Healthcare Reform, Indigent Nutrition, International Global Work in Pharmaceutical, Medicare and Medicaid, Nutrition, Pharmaceutical Industry Competitive Intelligence, Population Health Management, Genetics & Pharmaceutical, Population Health Management, Nutrition and Phytochemistry, Prescription Drugs Costs, Skilled Nursing Facilities, Technology Capital Expenses, Uninsured and Underinsured, tagged aca, ACO, affordable care, Affordable Care Act, Commonwealth Fund, Health care reform, Health insurance, health organizations, healthcare costs, healthcare models, healthcare quality, helathcare access, Institute of Medicine, Kaiser Family Foundation, Kaiser Foundation, Medicaid, NCHQ, Patient Protection and Affordable Care Act, uninsured on September 13, 2013| Leave a Comment »
This issue brief examines changes in health insurance coverage over the last decade, with a focus on how changes in the economy, particularly during the “Great Recession” of 2007 to 2009, have affected coverage and the number of uninsured. The paper finds that the number of uninsured grew substantially during the first recession of the decade, increasing by 5 million people from 2000 to 2004; increased more slowly during the brief recovery, growing by 2.1 million people from 2004 to 2007; and then again rose significantly during the Great Recession, rising by 5.7 million people since 2007.
The paper also finds that coverage, especially for children, through the Medicaid and Children’s Health Insurance Programs helped to prevent even more people from being uninsured. While the number of uninsured children declined in recent years, the number of uninsured adults rose. The only notable drop in uninsured adults was for young adults ages 19-25 in 2010, most likely due to the provision of the health reform law that permits young adults to stay on their parents’ insurance. The paper also considers trends in coverage by work status, race and ethnicity, citizenship status and geographical region.
http://kff.org/medicaid/issue-brief/changes-in-health-insurance-coverage-in-the/
Pizer SD, Frakt AB, Iezzoni LI. US Department of Veterans Affairs in Boston, MA.
Health Aff (Millwood). 2009;28(6):w1141-50. http://dx.doi.org/10.1377/hlthaff.28.6.w1141
http://www.ncbi.nlm.nih.gov/pubmed/19843552
Among nonelderly U.S. adults (ages 25-61), uninsurance rates increased from 13.7 percent in 2000 to 16.0 percent in 2005. Despite the existence of public insurance programs, rates remained high for low-income people reporting serious health conditions (25 percent across years) or disabilities (15 percent). Previous research has established that low-income workers, those facing more stringent Medicaid eligibility requirements, and people employed by smaller firms are more likely than others to lack health insurance. Residents of southern states had even higher rates (32 percent with health conditions, 22 percent with disabilities). Those who did not belong to a federally mandated Medicaid eligibility category were about twice as likely as others to be uninsured overall, and uninsurance among this group increased more rapidly over time.
To address this growing problem, President Barack Obama and leaders in Congress passed health insurance reform legislation that is still taking shape. A common feature of the major proposals at this point is that coverage would be expanded by building on existing arrangements. This approach allows people to keep their current insurance if they wish to do so. The Medicaid program is particularly complicated because it is jointly financed and operated by the federal and state governments and because each state has implemented it differently.
See Table 1.
Ultimately, if Congress decides not to eliminate categorical eligibility restrictions, our results indicate that the preservation of eligibility expansions for people with disabilities or chronic conditions would target a population that is particularly vulnerable to uninsurance and its deleterious effects on health.
By Chris Kaiser, Cardiology Editor, MedPage Today Sep 11, 2013 http://www.medpagetoday.com/TheGuptaGuide/PublicHealth/41539
In the U.S., the top 1% of patients ranked by their healthcare expenses accounted for 21% of total healthcare expenditures in 2010, with an annual mean expenditure of $87,570, according to 2010 Medical Expenditure Panel Survey from the Agency for Healthcare Research and Quality in Rockville, Md. In addition, the top 5% of the U.S. population ranked by healthcare expenses accounted for half of the total of healthcare expenditures, with an annual mean expenditure of $40,876, wrote Steven B. Cohen, PhD, and Namrata Uberoi, MPH, in the Statistical Brief No. 421. Both of these figures are down from 1996, when the top 1% accounted for 28% of the total healthcare expenditures and the top 5% accounted for slightly more than half. The total healthcare expenditures for 2010 were $1.26 trillion.
It is important that policy makers are aware of the the “concentration of healthcare expenditures … to help discern the factors most likely to drive healthcare spending and the characteristics of the individuals who incur them,” the authors noted.
Overall, there was a huge divide between the top and bottom 50% of the population in terms of total healthcare expenses. The top 50% accounted for 97% of total healthcare costs, while the lower 50% accounted for only 3% of the total healthcare expenditures. In terms of income status,
The report also broke down healthcare spending by the number of chronic conditions, age, race/ethnicity, sex, and insurance. The survey found that chronic diseases take a big chunk of healthcare dollars.
The top 5% of those with four or more chronic conditions accounted for 30% of all healthcare expenditures, with an annual mean of $82,000 — a figure that is
A report from 2012 found that Medicare could cut up to 10% of its spending if it focused on chronic disease prevention and coordinated care for those with chronic conditions. Conditioned on insurance coverage status, the uninsured had the most concentrated levels of healthcare expenditures and the lowest annual mean expenses. Regarding public insurance, the top 5% accounted for 56% of the total healthcare expenditures.
GM Kenney, S Zuckerman, D Goin, S McMorrow, Urban Institute May 2012
We use the Behavioral Risk Factor Surveillance System (BRFSS) to examine state-level changes in three key access indicators over the past decade. Specifically, we explore changes in the likelihood of having unmet medical needs due to cost, receiving a routine checkup, and receiving a dental visit for all nonelderly adults and for the subgroup of uninsured adults. We also consider differentials in access between uninsured and insured adults within each state in 2010, and how these differences are reflected in the relationship between access to care and state-level uninsurance rates.
We find that the deterioration in access to care observed in national trends during the past decade was evident in virtually every state in the country. Similarly, consistent with the national trends, the situation deteriorated more for the uninsured than for other adults in most states, which exacerbated the differentials in access and use between the insured and uninsured that had prevailed at the beginning of the previous decade. At the end of the decade, the uninsured in every state were at a dramatic disadvantage relative to the insured across the three access measures we examined. This analysis suggests that the potential benefits of the coverage expansion in the Affordable Care Act (ACA) are large and exist in every state.
We also found that states with higher uninsurance rates have worse access to care for all three measures, which implies that these states have the most to gain from the ACA. In particular, the ACA coverage expansion has the potential to reduce unmet needs due to costs and other cost-related barriers, problems that are more severe in states with high uninsurance rates.
Matthew Buettgens, Dean Resnick, Victoria Lynch, and Caitlin Carroll May 21, 2013
We use the Urban Institute’s American Community Survey – Health Insurance Policy Simulation Model (ACS-HIPSM) to estimate the effects of the Affordable Care Act on the non-elderly at the state and local level. This model builds off of the Urban Institute’s base HIPSM, which uses the Current Population Survey (CPS) as its core data set, matched to several other data sets including the Medical Expenditure Panel Survey-Household Component (MEPS-HC), to simulate changes under ACA. To create HIPSM-ACS, we apply the core behavioral components of the base HIPSM to ACS records to exploit the much larger sample size for more precise estimates at the state and sub-state level. The modeling on the ACS-HIPSM produces projections of coverage changes related to state Medicaid expansions, new health insurance options, subsidies for the purchase of health insurance, and insurance market reforms (see Appendix 1 for more detail on HIPSM).
We simulate eligibility for Medicaid/CHIP and subsidies using the Urban Institute Health Policy Center’s ACS Medicaid/CHIP Eligibility Simulation Model, which builds on the model developed for the CPS ASEC by Dubay and Cook. (Dubay, L. and A. Cook. 2009. “How Will the Uninsured be Affected by Health Reform?” Washington, DC: Kaiser Commission on Medicaid and the Uninsured.)
We simulate both pre-ACA eligibility and the MAGI-based eligibility introduced by the ACA. This allows us to simulate different scenarios for Medicaid maintenance-of-eligibility under the ACA. The distinction between pre-ACA eligible and newly eligible is also important in determining the share of a beneficiary’s costs paid by the federal government.
Using the three-year pooled sample, the model simulates eligibility for comprehensive Medicaid and CHIP coverage or subsidy using available information on the regulations for implementing the ACA, including the amount and extent of income disregards for eligibility pathways that do not change under the ACA and for maintenance-of-eligibility for each program and state in place as of approximately June 2010.
Under the ACA income eligibility is based on the IRS tax definition of modified adjusted gross income (MAGI), which includes the following types of income for everyone who is not a tax-dependent child: wages, business income, retirement income, investment income, Social Security, alimony, unemployment compensation, and financial and educational assistance (see Modeling Unemployment Compensation in the appendix). MAGI also includes the income of any dependent children9 required to file taxes, which for 2009 is wage income greater than $5,700 and investment income greater than $950. To compute family income as a ratio of the poverty level, we sum the person-level MAGI across the tax unit.
Current eligibility is determined based on state rules for 2010. State rules include income thresholds for the appropriate family7 size, asset tests, parent/family status, and the amount and extent of disregards8, for each program and state in place as of the middle of 2010 .
we estimate two separate probit models, each with the following covariates:
The dependent variable is an indicator of non-group non-exchange policy holder status. Again we compare each respondent’s predicted probability to a standard uniform random number and assign enrollment in the non-group non-exchange to those observations with probabilities that exceed the random number. Appendix Table 5 shows the overall new enrollment in the non-group non-exchange coming out of our model. It shows that the large majority of non-group enrollees outside the exchange are expected to come from single-person policyholders.
We develop a model, again based on HIPSM output, to predict which single ESI policy holders in the ACS are likely to switch to a family plan. We restrict our model to HIUs in which there is at least one single policy holder and at least one other member of the HIU that could potentially be covered by an ESI family plan. The eligible dependents include those with baseline non-group or uninsurance that had not already taken up coverage in a previous model. Note that we only model moving from an individual plan to a family plan; we did not model adding a dependent to a current family plan. Within the eligible group of single ESI policy holders, we use the following covariates to estimate the probability that they will switch to a family ESI policy:
These estimates assume that the ACA is fully implemented with the Medicaid expansion in all states and that the same basic implementation decisions are made across the states. At the time of writing, even states such as Massachusetts which have been on the forefront of ACA implementation had not finalized their plans, so any modeling of variation in state decisions would necessarily involve a lot of guesswork. Also, it will take several years for enrollment in new programs such as the exchanges and Medicaid expansion to ramp up so the full effects that are estimated under the simulation model would not be felt until 2016 or later. Enrollment in the initial years would also be affected by state and federal decisions. For example, in the proposed rules released by HHS in January 2012, the deadline for establishing unified eligibility and enrollment between Medicaid and the exchange was pushed back to 2015.
Ginde AA, Lowe RA, Wiler JL.
Department of Emergency Medicine, University of Colorado School of Medicine, Aurora, CO. http://www.ncbi.nlm.nih.gov/pubmed/22450213
Arch Intern Med. 2012 Apr 23;172(8):642-7. http://dx.doi.org/10.1001/archinternmed
Recent events have increased the instability of health insurance coverage. We compared emergency department (ED) use by newly insured vs continuously insured adults and by newly uninsured vs continuously uninsured adults. Overall, 20.7% of insured adults and 20.0% of uninsured adults had at least 1 ED visit. However, 29.5% of newly insured adults compared with 20.2% of continuously insured adults had at least 1 ED visit. Similarly, 25.7% of newly uninsured adults compared with 18.6% of continuously uninsured adults had at least 1 ED visit. After adjusting for demographics, socioeconomic status, and health status, recent health insurance status change was independently associated with greater ED use for newly insured adults (incidence rate ratio [IRR], 1.32; 95% CI, 1.22-1.42 vs continuously insured adults) and for newly uninsured adults (IRR, 1.39; 95% CI, 1.26-1.54 vs continuously uninsured adults). Among newly insured adults, this association was strongest for Medicaid beneficiaries (IRR, 1.45) but was attenuated for those with private insurance (IRR, 1.24) (P < .001 for interaction). Recent changes in health insurance status for newly insured adults and for newly uninsured adults were associated with greater ED use.
Catherine Hoffman, Julia Paradise
Annals of the New York Academy of Sciences 2008; 1136. http://dx.doi.org/10.1196/annals.1425.007
Reducing the Impact of Poverty on Health and Human Development: Scientific Approaches pages 149–160, June 2008
In the United States, where per capita health care costs are the highest in the world and continue to escalate, health insurance has become nearly essential. Having reasonable access to health care rests on many factors: the availability of health services in a community and personal care-seeking behavior, for example. However, these and other factors are often trumped by whether a person can afford the costs of needed care. Health insurance enables access to care by protecting individuals and families against the high and often unexpected costs of medical care, as well as by connecting them to networks and systems of health care providers.
Health insurance, poverty, and health are all interconnected in the United States. This article synthesizes a large and compelling body of health services research, finding a strong association between health insurance coverage and access to primary and preventive care, the treatment of acute and traumatic conditions, and the medical management of chronic illness. Moreover, by improving access to care, health insurance coverage is also fundamentally important to better health care and health outcomes. Research connects being uninsured with adverse health outcomes, including declines in health and function, preventable health problems, severe disease at the time of diagnosis, and premature mortality.
Most working-age adults obtain health coverage for themselves and their dependents as a benefit of employment. However, this benefit has been gradually eroding as health premiums, in tandem with higher health care costs, grow at a rate far outpacing rates of general inflation and wages. In 2005, 61% of the nonelderly had insurance through an employer, down from 66% in 2000.1 Low-wage workers are far less likely than higher-wage workers to have access to job-based coverage. In 2005, more than half of workers in poor families and more than a third of those in near-poor families had no offer of job-based coverage in the family.2 When it is available, health insurance is often unaffordable for low-income people, whose household budgets are strained to meet food, housing, and other basic needs.
http://onlinelibrary.wiley.com/store/10.1196/annals.1425.007/asset/image_n/NYAS_1136007_f1.gif Source: Kaiser Commission on Medicaid and the Uninsured/Urban Institute analysis of Current Population Survey, March 2007.
Those with Medicaid coverage are the most likely to be in fair or poor health because the program’s eligibility requirements include being severely disabled and/or low-income (fig. 2).
http://onlinelibrary.wiley.com/store/10.1196/annals.1425.007/asset/image_t/NYAS_1136007_f2_thumb.gif Source: Kaiser Commission on Medicaid and the Uninsured/Urban Institute analysis of Current Population Survey, March 2007.
The model for healthcare reform was selected from that enacted in Massachusetts. Important statements from the Massachusetts Act are as follows:
to promote patient-centeredness by, including, but not limited to, establishing
A provision called the individual mandate, requires all Americans to buy some form of health insurance. Whether it is constitutional was in question before the Supreme Court. While the mandate is separate from the provision allowing young adults up to the age of 26 to be covered under their parents’ policies, the court could have decided to scrap the entire law — instead of just the mandate — leaving millions of young adults in the lurch. The mandate was upheld.
For many young adults, affording health insurance on their own will be particularly difficult. The unemployment rate for young adults age 16 to 24 was 16.4% in March, twice the national average for the population as a whole. And many of those who do find jobs, often aren’t being offered health benefits. Less than a quarter, or 24%, of workers between the ages of 19 and 25 were offered health insurance by their employers in 2010, down from 34% in 2000, according to the Employee Benefit Research Institute, an independent public policy organization. Meanwhile, nearly 57% of the rest of the working population between the ages of 26 and 64 were covered.
Wed, 09/11/2013
Delivery of cancer care in the U.S. is facing a crisis stemming from a combination of factors—a growing demand for such care, a shrinking oncology work force, rising costs of cancer care, and the complexity of the disease and its treatment, says a new report from the Institute of Medicine. The report recommends ways to respond to these challenges and improve cancer care delivery, including by strengthening clinicians’ core competencies in caring for patients with cancer, shifting to team-based models of care, and communicating more effectively with patients.
Adding to stresses on the system is the complexity of cancer and its treatment, which has grown in recent years with the development of new therapies targeting specific abnormalities often present only in subsets of patients. Incorporating this new information into clinical care is challenging, the report says. Given the disease’s complexity, clinicians, patients, and patients’ families can find it difficult to formulate care plans with the necessary speed, precision, and quality; as a result, decisions about cancer care are often not sufficiently evidence-based.
Another challenge is the cost of cancer care, which is rising faster than other sectors of medicine, having increased from $72 billion in 2004 to $125 billion in 2010, says the report. The single largest insurer for those over 65, the Centers for Medicare and Medicaid Services (CMS), is struggling financially.
The report recommends strategies for improving the care of cancer patients, grounded in six components of high-quality cancer care. The components are ordered based on the priority level with which they should be addressed.
Institute of Medicine Calls for Immediate Reforms in Health Care (2012)
Dan Munro, Forbes
According to the Deloitte Center for Health Solutions, this number has been historically underreported – by a significant amount. In their report (The Hidden Costs of U.S. Health Care), they cite two important components that have not been included in tradtional calculations. The first is out-of-pocket spending by consumers on professional services and the second is the “imputed value of supervisory care provided to a friend or family member.” Using a conservative annual growth rate of 4% (from Deloitte’s baseline year of 2010), here’s what Deloitte suggests is our real NHE.
http://blogs-images.forbes.com/danmunro/files/2012/12/NHEbyDCforHS1.png
The Kaiser Family Foundation also provided a comparison of cumulative increases in health insurance premiums – relative to Workers’ Contributions, Inflation and Workers’ Earnings (from 2000 to 2012).
http://blogs-images.forbes.com/danmunro/files/2012/12/percentageincreasekff.png
Another annual chart is Medscape’s Physician Compensation Report: 2012 Results (slide #2 – 2011 data).
Judith Feder, Ph.D.
By Merrill Matthews and Mark E Litow, Forbes
Thanks to mandates that take effect in 2014, premiums in individual markets will shoot up.
Central to ObamaCare are requirements that
Guaranteed issue incentivizes people to forgo buying a policy until they get sick and need coverage (and then drop the policy after they get well). While ObamaCare imposes a financial penalty—
The result will be insurance pools that are smaller and sicker, and therefore more expensive.
How do we know these requirements will have such a negative impact on premiums? Eight states—New Jersey, New York, Maine, New Hampshire, Washington, Kentucky, Vermont and Massachusetts—enacted guaranteed issue and community rating in the mid-1990s and wrecked their individual (i.e., non-group) health-insurance markets.
States won’t experience equal increases in their premiums under ObamaCare. Ironically, citizens in states that have acted responsibly over the years by adhering to standard actuarial principles and limiting the (often politically motivated) mandates will see the biggest increases, because their premiums have typically been the lowest.
While ObamaCare won’t take full effect until 2014, health-insurance premiums in the individual market are already rising, and not just because of routine increases in medical costs. Insurers are adjusting premiums now in anticipation of the guaranteed-issue and community-rating mandates starting next year. There are newly imposed mandates, such as the coverage for children up to age 26, and what qualifies as coverage is much more comprehensive and expensive. Consolidation in the hospital system has been accelerated by ObamaCare and its push for Accountable Care Organizations.
Unlike the federal government, health insurers can’t run perpetual deficits. Something will have to give, which will likely open the door to making health insurance a public utility completely regulated by the government.
Merrill Matthews, Resident Scholar at Institute for Policy Innovation, Forbes
Subsidies cover a portion of the cost of health insurance, up to a maximum out of pocket for the family. The amount of the subsidy is based both on the cost of coverage and income. There has been a lot of head scratching over how to deal with the fact
So how does the government determine the correct level of subsidy? The PPACA has so many unknowns in the mix that actuaries don’t know how much to charge. This is a problem for setting annual rates.
Traditionally in the individual market, where people buy their own (i.e., non-group) health coverage, applicants sign a contract and the insurance company guarantees that premium for a year. No more. Health insurers started sending out notices in January informing insurance brokers and agents that
After carefully evaluating its individual market and rates, Aetna decided to discontinue its offer of an initial 12-month rate guarantee. This change applies to policies with a January 15, 2013 or later effective date, in all states where plans are sold. Existing members who are currently in a rate guarantee period will not be affected. Aetna published a notice saying in part, “While the policies will not have a 12-month rate guarantee, we fully expect the rates to stay the same until December 31, 2013.” While that announcement may alleviate the concerns of some, Aetna is not the only company ending the rate guarantee.
While the individual market has been relatively small (about 19 million people, according to the Employee Benefit Research Institute) compared to those with employer-based coverage (about 156 million), most honest analysts expect millions of employers to drop coverage and dump their employees into the individual market.
By David Pittman, Washington Correspondent, MedPage Today. Aug 27, 2013
An accountable care organization (ACO) established by a private insurer reduced costs of care for Medicare enrollees, a study in Massachusetts found. Providers participating in the Alternative Quality Contract (AQC) — an early commercial ACO backed by Blue Cross Blue Shield of Massachusetts — reduced spending on Medicare beneficiaries by 3.4% after 2 years compared with enrollee costs at nonparticipating providers, ( Journal of the American Medical Association).
Medicare enrollees served by 11 provider groups in the AQC from 2007-2010 were compared with Medicare patients served by non-AQC providers. The study looked at quarterly medical spending and five quality measures, such as avoidable hospitalizations and 30-day readmissions. The AQC started in 2009 with providers bearing a financial risk for spending in excess of a global budget, gaining from spending below the budget, and receiving rewards for meeting performance targets.
Per-enrollee spending was $150 higher for patients of AQC providers than for those of non-AQC providers before the ACO took effect in 2009. Year-1 savings weren’t significant (P=0.18), but
Savings came from reductions in outpatient services, including
Also, savings were greater in patients with five or more conditions (P=0.002). Previous research showed the AQC reduced quarterly spending on Blue Cross patients by $27 per enrollee in year two.
ACOs have received sour press of late as nine of 32 pioneer ACOs — Medicare’s first and most advanced ACO provider groups — told the agency last month they want to leave the program. Despite that outlook and ACOs’ struggles to achieve consistent cost savings, Medicare-led ACOs (253) now outnumber commercial ACOs (235), according to a recent report from the consulting group Leavitt Partners.
By David Pittman, Washington Correspondent, MedPage Today. Aug 22, 2013
Models such as PCMHs, ambulatory intensive care units, and medical neighborhoods should thrive on connecting patients’ clinical care with broader social services that can help provide better housing and other benefits. (ReportingOnHealth.org)
“The medical neighborhood coordinates care for patients at a community level, working with organizations in the community that can help expand the impact of healthcare and, more specifically, focus on the social determinants,” Manchanda (founder and president of HealthBegins) said. “And this fits more into the model of community-centered health home.” (Medicaid Medical Home)
Evidence is growing linking people’s physical environments and social conditions to their health. Three in four doctors wished the healthcare system would pay for the cost associated with connecting patients with needed social services. That aspect of the situation is improving with advent of PCMHs and other delivery models which pay for the care coordination of the most at-risk patients. This will be addressed by electronic medical records (EMRs) will help collect social history if EMR vendors provide an avenue for it to be requested and stored. The facilitation of internet communications will allow clinicians to share data with social services about their patients, and connect with patients themselves.
Aegis Health Group. 2013; 5(7).
Corporate America has long viewed the healthcare system as one of the biggest drains on the economy—and on the profitability of businesses nationwide. With the advent of Accountable Care Organizations as the model of the future for managing overall population health, hospitals are ideally positioned to harness this opportunity
In this paper hospital executives will learn about new approaches to this challenge along with some simple, tried-and-true rules of the road for attaining mutually beneficial partnerships with employers.
COST OF POOR HEALTH IN BILLIONS
They are ready to take control of the issues and turn them from business detractors to business advantages. Consider this:
On the flip side workers have felt the sting as well. With more employers scaling back benefits or selecting higher-deductible plans, employee out-of-pocket expenses and payroll deductions for premiums increased 82 percent, averaging $5,000 per year according to the same Towers Watson survey. The escalation of healthcare costs almost mirrors the increasingly poor health of U.S. adults. Only one in seven workers are of a normal weight and free from any chronic health conditions, such as diabetes, hypertension or heart disease.
A full 62 percent of employers want to increase employee wellness and preventive health programs. Hospitals are well positioned to provide
As the country moves toward an accountable care model of healthcare delivery, the timing has never been better for hospitals to take a leadership role in developing population health programs in the workplace and beyond.
Posted in Accountable Care Organizations, Affordable Care Act, Ecosystems & Industrial Concentration in the Medical Device Sector, Federal Budget Appropriations, Health Economics and Outcomes Research, Health Law & Patient Safety, Healthcare costs and reimbursement, HealthCare IT, Healthcare Reform, Indigent Nutrition, International Global Work in Pharmaceutical, Interviews with Scientific Leaders, Medical and Population Genetics, Medical Devices R&D Investment, Medicare and Medicaid, Nutrition, Personalized and Precision Medicine & Genomic Research, Pharmaceutical Industry Competitive Intelligence, Pharmaceutical R&D Investment, Population Health Management, Genetics & Pharmaceutical, Population Health Management, Nutrition and Phytochemistry, Prescription Drugs Costs, Regulated Clinical Trials: Design, Methods, Components and IRB related issues, Skilled Nursing Facilities, Technology Capital Expenses, Technology Transfer: Biotech and Pharmaceutical, Uncategorized, Uninsured and Underinsured, tagged aca, Accountable Care Organization, Accountable Care Organizations, Affordable Care Act, eldercare, Flexner Report, health care budget, insurance exchanges, integrated services in community, Joseph Goldberger, managing cost and quality, medical education, Medical research, National Institutes of Health, Patient Protection and Affordable Care Act, payment for medical care, sequestration on September 13, 2013| Leave a Comment »
Writer and Curator: Larry H. Bernstein, MD, FCAP
and
Curator and Editor: Aviva Lev-Ari, PhD, RN
Article ID #78: The Affordable Care Act: A Considered Evaluation. The Implementation of the ACA, Impact on Physicians and Patients, and the Dis-Ease of the Accountable Care Organizations. Published on 9/13/2013
WordCloud Image Produced by Adam Tubman
INTRODUCTION
This discussion is the second of two distinct chapters. The first is a clarification of what is contained in the Accountable Care Act (ACA), the model of care it is crafted from, the insurance mandate, the inclusion of groups considered high risk and uninsured, the inclusion of groups low risk and uninsured, and the economics involved in going from a fractured for profit health care industry to a more stable coverage for patients with problems in creating a new workable model from an actuarial standpoint, with the built in complexity of not just age, but education, achievement in the workforce, and a consolidating hospital and eldercare industry, the unpredictability of disease evolution, and add on the multicultural and social structures, as well as rapidly evolving communications and computational platforms needed to transform the U.S. Healthcare system.. The second is taken from selected articles on the care process in the New England Journal of Medicine about the cost and consequences for improving quality at lower cost. Dr. Justin Pearlman has chosen this topic to become as the Second Chapter in the Cardiovascular Disease Volume and Dr. Aviva Lev Ari has selected the sub-universe of sources been elaborated on in this Chapter
There are inherent problems at looking at this from a systems point of view, mainly impacted by the relationship of providers to hospitals and clinics, and by the relationships of insurers to the patients and providers in an Accountable Care Organization (ACO) model. These relationships have been evolving for many decades, first with the increased availability of highly skilled medical specialists trained in numerous university-based programs funded by Training Grants from the National Institutes of Health, then a high concentration of these skilled physicians in metropolitan locations, where there was an adequate patient-base for developing groups of refering physicians. Prior to WWII, there were many Asian physicians receiving their postgraduate training in the U.K. The number of foreign graduates coming to the U.S. Increased enormously with the opportunities that opened up in U.S. The first change in medical education that created a science-based professional came after the Flexner Report in 1910, sponsored by the Carnegie Endowment. Many aspects of the present-day American medical profession stem from the Flexner Report and its aftermath.The Report (also called Carnegie Foundation Bulletin Number Four) called on American medical schools to enact higher admission and graduation standards, and to adhere strictly to the protocols of mainstream science in their teaching and research. Joseph Goldberger discovered the cause of pellagra in 1916. When the 1918 influenza pandemic struck Washington, physicians from the then PHS laboratory were pressed into service treating patients in the District of Columbia because so many local doctors fell ill.
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In 1930, the Ransdell Act changed the name of the Hygienic Laboratory to National Institute (singular) of Health (NIH) and authorized the establishment of fellowships for research into basic biological and medical problems. The roots of this act extended to 1918, when chemists who had worked with the Chemical Warfare Service in World War I sought to establish an institute in the private sector to apply fundamental knowledge in chemistry to problems of medicine. In 1926, after no philanthropic patron could be found to endow such an institute, the proponents joined with Louisiana Senator Joseph E. Ransdell to seek federal sponsorship. The truncated form in which the bill was finally enacted in 1930 reflected the harsh economic realities imposed by the Great Depression. Nonetheless, this legislation marked a change in the attitude of the U.S. scientific community toward public funding of medical research.
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Vaccines and therapies to deal with tropical diseases were also critically important to the WWII war effort by the PHS. At the NIH’s Rocky Mountain Laboratory in Hamilton, Montana, yellow fever and typhus vaccines were prepared for military forces. In Bethesda as well as through grants to investigators at universities a synthetic substitute for quinine was sought to treat malaria. Research in the Division of Chemotherapy revealed that sodium deficiency was the critical element leading to death after burns or traumatic shock. This led to the widespread use of oral saline therapy as a first-aid measure on the battlefield. NIH and military physiologists collaborated on research into problems related to high altitude flying. As the war drew to a close, PHS officials guided through Congress the 1944 Public Health Service Act, which defined the shape of medical research in the post-war world. Two provisions in particular had an impact on the NIH. First, in 1946 the successful grants program of the NCI was expanded to the entire NIH. From just over $4 million in 1947, the program grew to more than $100 million in 1957 and to $1 billion in 1974. The entire NIH budget expanded from $8 million in 1947 to more than $1 billion in 1966. Between 1955 and 1968. In this period, there was expansion of the NIH extramural budget, as well, and the grants dispursed were in support of developing the medical faculty of the future. It has nothing to do with then organization of the practice of medicine, but it has contributed much to the widespread quality of american medical education.
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As the cost of healthcare was increasing, mainly after the Korean and Vietnam War periods, there was a medically initiated concept of a National not-for-profit health maintenance organization (HMO), which would be modeled after the likes of Mayo Clinic, Cleveland Clinic, the Kaiser Permanente Plan, and Geisinger. But the insurance industry was already mature, and the hospitals were closely tied to Aetna, CIGNA, and Blue Cross Blue Shields, which had the actuarial pieces needed. Then an HMO industry emerged with a for-profit motive. As the U.S. Became enmesshed in two military engagements in Iraq and Afganistan for a full decade, there was a fierce competition between the need to support military requirements and the need to support the welfare of the community, with brilliant accelerated achievements that brought the Human Genome Project to a successful conclusion in 2003, and from that emerged advances in both clinical laboratory diagnostics and imaging, and which portends to continuing significant advances in treatments in cardiology, surgery, endocrinology, and cancer. In order to succeed, there has been a redesign or rearrangement of how these services are delivered, with a business model intended to – in time – bring down costs, and to also improve quality. Ironically, there is an insufficiency of primary care physicians, even considering internal medicine, pediatrics, obstetrics, and general surgery, as well as osteopathic physicians.
Jonathan Oberlander, Ph.D., and Marisa Morrison, B.A.
N Engl J Med 2013; 369:105-107July 11, 2013 http://dx.doi.org/10.1056/NEJMp1306051
The Affordable Care Act (ACA) established the IPAB as a 15-member, nonelected board. Among other duties, the IPAB is empowered to recommend changes to Medicare if projected per-beneficiary spending growth exceeds specified targets. If Congress does not enact legislation containing those proposals or alternative policies that achieve the same savings, the IPAB’s recommendations are to be implemented by the secretary of health and human services. President Obama has proposed strengthening the board’s role by lowering the Medicare spending targets that would trigger IPAB action.
Because the board is prohibited by law from making recommendations that raise revenues, increase cost sharing of Medicare beneficiaries, or restrict benefits and eligibility, it is expected to focus on savings from medical providers. In January 2013, the GOP adopted a House rule declaring that the IPAB “shall not apply” in the current Congress, thereby rejecting the special procedures that the ACA had established for congressional consideration of IPAB recommendations.
On April 30, the chief actuary of the Centers for Medicare and Medicaid Services released a report projecting Medicare spending growth during 2011–2015. According to the report, per-person Medicare spending will grow at an average rate of 1.15% during that period, far below the target growth rate set by the ACA — the average of the Consumer Price Index (CPI) and the Medical CPI (see graph).
Projected Growth in Medicare Per Capita Spending, the Consumer Price Index (CPI), and the Medical CPI, 2011–2015.
The rate of increase in Medicare expenditures per enrollee has slowed since 2006, and because Medicare spending growth has moderated, the IPAB will be irrelevant to cost containment. 3 years after the ACA’s enactment, the IPAB still has no members. If no members are appointed, the power to recommend changes to Medicare when spending targets are exceeded does not disappear: it reverts to the secretary of health and human services.
The board’s appeal lies largely in its aspiration to remove politics from Medicare — to create a policymaking process that is informed by experts and insulated from pressures outside their professional overview. If Medicare spending growth accelerates, the IPAB’s role could expand. But that future is uncertain.
The Road Ahead for the Affordable Care Act
John E. McDonough, Dr.P.H.
N Engl J Med 2012; 367:199-201 http://dx.doi.org/10.1056/NEJMp1206845
http://www.nejm.org/doi/full/10.1056/NEJMp1206845
The Affordable Care Act (ACA), the U.S. health care reform law enacted in 2010, was upheld as constitutional by the U.S. Supreme Court on June 28, 2012. As a result of the Court’s ruling –
stand unaltered despite the Court-ordered switch in the basis for constitutional legitimacy from the Commerce Clause to Congress’s taxing authority.
One consequential outcome of the ruling is the continuing benefit, and harm averted, for millions of Americans from ACA provisions that have already been implemented. Those benefiting include more than 6 million young adults enrolled in their parents’ insurance plans, 5.2 million Medicare enrollees who have saved on prescription-drug costs because of the shrinking Part D “doughnut hole,” 600,000 new adult Medicaid enrollees in seven states that have already expanded Medicaid eligibility, 12.8 million consumers who will receive more than $1 billion in insurance-premium rebates, and many others.
Also undisturbed are the ACA’s numerous system reforms, such as accountable care organizations, patient-centered medical homes, the Prevention and Public Health Fund, and the Patient-Centered Outcomes Research Institute. Since the ACA’s passage, health system innovation has surged — a dynamic that would have been undermined by a negative Court ruling.
The biggest change involves Medicaid. The ACA required that Medicaid serve nearly all legal residents with incomes below 138% of the federal poverty level. As a result, there is a new inequity in the health system: by 2014, all Americans will have guaranteed access to affordable health insurance except adults with incomes below the poverty level who were previously ineligible for Medicaid (those with incomes between 100 and 138% of the poverty level will be allowed to obtain coverage through insurance exchanges). States have strong economic incentives to expand Medicaid, since the federal government will pay 100% of expansion costs between 2014 and 2016. By 2020, the federal share will drop to no less than 90% — much more generous than the 50 to 83% that the federal government contributes for traditional Medicaid and the Children’s Health Insurance Plan.
The current implementation queue includes writing definitions and rules for private health insurance markets, clarifying rules for determining required “essential health benefits,” explaining how employer-responsibility provisions will be devised, and much more. The ACA is the first U.S. law to attempt comprehensive reform touching nearly every aspect of our health system. The law addresses far more than coverage, including health system quality and efficiency, prevention and wellness, the health care workforce, fraud and abuse, long-term care, biopharmaceuticals, elder abuse and neglect, the Indian Health Service, and other matters.
Encouraging competition among health plans, even if one of them is “public,” will also fail to solve the cost problem. With the exception of highly integrated organizations, such as Kaiser Permanente, health plans have only two tools to control costs: financial disincentives for patients and fee reductions for providers. Acceptable out-of-pocket maximums, however, vitiate economic incentives to restrain use, particularly for expensive care such as inpatient care. Unable to alter provider behavior, health plans primarily try to avoid enrolling people who are likely to need costly care.
McDonough J.E.N Engl J Med 2013; 368:1269-1271 http://dx.doi.org/10.1056/NEJMp1303266
In August 2011, in an agreement to raise the nation’s debt ceiling, bipartisan majorities in the House and Senate approved the Budget Control Act of 2011 (BCA) to reduce the deficit by $1.2 trillion between 2013 and 2021. The BCA established a threat of across-the-board cuts, or “sequestration,” if the Joint Select Committee on Deficit Reduction failed to approve, and Congress to enact, alternative reductions. Sequestration became operational on March 1. Of the $1.2 trillion in cuts, $216 billion will be reductions in debt-service payments, and the remaining $984 billion will be split evenly over 9 years at $109 billion per year, and further adjusted and split evenly between cuts to national defense and nondefense functions at $42.667 billion each.
The $42.667 billion per year in nondefense cuts will not fall equally on all health-related government programs. Nonexempt and nondefense discretionary funding faces reductions of 7.6 to 8.2% in this fiscal year; certain programs such as Medicare and community health centers will have 2% reductions; and certain programs such as Medicaid and the Veterans Health Administration are exempt.
Impact of Budget Sequestration on Key Federal Health and Safety Programs, Fiscal Year 2013.
Medicare funding will be cut by 2% ($11.08 billion) through reductions in payments to hospitals, physicians, and other health care providers, as well as insurers participating in Medicare Advantage (Part C). The BCA prohibits cuts affecting premiums for Medicare Parts B and D, cost sharing, Part D subsidies, and Part A trust-fund revenues. The sequestration cuts arrive just as Medicare is beginning to fully implement the savings and cuts required by the Affordable Care Act (ACA), which the Congressional Budget Office estimates will slow Medicare’s rate of growth by $716 billion between 2013 and 2022. The National Institutes of Health (NIH) faces an 8.2% across-the-board reduction for the 7 months remaining in fiscal 2013, equaling cuts of $1.55 billion.
The Centers for Disease Control and Prevention (CDC), which is still recovering from major budget reductions in 2011, anticipates effective reductions of 8 to 10% for the remainder of the year. The American Public Health Association has projected that the reductions could result in 424,000 fewer HIV tests (the CDC funded 3.26 million in 2010) and 50,000 fewer immunizations for adults and children (from a baseline of about 300 million), elimination of tuberculosis programs in 11 states, and shutting down of the National Healthcare Safety Network.
Unaffected for all 9 years of the sequester are most expenses associated with the ACA. Medicaid is exempt, as is funding for its expansion, beginning next January, to all lower-income Americans in states that choose to participate. Also exempt are private insurance subsidies that will be available next January through new health insurance exchanges, because they were designed as refundable tax credits, another BCA-exempt category. Finally, the Children’s Health Insurance Plan, the Supplemental Nutrition Assistance Program, Temporary Assistance to Needy Families, and Supplemental Security Income are all exempt.
Rosenbaum S.N Engl J Med 2012; 367:2368-2369 http://dx.doi.org/10.1056/NEJMp1213901
Medicaid is a veteran of decades of warfare over its size and cost. Nevertheless, the program now plays a vital role in the U.S. health care system and a foundational role in health care reform. The central question, as we approach a major debate over U.S. spending and federal deficits, is how to preserve this role and shield Medicaid from crippling spending reductions. The Budget Control Act, which provides the initial framework for this debate, insulates Medicaid from sequestration. Budgetary protections for Medicaid date to the 1980s, but today’s politics are less tolerant of programs for poor and vulnerable populations. Medicaid is also at a deep political disadvantage. Medicaid is unequaled among federal grant programs: more than 60 million children and adults rely on the program, and it’s projected to grow to 80 million beneficiaries by 2020 if all states adopt the eligibility expansion in the Affordable Care Act (ACA). Medicaid’s cost is driven by high enrollment, not excessive per capita spending.2 As a result, there’s very little money to wring out of Medicaid without shaking its structure in ways that reduce basic coverage. Medicaid is part of the base on which health care reform rests; if it is not expanded per the ACA, the nation will lose its chance at near-universal health insurance coverage, which is essential to achieving systemwide savings and halting a $50 billion annual cost shift to insurers and patients. Deep federal spending reductions could lead states to abandon Medicaid expansion as a result of a confluence of factors —
Considerable evidence shows its effectiveness: most recently, a study by Sommers et al. documented its positive effects on health and health care. Experts in Medicaid spending also acknowledge the program’s operational efficiencies, achieved by states through the aggressive use of managed care and strict controls on spending for long-term care. Much of the health care that Medicaid beneficiaries receive is furnished through safety-net providers such as community health centers, which are highly efficient and accustomed to operating on tight budgets with only limited access to costly specialty care. Furthermore, Medicaid’s physician payments are substantially lower than those from commercial insurers and Medicare — a disparity that unfortunately limits provider participation even as it helps to keep per capita spending low. Indeed, the CBO has found that insuring the poor through Medicaid will cost 50% less per capita than doing so through tax-subsidized private insurance plans offered through state health insurance exchanges.
The essential task is to thread the needle by accelerating efficiency reforms in health care payment and organization that, in turn, can generate savings over time while not damaging Medicaid’s role as a pillar of health care reform. Of particular importance is a heightened focus, begun under the ACA, on reforms that emphasize community care for millions of severely disabled children and adults, including patients who are dually enrolled in Medicare and Medicaid and who rely heavily on long-term institutional care.
Wilensky G.R. N Engl J Med 2012; 367:1479-1481 http://dx.doi.org/10.1056/NEJMp1210763
U.S. health care suffers from three major problems: millions of people go without insurance, health care costs are rising at unaffordable rates, and the quality of care is not what it should be. The Affordable Care Act (ACA) primarily addresses the first — and easiest — of these problems by expanding coverage to a substantial number of the uninsured. Solutions to the other two remain aspirations. The ACA’s primary accomplishment is that approximately 30 million previously uninsured people may end up with coverage — about half with subsidized private coverage purchased in the mostly yet-to-be-formed state insurance exchanges and the other half through Medicaid expansions. The law’s most controversial provision remains the individual mandate, which requires people either to have insurance coverage or to pay a penalty. The penalty for not having insurance is very small, particularly for younger people with modest incomes. It would have been smarter to mimic Medicare’s policies: seniors who don’t purchase the voluntary parts of Medicare covering physician services and outpatient prescription drugs during the first year in which they lack comparable coverage must pay a penalty for every month they have gone without coverage whenever they finally do purchase it.
Despite widespread recognition that fee-for-service reimbursement rewards providers for the quantity and complexity of services and encourages fragmentation in care delivery, the ACA retains all the predominantly fee-for-service reimbursement strategies currently used in Medicare. Much of the coverage expansion is financed through Medicare budget savings, which are produced by reducing the fees paid by Medicare to institutional providers such as hospitals, home care agencies, and nursing homes — but using the same perverse reimbursement system currently in place. Reducing payments to institutional providers should not be confused with lowering the cost of providing care.
The ACA also provides Medicare “productivity adjustments,” which assume that inflation adjustments can be reduced over time because institutions will become more productive, whether or not hospitals and other providers actually find ways to increase their productivity. Unless these institutions find ways to reduce costs, lower Medicare reimbursements will force providers to bargain for higher payments from private insurers. And eventually, seniors’ access to services will be threatened. The Medicare actuary expects that 15% of institutional providers will lose money on their Medicare business by 2019, and the proportion will increase to 25% by 2030 — a situation that he calls unsustainable
Most troubling, the ACA contains no reform of the way physicians are paid, which is the most dysfunctional part of the Medicare program. Through the Resource-Based Relative Value Scale, physicians are reimbursed on the basis of service codes, and payment for each physician service is reduced whenever aggregate spending on physician services exceeds a prespecified limit. This system disregards whether clinicians are providing low-cost, high-value care for patients. Given physicians’ key role in providing patient care, it’s impossible to imagine a reformed delivery system without one that rewards them for providing clinically appropriate care efficiently.
What is needed are reforms that create clear financial incentives that promote value over volume, with active engagement by both consumers and the health care sector. Market-friendly reforms require empowering individuals, armed with good information and nondistorting subsidies, to choose the type of Medicare delivery system they want. Being market-friendly means allowing seniors to buy more expensive plans if they wish, by paying the extra cost out of pocket, or to buy coverage in health plans with more tightly structured delivery systems at lower prices if that’s what suits them.
John K. Iglehart N Engl J Med 2012; 366:1562-1563 http:dx.doi.org/10.1056/NEJMp1114236
http://www.nejm.org/doi/full/10.1056/NEJMp1114236
Disparate voices from the White House, a national fiscal commission, Congress, a Medicare advisory body, private foundations, and academic medical leaders are advocating changes to Medicare’s investment in graduate medical education (GME), which currently totals $9.5 billion annually. They offer various prescriptions, including reducing federal support, developing new achievement measures for which GME programs should be held accountable, and seeking independent assessment of the governance and financing of training programs.
The influential GME community has withstood most past efforts to change Medicare’s GME policies. But recognizing today’s more challenging political environment, the Association of American Medical Colleges (AAMC) has begun discussing alternative methods of financing GME that could better align training with the future health care delivery system and address U.S. workforce needs. The association is also examining the influence of student debt on the enrollment of a diverse student body.
When Congress enacted Medicare in 1965, it assigned to the program functions that reached well beyond its mission of financing health care for the elderly. One function was supporting GME, at least until the society at large undertook “to bear such education costs in some other way.” Almost 50 years later, Medicare remains the largest supporter of GME, providing both direct payments to hospitals that cover medical education expenses related to the care of Medicare patients (about $3 billion per year) and an indirect medical education (IME) adjustment to teaching hospitals for the added patient-care costs associated with training (about $6.5 billion).
In its 2013 budget, unveiled on February 13, 2012, the Obama administration proposed reducing Medicare’s IME adjustment by $9.7 billion over 10 years, beginning in 2014, citing a report from the Medicare Payment Advisory Commission (MedPAC) indicating that Medicare’s IME adjustments “significantly exceed the actual added patient care costs these hospitals incur.” The administration also proposed that the secretary of health and human services be granted the authority to assess GME programs’ performance in instilling in residents the necessary skills to promote high-quality health care. Similarly, MedPAC had recommended redirecting about half the IME adjustments ($3.5 billion) into “incentive payments” that GME programs could earn by meeting performance standards. The Obama budget would also eliminate coverage of the IME expenses of free-standing children’s hospitals with pediatric residency programs — which do not treat Medicare patients — reducing their federal support by 66% (to $88 million). Moreover, Congress has revealed its uncertainty over how to change federal workforce policy. In the Affordable Care Act (ACA), Congress emphasized the importance of expanding the primary care workforce. But legislators rejected the AAMC’s call to expand the number of Medicare-funded GME positions by 15% in response to reported physician shortages in some specialties.
On December 21, seven senators — Democrats Michael Bennet (CO), Jeff Bingaman (NM), Mark Udall (CO), and Tom Udall (NM) and Republicans Mike Crapo (ID), Chuck Grassley (IA), and Jon Kyl (AZ) — sent a letter to the Institute of Medicine (IOM) encouraging it to “conduct an independent review of the governance and financing of our system of [GME].” They urged the IOM to explore subjects including accreditation; reimbursement policy; the use of GME to better predict and ensure adequate workforce supply in terms of type of provider, specialty, and demographic mix; GME’s role in care of the underserved; and use of GME to ensure the creation of a workforce with the skills necessary for addressing future health care needs. The senators emphasized their interest “in IOM’s observations about the uneven distribution of GME funding across states based on need and capacity, and how to address this inequity.” In an interview, Bingaman said he initiated the letter for the same reasons he had championed creation of a National Health Care Workforce Commission as part of the ACA: to strengthen the government’s resolve to do “a more credible job of assessing workforce shortages” and because he believes Medicare’s GME policies are “outmoded.”
The priorities cited in the IOM letter parallel some of the recommendations of a group of academic medical leaders who gathered at two conferences underwritten by the Josiah Macy Jr. Foundation. At the first conference, in October 2010, the top recommendation was that “an independent external review of the goals, governance, and financing of the GME system should be undertaken by the Institute of Medicine, or a similar body.”3 George Thibault, president of the Macy Foundation, says the group concluded that “because GME is a public good and is significantly financed with public dollars, the GME system must be accountable to the needs of the public.” Acknowledging that some people in academic medicine “favor a behind-the-scenes discussion of GME reform alternatives,” Thibault noted, “I believe we should be upfront, providing examples of change that could influence the thinking of policymakers.” The foundation awarded the IOM $750,000 — about half the support it needs for the GME study.
Among subjects under discussion are the collection of more data highlighting the importance of the safety-net functions and unique services of academic medical centers and the creation of a long-term vision for GME financing that is more closely aligned with emerging care delivery models, such as accountable care organizations. The association is also revisiting a potential financial model under which all health care payers would explicitly cover GME expenses. Private insurers maintain that they accomplish this implicitly by paying teaching hospitals more for clinical services than they pay most other hospitals. GME leaders think one possibility would be to include the costs of residency training when calculating premium amounts for products sold through health insurance exchanges. Similarly, a recent Carnegie Foundation report asserted that “GME redesign demands . . . a more broad-based, less politicized flow of funds.”
Dr. Darrell Kirch noted, CEO of AAMC, “A significant step forward is the announcement by the ACGME [Accreditation Council for Graduate Medical Education] describing major changes in how the nation’s residency programs will be accredited in the future, putting in place an outcomes-based evaluation system by which new physicians will be measured for their competency in performing the essential tasks necessary for clinical practice in the 21st century.”
Elliott S. Fisher, M.D., M.P.H., Donald M. Berwick, M.D., M.P.P., and Karen Davis, Ph.D.
N Engl J Med 2009; 360:2495-2497 http://dx.doi.org/10.1056/NEJMp0903923
http://www.nejm.org/doi/full/10.1056/NEJMp0903923
The recent commitment by several major stakeholders — including the American Medical Association — to slowing the growth of health care spending is a promising development. But the controversy about whether the organizations actually agreed to a 1.5-percentage-point reduction in annual spending growth is just one indication that success is still far from assured.
Two threats in particular put reform at risk: conflicting doctrines (regarding the creation of a new public insurance option and government support for comparative-effectiveness studies) and opposition to change among some current stakeholders. In the face of this uncertainty, physicians have a choice: to wait and see what happens or to lead the change our country needs. We’d prefer the latter.
The first level is aims. For health care reform, we propose that physicians, through their advocacy, help lead the country to embrace the so-called triple aim: better experience of care (safe, effective, patient-centered, timely, efficient, and equitable), better health for the population, and lower total per capita costs.
The second level is the design of the care processes that affect the patient — clinical “microsystems.” Health care microsystems are famously unreliable, variable in costs, and often unsafe. Physicians, through their participation in quality-improvement initiatives in their practices and hospitals, can and should lead the needed changes in the systems of care in which they work, to make them safer, more reliable, more patient-centered, and more affordable.
However, neither physicians nor anyone else on the front lines can improve care much on their own. Their most important source of support for improvement is the third level described by the IOM — the health care organizations that house almost all clinical microsystems and can ensure coordination among them. We need organizations large enough to be accountable for the full continuum of patients’ care as well as for achieving the triple aim. We will create a high-performing health care system only if integrated delivery systems become the mainstay of organizational design. Organizations could be virtually integrated, such as networks of independent physicians sharing electronic health records and administrative and clinical support for care management and quality improvement, or structurally integrated, such as multispecialty group practices or staff-model health maintenance organizations. Fostering the development of such accountable care organizations need not be disruptive to patients or providers: almost all physicians already work within natural referral networks that provide the vast majority of care to patients seen by the primary care physicians within the network.
The IOM’s fourth level is the environment, which includes the payment, regulatory, legal, and educational systems. On this front, too, we need physician advocacy. The United States cannot achieve the triple aim without health insurance for everyone. Integrated delivery systems that are accountable for populations won’t thrive unless payment systems encourage their development and unless we change the laws and regulations — including proscriptions of gainsharing and anti-kickback rules — that prevent cooperation among health care professionals and organizations.
If stakeholders can agree on such a vision of health care reform, perhaps we could shift our focus from the conflict over whether a new public plan should be created to a more constructive insistence that all health plans, whether public or private, focus on the development of professionally led, integrated systems.
If health care providers and suppliers could actually achieve this reduction in growth rates, the federal government would harvest about $1.1 trillion in savings over the 11-year period — enough, perhaps, to close the deal on affordable health insurance for all. Others would also see savings: $497 billion for employers, $529 billion for state and local governments, and $671 billion for households. One simple way for physicians to start contributing to this goal is by reassessing and scaling back, where appropriate, their use of clinical practices now listed as “overused” by the National Quality Forum’s National Priorities Partnership.
Editor’s Note: On the eve of the first anniversary of the Supreme Court’s ruling to uphold most provisions of the Affordable Care Act (ACA), Medscape Editor-in-Chief Eric J. Topol, MD, questioned Secretary of Health and Human Services (HHS) Kathleen Sebelius about the act’s effect on medical technology, clinical trial participation, genetic testing, primary care, and patient safety.
Introduction
Feder J. N Engl J Med 2013; 369:400-401
A Medicare payment approach in which savings and risk are shared may achieve a better balance of cost, quality, and access than a system of single bundled payments, at least until our capacity to measure patients’ care needs and outcomes is sufficiently robust.
3 of 5 in Series: The Essentials of Healthcare Reform
http://www.dummies.com/how-to/content/healthcare-reform-2014-mandated-coverage-insurance.html
The Affordable Care Act federal and state officials are working with leaders in the health and insurance industries to restructure our nation’s healthcare system. That restructuring means most Americans will be required to have health insurance and most businesses will be required to offer it to their employees. It also means the creation of another kind of insurance plan called a health insurance exchange.
The government will require most Americans to have health insurance by 2014. The government has enacted this provision as a way to get healthy people who don’t feel the need to pay for coverage to buy insurance. That way, the healthy people can help fund the cost of people who require more medical care.
Several states filed, and lost, a suit against the federal government saying that it is unconstitutional to make individual citizens to buy health insurance.
If you don’t have coverage and you’re not in one of the groups that is an exception to the rule, you’ll pay a penalty. You may not be required to purchase health insurance if you
If you’re penalized, the amount you’ll be fined will go up each year for the first three years. In 2014, you’ll pay $95 or 1 percent of your taxable income, whichever is greater. In 2015, the fine will be $325 or 2 percent of taxable income, and in 2016 the penalty will be $695 or 2.5 percent of income. Each year after 2016, the government will refigure the fine based on a cost-of-living adjustment.
To help you meet the cost of mandated insurance, the government will offer premium credits and cost sharing subsidies if you and your family meet certain income guidelines and if you enroll in one of the new state-run insurance exchanges.
If your income falls between 133 and 400 percent of the federal poverty level (FPL), you could receive premium credits that will lower the maximum amount of premium you have to pay for your coverage.
States don’t have to set up the exchanges. If a state chooses not to, the federal government can come in and create them. States that do opt for exchanges will decide whether they’ll be run by a government or not-for-profit entity.
Victor R. Fuchs, Ph.D
N Engl J Med 2009; 360:208-209 http://dx.doi.org/10.1056/NEJMp0809733
http://www.nejm.org/doi/full/10.1056/NEJMp0809733
First, many organizations and individuals prefer the status quo. This category includes health insurance companies; manufacturers of drugs, medical devices, and medical equipment; companies that employ mostly young, healthy workers and therefore have lower health care costs than they would if required to help subsidize care for the poor and the sick; high-income employees, whose health insurance is heavily subsidized through a tax exemption for the portion of their compensation spent on health insurance; business leaders and others who are ideologically opposed to a larger role of government; highly paid physicians in some surgical and medical specialties; and workers who mistakenly believe that their employment-based insurance is a gift from their employer rather than an offset to their potential take-home pay.
Second, as Niccoló Machiavelli presciently wrote in 1513, “There is nothing more difficult to manage, more dubious to accomplish, nor more doubtful of success . . . than to initiate a new order of things. The reformer has enemies in all those who profit from the old order and only lukewarm defenders in all those who would profit from the new order.”
Third, our country’s political system renders Machiavelli’s Law of Reform particularly relevant in the United States, where many potential “choke points” offer opportunities to stifle change. The problem starts in the primary elections in so-called safe congressional districts, where special-interest money can exert a great deal of influence because of low voter turnout. The fact that Congress has two houses increases the difficulty of passing complex legislation, especially when several committees may claim jurisdiction over portions of a bill. Also, a supermajority of 60% may be needed to force a vote in the filibuster-prone Senate.
Fourth, reformers have failed to unite behind a single approach. Disagreement among reformers has been a major obstacle to substantial reform since early in the last century. According to historian Daniel Hirshfield, “Some saw health insurance primarily as an educational and public health measure, while others argued that it was an economic device to precipitate a needed reorganization of medical practice. . . . Some saw it as a device to save money for all concerned, while others felt sure that it would increase expenditures significantly.” These differences in objectives persist to this day.
Jayne O’Donnell , USA TODAY
http://www.usatoday.com/story/news/nation/2013/09/12/health-insurance-sales-retail-stores-malls/2789897/
,The new health law known as the Affordable Care Act means most uninsured Americans are required to have insurance beginning March 31 or pay a penalty at tax time in 2015.
Insurers need to sign up as many healthy, younger people as they can to pay for all of the older, sick customers they will be taking on. The law prohibits insurers from denying people insurance because of pre-existing health problems and limits how much more they can charge older than younger people.
So, for the first time, insurers are fiercely competing to attract individual consumers and turning to traditional retail marketing techniques to do so, luring them into stores with special events and using splashy advertising. As any retailer knows, they have the greatest chance of converting shoppers to customers once they have them in their retail locations or on their sites.
Toby Cosgrove, CEO and President at Cleveland Clinic
The latest medical breakthrough hasn’t gotten much press, but it’s changing medicine even as we speak. It’s the dawning realization that healthcare is not about how many patients you can see, how many tests and procedures you can order, or how much you can charge for these things. The breakthrough is the understanding that healthcare is a value proposition, which means getting patients the right care, at the right time, in the right place. It’s a matter of focusing on outcomes and cost, so that more Americans will start getting what they pay for in healthcare dollars.
Value-based care focuses on two targets: outcomes and cost. Until recently, providers pursued these goals separately, with doctors concentrating on outcomes and the administrators trying to control costs. Value-based care does something different. It works to bring these targets into alignment. The caregivers in a value-based provider work with cost-experts as a team to simultaneously improve outcomes and lower expenses.
Doctors, hospitals and payers are partners in the move to value-based care. The Affordable Care Act includes incentives for providers to improve outcomes and lower costs. But this is one breakthrough that will take time for implementation nationwide. Providers who make the transition early will be rewarded with more satisfied patients, lower expenses and pride in a job well done.
According to AAMC, the language in the final rule requires that the order to admit a patient be written by a practitioner “who has admitting privileges at the hospital,” something that few residents have as they are not considered members of the hospital’s medical staff.
AAMC said it brought the issue to CMS’s attention during an Open Door Forum call Aug. 15. The agency acknowledged it did not intend to prohibit residents from admitting patients, and said it would be issuing a Q&A. However, AAMC said until the issue can be resolved “to the satisfaction of the teaching hospital community,” CMS should make clear to all contractors that no inpatient admission should be denied because it was ordered by a resident while under the supervision of an attending physician.
AAMC said CMS should delay enforcing the new requirements for at least six months following the release of the guidance so hospitals will have sufficient time to understand the rules, educate physicians and others, and ensure that they have put in place the mechanisms that are needed to comply with the new requirements.
“As short inpatient stays have been a focus of audits by [Recovery Audit Contractors], hospitals feel especially at risk for failure to properly implement CMS requirements,” AAMC said.
The letter is available at http://op.bna.com/hl.nsf/r?Open=nwel-9auqls.
Posted in Biological Networks, Gene Regulation and Evolution, Biomedical Measurement Science, Calcium Signaling, Cardiovascular Pharmacogenomics, Cell Biology, Signaling & Cell Circuits, Chemical Biology and its relations to Metabolic Disease, Computational Biology/Systems and Bioinformatics, Cytoskeleton, Disease Biology, Small Molecules in Development of Therapeutic Drugs, Electrophysiology, Frontiers in Cardiology and Cardiovascular Disorders, Genome Biology, Genomic Testing: Methodology for Diagnosis, Health Economics and Outcomes Research, International Global Work in Pharmaceutical, Medical and Population Genetics, Metabolomics, Molecular Genetics & Pharmaceutical, Nutrigenomics, Nutrition, Origins of Cardiovascular Disease, Personalized and Precision Medicine & Genomic Research, Pharmacogenomics, Pharmacotherapy of Cardiovascular Disease, Population Health Management, Genetics & Pharmaceutical, Population Health Management, Nutrition and Phytochemistry, Proteomics, Systemic Inflammatory Response Related Disorders, tagged Aviva Lev-Ari, beta adrenergic, Ca++, Ca2+/calmodulin-dependent protein kinase, CaK isoforms, CaKMII, calcium leak, calcium signaling, cardiac arrhythmias, cardiovascular, Congenital Heart Disease, cytoplasmic, cytosolic calcium, Excitation-contraction coupling, Heart Failure, heart rate variation, isoform, Justin Pearlman, Larry H. Bernstein, nuclear variant, PLB, regulation of calcium homeostasis, Smooth muscle tissue, splice variants, voltage-gated L-type channels on September 9, 2013| Leave a Comment »
Author and Curator: Larry H Bernstein, MD, FCAP
Author and Cardiovascular Three-volume Series, Editor: Justin Pearlman, MD, PhD, FACC, and
Curator: Aviva Lev-Ari, PhD, RN
Abbreviations
AP, action potential; ARVD2, arrhythmogenic right ventricular cardiomyopathy type 2; CaMKII, Ca2+/calmodulim-dependent protein kinase II; CICR, Ca2+ induced Ca2+ release;CM, calmodulin; CPVT, catecholaminergic polymorphic ventricular tachycardia; ECC, excitation–contraction coupling; FKBP12/12.6, FK506 binding protein; HF, heart failure; LCC, L-type Ca2+ channel; P-1 or P-2, phosphatase inhibitor type-1 or type-2; PKA, protein kinase A; PLB, phosphoplamban; PP1, protein phosphatase 1; PP2A, protein phosphatase 2A; RyR1/2, ryanodine receptor type-1/type-2; SCD, sudden cardiac death; SERCA, sarcoplasmic reticulum Ca2+ ATPase; SL, sarcolemma; SR, sarcoplasmic reticulum.
This is Part V of a series on the cytoskeleton and structural shared thematics in cellular movement and cellular dynamics.
The Series consists of the following articles:
Part I: Identification of Biomarkers that are Related to the Actin Cytoskeleton
Larry H Bernstein, MD, FCAP
Part II: Role of Calcium, the Actin Skeleton, and Lipid Structures in Signaling and Cell Motility
Larry H. Bernstein, MD, FCAP, Stephen Williams, PhD and Aviva Lev-Ari, PhD, RN
Part III: Renal Distal Tubular Ca2+ Exchange Mechanism in Health and Disease
Larry H. Bernstein, MD, FCAP, Stephen J. Williams, PhD and Aviva Lev-Ari, PhD, RN
Part IV: The Centrality of Ca(2+) Signaling and Cytoskeleton Involving Calmodulin Kinases and Ryanodine Receptors in Cardiac Failure, Arterial Smooth Muscle, Post-ischemic Arrhythmia, Similarities and Differences, and Pharmaceutical Targets
Larry H Bernstein, MD, FCAP, Justin Pearlman, MD, PhD, FACC and Aviva Lev-Ari, PhD, RN
Part V: Heart, Vascular Smooth Muscle, Excitation-Contraction Coupling (E-CC), Cytoskeleton, Cellular Dynamics and Ca2 Signaling
Larry H Bernstein, MD, FCAP, Justin Pearlman, MD, PhD, FACC and Aviva Lev-Ari, PhD, RN
Part VI: Calcium Cycling (ATPase Pump) in Cardiac Gene Therapy: Inhalable Gene Therapy for Pulmonary Arterial Hypertension and Percutaneous Intra-coronary Artery Infusion for Heart Failure: Contributions by Roger J. Hajjar, MD
Aviva Lev-Ari, PhD, RN
Part VII: Cardiac Contractility & Myocardium Performance: Ventricular Arrhythmias and Non-ischemic Heart Failure – Therapeutic Implications for Cardiomyocyte Ryanopathy (Calcium Release-related Contractile Dysfunction) and Catecholamine Responses
Justin Pearlman, MD, PhD, FACC, Larry H Bernstein, MD, FCAP and Aviva Lev-Ari, PhD, RN
In the first part, we discussed common MOTIFs across cell-types that are essential for cell division, embryogenesis, cancer metastasis, osteogenesis, musculoskeletal function, vascular compliance, and cardiac contractility. This second article concentrates on specific functionalities for cardiac contractility based on Ca++ signaling in excitation-contraction coupling. The modifications discussed apply specifically to cardiac muscle and not to skeletal muscle. Considering the observations described might raise additional questions specifically address to the unique requirements of smooth muscle, abundant in the GI tract and responsible for motility in organ function, and in blood vessel compliance or rigidity. Due to the distinctly different aspects of the cardiac contractility and contraction force, and the interactions with potential pharmaceutical targets, there are two separate articles on calcium signaling and cardiac arrhythmias or heart failure (Part 2 and Part 3). Part 2 focuses on the RYANODINE role in cardiac Ca(2+) signaling and its effect in heart failure. Part 3 takes up other aspects of heart failure and calcium signaling with respect to phosporylation/dephosphorylation. I add a single review and classification of genetic cardiac disorders of the same cardiac Ca(2+) signaling and the initiation and force of contraction. Keep in mind that the heart is a syncytium, and this makes a huge difference compared with skeletal muscle dynamics. In Part 1 there was some discussion of the importance of Ca2+ signaling on innate immune system, and the immunology will be further expanded in a fourth of the series.
This second article on the cardiomyocyte and the Ca(2+) cycling between the sarcomere and the cytoplasm, takes a little distance from the discussion of the ryanodine that precedes it. In this discussion we found that there is a critical phosphorylation/dephosphorylation balance that exists between Ca(+) ion displacement and it occurs at a specific amino acid residue on the CaMKIId, specific for myocardium, and there is a 4-fold increase in contraction and calcium release associated with this CAM kinase (ser 2809) dependent exchange. These events are discussed in depth, and the research holds promise for therapeutic application. We also learn that Ca(2+) ion channels are critically involved in the generation of arrhythmia as well as dilated and hypertrophic cardiomyopathy. In the case of arrhythmiagenesis, there are two possible manners by which this occurs. One trigger is Ca(2+) efflux instability. The other is based on the finding that when the cellular instability is voltage driven, the steady-state wavelength (separation of nodes in space) depends on electrotonic coupling between cells and the steepness of APD and CV restitution. The last article is an in depth review of the genetic mutations that occur in cardiac diseases. It is an attempt at classifying them into reasonable groupings. What are the therapeutic implications of this? We see that the molecular mechanism of cardiac function has been substantially elucidated, although there are contradictions in experimental findings that are unexplained. However, for the first time, it appears that personalized medicine is on a course that will improve health in the population, and the findings will allow specific targets designed for the individual with a treatable impairment in cardiac function that is identifiable early in the course of illness. This article is a continuation to the following articles on tightly related topics: Part I: Identification of Biomarkers that are Related to the Actin Cytoskeleton Larry H Bernstein, MD, FCAP http://pharmaceuticalintelligence.com/2012/12/10/identification-of-biomarkers-that-are-related-to-the-actin-cytoskeleton/ Part II: Role of Calcium, the Actin Skeleton, and Lipid Structures in Signaling and Cell Motility Larry H. Bernstein, MD, FCAP, Stephen Williams, PhD and Aviva Lev-Ari, PhD, RN http://pharmaceuticalintelligence.com/2013/08/26/role-of-calcium-the-actin-skeleton-and-lipid-structures-in-signaling-and-cell-motility/ Part III: Renal Distal Tubular Ca2+ Exchange Mechanism in Health and Disease Larry H. Bernstein, MD, FCAP, Stephen J. Williams, PhD and Aviva Lev-Ari, PhD, RN http://pharmaceuticalintelligence.com/2013/09/02/renal-distal-tubular-ca2-exchange-mechanism-in-health-and-disease/ Part IV: The Centrality of Ca(2+) Signaling and Cytoskeleton Involving Calmodulin Kinases and Ryanodine Receptors in Cardiac Failure, Arterial Smooth Muscle, Post-ischemic Arrhythmia, Similarities and Differences, and Pharmaceutical Targets Larry H Bernstein, MD, FCAP, Justin Pearlman, MD, PhD, FACC and Aviva Lev-Ari, PhD, RN http:/pharmaceuticalintelligence.com/2013.09.089/lhbern/The Centrality of Ca(2+) Signaling and Cytoskeleton Involving Calmodulin Kinases and Ryanodine Receptors in Cardiac Failure, Arterial Smooth Muscle, Post-ischemic Arrhythmia, Similarities and Differences, and Pharmaceutical Targets
Larry H Bernstein, MD, FCAP, Justin Pearlman, MD, PhD, FACC and Aviva Lev-Ari, PhD, RN http://pharmaceuticalintelligence.com/2013/08/26/heart-smooth-muscle-excitation-contraction-coupling-cytoskeleton-cellular-dynamics-and-ca2-signaling/ Part VI: Calcium Cycling (ATPase Pump) in Cardiac Gene Therapy: Inhalable Gene Therapy for Pulmonary Arterial Hypertension and Percutaneous Intra-coronary Artery Infusion for Heart Failure: Contributions by Roger J. Hajjar, MD Curator: Aviva Lev-Ari, PhD, RN http://pharmaceuticalintelligence.com/2013/08/01/calcium-molecule-in-cardiac-gene-therapy-inhalable-gene-therapy-for-pulmonary-arterial-hypertension-and-percutaneous-intra-coronary-artery-infusion-for-heart-failure-contributions-by-roger-j-hajjar/ and Advanced Topics in Sepsis and the Cardiovascular System at its End Stage Larry H Bernstein, MD, FCAP http://pharmaceuticalintelligence.com/2013/08/18/advanced-topics-in-sepsis-and-the-cardiovascular-system-at-its-end-stage/
EG Kranias, RC Gupta, G Jakab, HW Kim, NAE Steenaart, ST Rapundalo Molecular and Cellular Biochemistry 06/1988; 82(1):37-44. · 2.06 Impact Factor http://www.researchgate.net/publication/6420466_Protein_phosphatases_decrease_sarcoplasmic_reticulum_calcium_content_by_stimulating_calcium_release_in_cardiac_myocytes Canine cardiac sarcoplasmic reticulum is phosphorylated by
Both types of phosphorylation are associated with
The stimulatory effects of the protein kinases on the calcium pump may be reversed by an endogenous protein phosphatase, which
Thus, the calcium pump in cardiac sarcoplasmic reticulum appears to be under reversible regulation mediated by protein kinases and protein phosphatases. 
I Györke, S Györke. Biophysical Journal 01/1999; 75(6):2801-10. · 3.65 Impact factor http:// www.researchgate.net/publication/13459335/Regulation_of_the_cardiac_ryanodine_receptor_channel_by_luminal_Ca2_involves_luminal_Ca2_sensing_sites The mechanism of activation of the cardiac calcium release channel/ryanodine receptor (RyR) by luminal Ca(2+) was investigated in native canine cardiac RyRs incorporated into lipid bilayers in the presence of 0.01 microM to 2 mM Ca(2+) (free) and 3 mM ATP (total) on the cytosolic (cis) side and 20 microM to 20 mM Ca(2+) on the luminal (trans) side of the channel and with Cs+ as the charge carrier. Under conditions of low [trans Ca(2+)] (20 microM), increasing [cis Ca(2+)] from 0.1 to 10 microM caused a gradual increase in channel open probability (Po). Elevating [cis Ca(2+)] [cytosolic] above 100 microM resulted in a gradual decrease in Po. Elevating trans [Ca(2+)] [luminal] enhanced channel activity (EC50 approximately 2.5 mM at 1 microM cis Ca2+) primarily by increasing the frequency of channel openings. The dependency of Po on trans [Ca2+] [luminal] was similar at negative and positive holding potentials and was not influenced by high cytosolic concentrations of the fast Ca(2+) chelator, 1,2-bis(2-aminophenoxy)ethane-N,N,N, N-tetraacetic acid. Elevated luminal Ca(2+)
Potentiation of Po by increased luminal Ca(2+) occurred irrespective of whether the electrochemical gradient for Ca(2+) supported a cytosolic-to-luminal or a luminal-to-cytosolic flow of Ca(2+) through the channel. These results rule out the possibility that under our experimental conditions, luminal Ca(2+) acts by interacting with the cytosolic activation site of the channel and suggest that the effects of luminal Ca2+ are mediated by distinct Ca(2+)-sensitive site(s) at the luminal face of the channel or associated protein. 
D Terentyev, S Viatchenko-Karpinski, I Gyorke, R Terentyeva and S Gyorke Texas Tech University Health Sciences Center, Lubbock, TX J Physiol 2003; 552(1), pp. 109–118. http://dx.doi.org/10.1113/jphysiol.2003.046367 Phosphorylation/dephosphorylation of Ca2+ transport proteins by cellular kinases and phosphatases plays an important role in regulation of cardiac excitation–contraction coupling; furthermore,
However, the precise mechanisms of action of these enzymes on intracellular Ca2+ handling in normal and diseased hearts remains poorly understood. We have investigated
Exposure of myocytes to PP1 or PP2A caused a dramatic increase in frequency of Ca(2+) sparks followed by a nearly complete disappearance of events, which were accompanied by depletion of the SR Ca(2+) stores, as determined by application of caffeine. These changes in
could be prevented by the inhibitors of PP1 and PP2A phosphatase activities okadaic acid and calyculin A. At the single channel level, PP1 increased the open probability of RyRs incorporated into lipid bilayers. PP1-medited RyR dephosphorylation in our permeabilized myocytes preparations was confirmed biochemically by quantitative immunoblotting using a phosphospecific anti-RyR antibody. Our results suggest that
In heart muscle cells, the process of excitation–contraction (EC) coupling is mediated by
Once activated, the RyR channels allow Ca(2+) to be released from the SR into the cytosol to induce contraction. This mechanism is known as Ca(2+)-induced calcium release (CICR) (Fabiato, 1985; Bers, 2002). During relaxation, most of the Ca(2+) is resequestered into the SR by the Ca(2+)-ATPase. The amount of Ca(2+) released and the force of contraction depend on
F1.large calcium movement and RyR2 receptor 
calcium release calmodulin + ER Reversible phosphorylation of proteins composing the EC coupling machinery plays an important role in regulation of cardiac contractility (Bers, 2002). Thus, during stimulation of the b-adrenergic pathway, phosphorylation of several target proteins, including
by protein kinase A (PKA) leads to an overall increase in SR Ca2+ release and contractile force in heart cells (Callewaert et al. 1988, Spurgeon et al. 1990; Hussain & Orchard, 1997; Zhou et al. 1999; Song et al. 2001; Viatchenko-Karpinski & Gyorke, 2001). PKA-dependent phosphorylation of the L-type Ca(2+) channels increases the Ca2+ current (ICa), increasing both
(Callewaert et al. 1988; Hussain & Orchard, 1997; Del Principe et al. 2001). Phosphorylation of phospholamban (PLB) relieves the tonic inhibition dephosphorylated PLB exerts on the SR Ca(2+)-ATPase (SERCA) resulting in enhanced SR Ca(2+) accumulation and enlarged Ca(2+) release (Kranias et al. 1985; Simmermann & Jones, 1998). With regard to the RyR, despite clear demonstration of phosphorylation of the channel in biochemical studies (Takasago et al. 1989; Yoshida et al. 1992), the consequences of this reaction to channel function have not been clearly defined. RyR phosphorylation by PKA and Ca(2+)–calmodulin dependent protein kinase (CaMKII) has been reported to increase RyR activity in lipid bilayers (Hain et al. 1995; Marx et al. 2000; Uehara et al. 2002). Moreover, it has been reported that in heart failure (HF), hyperphosphorylation of RyR causes
However, other studies have reported no functional effects (Li et al. 2002) or even found phosphorylation to reduce RyR channel steady-state open probability (Valdivia et al. 1995; Lokuta et al. 1995). The action of protein kinases is opposed by dephosphorylating phosphatases. Three types of protein phosphatases (PPs), referred to as PP1, PP2A and PP2B (calcineurin), have been shown to influence cardiac performance (Neumann et al. 1993; Rusnak & Mertz, 2000). Overall, according to most studies phosphatases appear to downregulate SR Ca(2+) release and contractile performance (Neumann et al. 1993; duBell et al. 1996, 2002; Carr et al. 2002; Santana et al. 2002). Furthermore, PP1 and PP2A activities appear to be increased in heart failure (Neumann, 2002; Carr et al. 2002). However, again the precise mode of action of these enzymes on intracellular Ca(2+) handling in normal and diseased hearts remains poorly understood. In the present study, we have investigated the effects of protein phosphatases PP1 and PP2A on local Ca(2+) release events, Ca(2+) sparks, in cardiac cells. Our results show that
These results provide novel insights into the mechanisms and potential role of protein phosphorylation/dephosphorylation in regulation of Ca(2+) signaling in normal and diseased hearts. 
[1] PP1 caused an early transient potentiation of Ca2+ spark frequency followed by a delayed inhibition of event occurrence. [2] PP1 produced similar biphasic effects on the magnitude and spatio-temporal characteristics of Ca(2+) sparks Specifically, during the potentiatory phase (1 min after addition of the enzyme), PP1 significantly increased
during the inhibitory phase (5 min after addition of the enzyme),
The SR Ca(2+) content decreased by 35 % or 69 % following the exposure of myocytes to either 0.5 or 2Uml_1 PP1, respectively (Fig. 1C). Qualitatively similar results were obtained with phosphatase PP2A. Similar to the effects of PP1, PP2A (5Uml_1) produced a transient increase in Ca(2+) spark frequency (~4-fold) followed by a depression of event occurrence and decreased SR Ca(2+) content (by 82 % and 65 %, respectively). Also similar to the action of PP1, PP2A increased
Together, these results suggest that phosphatases enhance spark-mediated SR Ca2+ release, leading to decreased SR Ca(2+) content. Preventive effects of calyculin A and okadaic acid Preventive effects of ryanodine
F3.large cardiomyocyte SR 
F2.large RyR and calcium 
coupled receptors The cardiac RyR is phosphorylated at Ser-2809 (in the rabbit sequence) by both PKA and CAMKII (Witcher et al. 1991; Marx et al. 2000). Although additional phosphorylation sites may exist on the RyR (Rodriguez et al. 2003), but Ser-2809 is believed to be the only site that is phosphorylated by PKA, and RyR hyperphosphorylation at this site has been reported in heart failure (Marx et al. 2000). To test whether indeed phosphatases dephosphorylated the RyR in our permeabilized myocyte experiments we performed quantitative immunoblotting using an antibody that specifically recognizes the phosphorylated form of the RyR at Ser-2809 (Rodriguez et al. 2003). Myocytes exhibited a significant level of phosphorylation under baseline conditions. Maximal phosphorylation was 201 % of control. When exposed to 2Uml_1 PP1, RyR phosphorylation was 58 % of the control basal condition. Exposing to a higher PP1 concentration (10Uml_1) further reduced RyR phosphorylation to 22% of control. Thus, consistent with the results of our functional measurements,
Figure 1. Effects of PP1 on properties of Ca(2+) sparks and SR Ca(2+) content in rat permeabilized myocytes see . http://dx.doi.org/10.1113/jphysiol.2003.046367 A, spontaneous Ca(2+) spark images recorded under reference conditions, and 1 or 5 min after exposure of the cell to 2Uml_1 PP1. Traces below the images are Ca(2+) transients induced by application of 10 mM caffeine immediately following the acquisition of sparks before (3 min) and after (5 min) application of PP1 in the same cell. The Ca(2+) transients were elicited by a whole bath application of 10 mM caffeine. B, averaged spark frequency at early (1 min) and late (5 min) times following the addition of either 0.5 or 2Uml_1 of PP1 to the bathing solution. C, averaged SR Ca(2+) content for 0.5 or 2Uml_1 of PP1 measured before and 5 min after exposure to the enzyme. Data are presented as means ± S.E.M. of 6 experiments in different cells. Figure 2. Effects of PP2A on properties of Ca2+ sparks and SR Ca2+ content in rat permeabilized myocytes see . http://dx.doi.org/10.1113/jphysiol.2003.046367 A, spontaneous Ca(2+) spark images recorded under reference conditions, and 1 or 5 min after exposure of the cell to 5Uml_1 PP2A. Traces below the images are Ca(2+) transients induced by application of 10 mM caffeine immediately following the acquisition of sparks before (3 min) and after (5 min) application of PP2A in the same cell. B and C, averaged spark frequency (B) and SR Ca(2+) content (C) for the same conditions as in A. Data are presented as means ± S.E.M. of 6 experiments in different cells.
In the present study, we have investigated the impact of physiologically relevant exogenous protein phosphatases PP1 and PP2A on RyR-mediated SR Ca(2+) release (measured as Ca(2+) sparks) in permeabilized heart cells. Our principal finding is that
These results have important ramifications for understanding the mechanisms and role of protein phosphorylation/dephosphorylation in
Since protein dephosphorylation clearly resulted in increased functional activity of the Ca(+)release channel, our results imply that a reverse, phosphorylation reaction should reduce RyR activity. If indeed such effects take place, why do they not manifest in inhibition of Ca(+)sparks? One possibility is that enhanced Ca(+) uptake by SERCA
In addition, the potential inhibitory influence of protein phosphorylation on RyR activity in myocytes could be countered by feedback mechanisms involving changes in luminal Ca(2+)(Trafford et al. 2002; Gyorke et al. 2002). In particular, reduced open probability of RyRs would be expected to lead to
as demonstrated for the RyR channel inhibitor tetracaine (Gyorke et al. 1997; Overend et al. 1997). Thus
could explain at least in part why PKA-mediated protein phoshorylation results in maintained potentiation of Ca(2+) sparks despite a potential initial decrease in RyR activity.
Marx et al. (2000) have proposed that enhanced levels of circulating catecholamines lead to increased phosphorylation of RyR in heart failure. Based on biochemical observations as well as on studying properties of single RyRs incorporated into artificial lipid bilayers, these investigators have hypothesized that
We show that the mode of modulation of RyRs by phosphatases does not support this hypothesis as
Interestingly, our results provide the basis for a different possibility in which
It has been reported that PP1 and PP2 activities are increased in heart failure (Huang et al. 1999; Neumann et al. 1997; Neuman, 2002). Furthermore, overexpression of PP1 or ablation of the endogenous PP1 inhibitor, l-1, results in
Our finding that PP1 causes depletion of SR Ca(2+) stores by activating RyRs could account for, or contribute to, these results.
1 DelPrincipe F, Egger M, Pignier C & Niggli E (2001). Enhanced E-C coupling efficiency after beta-stimulation of cardiac myocytes. Biophys J 80, 64a. 2 Gyorke I & Gyorke S (1998). Regulation of the cardiac ryanodine receptor channel by luminal Ca2+ involves luminal Ca2+ sensing sites. Biophys J 75, 2801–2810. 3 Gyorke S, Gyorke I, Lukyanenko V, Terentyev D, Viatchenko-Karpinski S & Wiesner TF (2002). Regulation of sarcoplasmic reticulum calcium release by luminal calcium in cardiac muscle. Front Biosci 7, d1454–d1463. 4 Gyorke I, Lukyanenko V & Gyorke S (1997). Dual effects of tetracaine on spontaneous calcium release in rat ventricular myocytes. J Physiol 500, 297–309. 5 MacDougall LK, Jones LR & Cohen P (1991). Identification of the major protein phosphatases in mammalian cardiac muscle which dephosphorylate phospholamban. Eur J Biochem 196, 725–734. 6 Marx SO, Reiken S, Hisamatsu Y, Jayaraman T, Burkhoff D, Rosemblit N & Marks AR (2000). PKA phosphorylation dissociates FKBP12.6 from the calcium release channel (ryanodine receptor): defective regulation in failing hearts. Cell 101, 365–376. 7 Rodriguez P, Bhogal MS & Colyer J (2003). Stoichiometric phosphorylation of cardiac ryanodine receptor on serine-2809 by calmodulin-dependent kinase II and protein kinase A. J Biol Chem (in press).
T Zhang, LS Maier, ND Dalton, S Miyamoto, J Ross, DM Bers, JH Brown. University of California, San Diego, La Jolla, Calif; and Loyola University, Chicago, Ill. Circ Res. 2003;92:912-919. http://dx.doi.org/10.1161/01.RES.0000069686.31472.C5 Recent studies have demonstrated that transgenic (TG) expression of either Ca(2+)/calmodulin-dependent protein kinase IV (CaMKIV) or CaMKIIδB, both of which localize to the nucleus, induces cardiac hypertrophy. However,
In the present study, we demonstrate that
To determine whether enhanced activity of this cytoplasmic δC isoform of CaMKII can lead to phosphorylation of Ca(2+) regulatory proteins and induce hypertrophy, we generated TG mice that expressed the δC isoform of CaMKII. Immunocytochemical staining demonstrated that the expressed transgene is confined to the cytoplasm of cardiomyocytes isolated from these mice. These mice develop a dilated cardiomyopathy with up to a 65% decrease in fractional shortening and die prematurely. Isolated myocytes are enlarged and exhibit reduced contractility and altered Ca2(2+) handling. Phosphorylation of the ryanodine receptor (RyR) at a CaMKII site is increased even before development of heart failure, and
These findings are the first to demonstrate that CaMKIIδC can mediate phosphorylation of Ca(2+) regulatory proteins in vivo and provide evidence for the involvement of CaMKIIδC activation in the pathogenesis of dilated cardiomyopathy and heart failure. Multifunctional Ca(2+)/calmodulin-dependent protein kinases (CaM kinases or CaMKs) are transducers of Ca2+ signals that phosphorylate a wide range of substrates and thereby affect Ca(2+)-mediated cellular responses.1 The family includes CaMKI and CaMKIV, monomeric enzymes activated by CaM kinase kinase,2,3 and CaMKII, a multimer of 6 to 12 subunits activated by autophosphorylation.1 The CaMKII subunits α, β, γ, and δ show different tissue distributions,1 with
CaMKII has been implicated in several key aspects of acute cellular Ca(2+) regulation related to cardiac excitation-contraction (E-C) coupling. CaMKII
Phosphorylation of RyR has been suggested to alter the channel open probability,14,15 whereas phosphorylation of PLB has been suggested to regulate SR Ca(2+) uptake.14 It is also likely that CaMKII phosphorylates the L-type Ca(2+) channel complex or an associated regulatory protein and thus
Thus, CaMKII has significant effects on E-C coupling and cellular Ca(2 +) regulation. Nothing is known about the CaMKII isoforms regulating these responses. Contractile dysfunction develops with hypertrophy, characterizes heart failure, and is associated with changes in cardiomyocyte (Ca2+) homeostasis.20 CaMKII expression and activity are altered in the myocardium of rat models of hypertensive cardiac hypertrophy21,22 and heart failure,23 and
Several transgenic mouse models have confirmed a role for CaMK in the development of cardiac hypertrophy, as originally suggested by studies in isolated neonatal rat ventricular myocytes.9,26–28 Hypertrophy develops in transgenic mice that overexpress CaMKIV,27 but this isoform is not detectable in the heart,4,29 and CaMKIV knockout mice still develop hypertrophy after transverse aortic constriction (TAC).29 Transgenic mice overexpressing calmodulin developed severe cardiac hypertrophy,30 later shown to be associated with an increase in activated CaMKII31; the isoform of CaMKII involved in hypertrophy could not be determined from these studies. We recently reported that transgenic mice that overexpress CaMKIIδB, which is highly concentrated in cardiomyocyte nuclei, develop hypertrophy and dilated cardiomyopathy.32 To determine whether
we generated transgenic (TG) mice that expressed the δC isoform of CaMKII under the control of the cardiac specific α-myosin heavy chain (MHC) promoter. Our findings implicate CaMKIIδC in the pathogenesis of dilated cardiomyopathy and heart failure and suggest that
Ca(2+) and contraction RyR 
yuan_image3 Ca++ exchange
To determine whether CaMKII was regulated in pressure overload–induced hypertrophy, CaMKIIδ expression and phosphorylation were examined by Western blot analysis using left ventricular samples obtained at various times after TAC. A selective increase (1.6-fold) in the lower band of CaMKIIδwas observed as early as 1 day and continuously for 4 days (2.3-fold) and 7 days (2-fold) after TAC (Figure 1A). To confirm that CaMKIIδC was increased and determine whether this occurred at the transcriptional level, we performed semiquantitative RT-PCR using primers specific for the CaMKIIδC isoform. These experiments revealed that
In addition to examining CaMKII expression, the activation state of CaMKII was monitored by its autophosphorylation, which confers Ca2-independent activity.
see http://dx.doi.org/10.1161/01.RES.0000069686.31472.C5 A, Western blot analysis of total CaMKII in left ventricular (LV) homogenates obtained at indicated times after TAC. Cardiomyocytes transfected with CaMKIIδB and δC (right) served as positive controls and molecular markers. Top band (58 kDa) represents CaMKIIδB plus δ9, and the bottom band (56 kDa) corresponds to CaMKIIδC. *P0.05 vs control. B, Semiquantitative RT-PCR using primers specific for CaMKIIδC isoform (24 cycles) and GAPDH (19 cycles) using total RNA isolated from the same LV samples. C, Western blot analysis of phospho-CaMKII in LV homogenates obtained at various times after TAC. Three bands seen for each sample represent CaMKIIγ subunit (uppermost), CaMKIIδB plus δ9 (58 kDa), and CaMKIIδC (56 kDa). Quantitation is based on the sum of all of the bands. *P0.05 vs control.
see http://dx.doi.org/10.1161/01.RES.0000069686.31472.C5 A, Transgene copy number based on Southern blots using genomic DNA isolated from mouse tails (digested with EcoRI). Probe (a 32P-labeled 1.7-kb EcoRI-SalI -MHC fragment) was hybridized to a 2.3-kb endogenous fragment (En) and a 3.9-kb transgenic fragment (TG). Transgene copy number was determined from the ratio of the 3.9-kb/2.3-kb multiplied by 2. B, Immunocytochemical staining of ventricular myocytes isolated from WT and CaMKIIδTG mice. Myocytes were cultured on laminin-coated slides overnight. Transgene was detected by indirect immunofluorescence staining using rabbit anti-HA antibody (1:100 dilution) followed by FITC-conjugated goat antirabbit IgG antibody (1:100 dilution). CaMKIIδB localization to the nucleus in CaMKIIδB TG mice (see Reference 32) is shown here for comparative purpose. C, Quantitation of the fold increase in CaMKIIδprotein expression in TGL and TGM lines. Different amounts of ventricular protein (numbers) from WT control, TG () and their littermates () were immunoblotted with an anti-CaMKIIδ antibody. Standard curve from the WT control was used to calculate fold increases in protein expression in TGL and TGM lines. D, Phosphorylated CaMKII in ventricular homogenates was measured by Western blot analysis (n5 for each group). **P0.01 vs WT.
TG mice expressing HA-tagged rat wild-type CaMKIIδC under the control of the cardiac-specific α-MHC promoter were generated as described in Materials and Methods. By Southern blot analysis, 3 independent TG founder lines carrying 3, 5, and 15 copies of the transgene were identified. They were designated as TGL (low copy number), TGM (medium copy number), and TGH (high copy number), The founder mice from the TGH line died at 5 weeks of age with marked cardiac enlargement. The other two lines showed germline transmission of the transgene. The transgene was expressed only in the heart. Although CaMKII protein levels in TGL and TGM hearts were increased 12- and 17-fold over wild-type (WT) controls (Figure 2C), the amount of activated CaMKII was only increased 1.7- and 3-fold in TGL and TGM hearts (Figure 2D). The relatively small increase in CaMKII activity in the TG lines probably reflects the fact that the enzyme is not constitutively activated and that the availability of Ca2/CaM, necessary for activation of the overexpressed CaMKII, is limited. Importantly,
There was significant enlargement of hearts from CaMKIIδC TGM mice by 8 to 10 weeks [see http://dx.doi.org/10.1161/01.RES.0000069686.31472.C5%5D (Figure 3A) and from TGL mice by 12 to 16 weeks. Histological analysis showed ventricular dilation (Figure 3B), cardiomyocyte enlargement (Figure 3C), and mild fibrosis (Figure 3D) in CaMKIIδC TG mice. Quantitative analysis of cardiomyocyte cell volume from 12-week-old TGM mice gave values of 54.7 + 0.1 pL for TGM (n = 96) versus 28.6 + 0.1 pL for WT littermates (n=94; P0.001). Ventricular dilation and cardiac dysfunction developed over time in proportion to the extent of transgene expression. Left ventricular end diastolic diameter (LVEDD) was increased by 35% to 45%, left ventricular posterior wall thickness (LVPW) decreased by 26% to 29% and fractional shortening decreased by 50% to 60% at 8 weeks for TGM and at 16 weeks for TGL. None of these parameters were significantly altered at 4 weeks in TGM or up to 11 weeks in TGL mice, indicating that heart failure had not yet developed. Contractile function was significantly decreased. Figure 6. Dilated cardiomyopathy and dysfunction in CaMKIIδC TG mice at both whole heart and single cell levels. [see Fig 6: http://dx.doi.org/10.1161/01.RES.0000069686.31472.C5] C, Decreased contractile function in ventricular myocytes isolated from 12-week old TGM and WT controls presented as percent change of resting cell length (RCL) stimulated at 0.5 Hz. Representative trace and mean values are shown. *P0.05 vs WT. Figure 7. Phosphorylation of PLB in CaMKIIδC TG mice. [see Fig 7: http://dx.doi.org/10.1161/01.RES.0000069686.31472.C5] Thr17 and Ser16 phosphorylated PLB was measured by Western blots using specific anti-phospho antibodies. Ventricular homogenates were from 12- to 14-week-old WT and TGM mice (A) or 4 to 5-week-old WT and TGM mice (B). Data were normalized to total PLB examined by Western blots (data not shown here). n = 6 to 8 mice per group; *P0.05 vs WT.
To assess the possible involvement of phosphorylation of Ca2cycling proteins in the phenotypic changes observed in the CaMKIIC TG mice, we first compared PLB phosphorylation state in homogenates from 12- to 14-week-old TGM and WT littermates. Western blots using antibodies specific for phosphorylated PLB showed a 2.3-fold increase in phosphorylation of Thr17 (the CaMKII site) in hearts from TGM versus WT (Figure 7A). Phosphorylation of PLB at the CaMKII site was also increased 2-fold in 4- to 5-week-old TGM mice (Figure 7B). Significantly, phosphorylation of the PKA site (Ser16) was unchanged in either the older or the younger TGM mice (Figures 7A and 7B). (see http://dx.doi.org/10.1161/01.RES.0000069686.31472.C5) To demonstrate that the RyR2 phosphorylation changes observed in the CaMKII transgenic mice are not secondary to development of heart failure, we performed biochemical studies examining RyR2 phosphorylation in 4- to 5-week-old TGM mice. At this age, most mice showed no signs of hypertrophy or heart failure (see Figure 6B) and there was no significant increase in myocyte size (21.3 + 1.3 versus 27.7 + 4.6 pL; P0.14). Also, twitch Ca2 transient amplitude was not yet significantly depressed, and mean δ [Ca2+]i (1 Hz) was only 20% lower (192 + 36 versus 156 + 13 nmol/L; P0.47) versus 50% lower in TGM at 13 weeks.33 The in vivo phosphorylation of RyR2, determined by back phosphorylation, was significantly (2.10.3-fold; P0.05) increased in these 4- to 5-week-old TGM animals (Figure 8C), an increase equivalent to that seen in 12- to 14-week-old mice. We also performed the RyR2 back-phosphorylation assay using purified CaMKII rather than PKA. RyR2 phosphorylation at the CaMKII site was also significantly increased (2.2 + 0.3-fold; P0.05) in 4- to 5-week-old TGM mice (Figure 8C). (http://dx.doi.org/10.1161/01.RES.0000069686.31472.C5) The association of CaMKII with the RyR2 is consistent with a physical interaction between this protein kinase and its substrate. The catalytic subunit of PKA and the phosphatases PP1 and PP2A were also present in the RyR2 immunoprecipitates, but not different in WT versus TG mouse hearts (Figure 8D). These data provide further evidence that
However, the CaMK genes expressed in these mice are neither the endogenous isoforms of the enzyme nor the isoforms likely to regulate cytoplasmic Ca(2+) handling, because they localize to the nucleus.
We suggest that the CaMKIIδ isoforms are differentially regulated in pressure-overload–induced hypertrophy, because the expression of CaMKIIδC is selectively increased as early as 1 day after TAC. Studies using RT-PCR confirm that
In conclusion, we demonstrate here that CaMKIIδC can phosphorylate RyR2 and PLB when expressed in vivo at levels leading to 2- to 3-fold increases in its activity. Similar increases in CaMKII activity occur with TAC or in heart failure. Data presented in this study and in the accompanying article33 suggest that altered phosphorylation of Ca(2+) cycling proteins is a major component of the observed decrease in contractile function in CaMKIIδC TG mice. The occurrence of increased CaMKII activity after TAC, and of RyR and PLB phosphorylation in the CaMKIIδC TG mice suggest that
These results have major implications for considering CaMKII and its isoforms in exploring new treatment strategies for heart failure.
Daisuke Sato and Colleen E. Clancy Department of Pharmacology, University of California – Davis, Davis, CA. Biomedical Engineering and Computational Biology 2013:5: 69–75 http://www.la-press.com. http://dx.doi.org/10.4137/BECB.S10960 Abstract: Cardiac alternans describes contraction of the ventricles in a strong-weak-strong-weak sequence at a constant pacing frequency. Clinically, alternans manifests as alternation of the T-wave on the ECG and predisposes individuals to arrhythmia and sudden cardiac death. In this review, we focus on the fundamental dynamical mechanisms of alternans and show how alternans at the cellular level underlies alternans in the tissue and on the ECG. A clear picture of dynamical mechanisms underlying alternans is important to allow development of effective anti-arrhythmic strategies. The cardiac action potential is the single cellular level electrical signal that triggers contraction of the heart.1 Under normal conditions, the originating activation signal comes from a small bundle of tissue in the right atrium called the sinoatrial node (SAN). The action potentials generated by the SAN initiate an excitatory wave that, in healthy tissue, propagates smoothly through a well-defined path and causes excitation and contraction in the ventricles. In disease states, the normal excitation pathway is disrupted and a variety of abnormal rhythms can occur, including cardiac alternans, a well-known precursor to sudden cardiac death. Cardiac alternans was initially documented in 1872 by a German physician, Ludwig Traube.2 He observed contraction of the ventricles in a strong-weak-strong-weak sequence even though the pacing frequency was constant. Clinically, alternans manifests as alternation of the T-wave on the ECG, typically in the microvolt range. It is well established that individuals with microvolt T-wave alternans are at much higher risk for arrhythmia and sudden cardiac death. A clear picture of physiological mechanisms underlying alternans is important to allow development of effective anti-arrhythmic drugs. It is also important to understand dynamical mechanisms because while the cardiac action potential is composed of multiple currents, each of which confers specific properties, revelation of dynamical mechanisms provides a unified fundamental view of the emergent phenomena that holds independently of specific current interactions. The ventricular myocyte is an excitable cell providing the cellular level electrical activity that underlies cardiac contraction. Under resting conditions, the membrane potential is about -80 mV. When the cell is stimulated, sodium (Na) channels open and the membrane potential goes above 0 mV. Then, a few ms later, the inward current L-type calcium (Ca) current activates and maintains depolarization of the membrane potential. During this action potential plateau, several types of outward current potassium (K) channels also activate. Depending on the balance between inward and outward currents, the action potential duration (APD) is determined.The diastolic interval (DI) that follows cellular repolarization describes the duration the cell resides in the resting state until the next excitation. During the DI, channels recover with kinetics determined by intrinsic time constants. APD restitution defines the relationship between the APD and the previous DI (Fig. 1 top panel). In most cases1, the APD becomes longer as the previous DI becomes longer due to recovery of the L-type Ca channel (Fig. 1, bottom panel), and thus the APD restitution curve has a positive slope. Figure 1. (Top): APD and DI. (Bottom): The physiological mechanism of APD alternans involves recovery from inactivation of ICaL. [see http://dx.doi.org/10.4137/BECB.S10960]
In 1968 Nolasco and Dahlen showed graphically that APD alternans occurs when the slope of the APD restitution curve exceeds unity. Why is the steepness of the slope important? As shown graphically in Figure 2, APD alternans amplitude is multiplied by the slope of the APD restitution curve in each cycle. When the slope is larger than one, then the alternans amplitude will be amplified until the average slope reaches 1 or the cell shows a 2:1 stimulus to response ratio. The one-dimensional mapping between APD and DI fails to explain quasi-periodic oscillation of the APD. Figure 2. APD restitution and dynamical mechanism of APD alternans. [see http://dx.doi.org/10.4137/BECB.S10960]
A strong-weak-strong-weak oscillation in contraction implies that the Ca transient (CaT) is alternating. Until 1999 it was assumed that if the APD is alternating then the CaT alternates because the CaT follows APD changes. However, Chudin et al showed that CaT can alternate even when APD is kept constant during pacing with a periodic AP clamp waveform.14 This implies that the intracellular Ca cycling has intrinsic nonlinear dynamics. A critical component in this process is the sarcoplasmic reticulum (SR), a subcellular organelle that stores Ca inside the cell. When Ca enters a cell through the L-type Ca channel (or reverse mode Na-Ca exchanger (NCX) ryanodine receptors open and large Ca releases occur from the SR (Ca induced Ca release). The amount of Ca release steeply depends on SR Ca load. This steep relation between Ca release and SR Ca load is the key to induce CaT alternans. A one-dimensional map between Ca release and SR calcium load can be constructed to describe the relationship21 similar to the map used in APD restitution.
A number of experimental and computational studies have been undertaken to identify molecular mechanisms of CaT alternans by identifying the specific components in the calcium cycling process critical to formation of CaT alternans. These components include SR Ca leak and load, Ca spark frequency and amplitude, and rate of SR refilling. For example, experiments have shown that alternation in diastolic SR Ca is not required for CaT alternans.24 In addition, stochastic openings of ryanodine receptors (RyR) lead to Ca sparks that occur randomly, not in an alternating sequence that would be expected to underlie Ca altern-ans. So, how do local random sparks and constant diastolic SR calcium load lead to global CaT alternans? Mathematical models with detailed representations of subcellular Ca cycling have been developed in order to elucidate the underlying mechanisms. Modeling studies have shown that even when SR Ca load is not changing, RyRs, which are analogous to ICaL in APD alternans, recover gradually from refractoriness. As RyR availability increases (for example during a long diastolic interval) a single Ca spark from a RyR will be larger in amplitude and recruit neighboring Ca release units to generate more sparks. The large resultant CaT causes depletion of the SR and when complete recovery of RyRs does not occur prior to the arrival of the next stimulus, the subsequent CaT will be small. This process results in an alternans of CaT amplitude from beat-to-beat.
Importantly, the membrane voltage and intracellular Ca cycling are coupled via Ca sensitive channels such as the L-type Ca channel and the sodium-calcium exchanger (NCX). The membrane voltage dynamics and the intracellular Ca dynamics are bi-directionally coupled. One direction is from voltage to Ca. As the DI becomes longer, the CaT usually becomes larger since the recovery time for the L-type Ca channel in increased and the SR Ca release becomes larger. The other direction is from Ca to voltage. Here we consider two major currents, NCX and ICaL. As the CaT becomes larger, forward mode NCX becomes larger and prolongs APD. On the other hand, as the CaT becomes larger, ICaL becomes smaller due to Ca-induced inactivation, and thus, larger CaT shortens the APD. Therefore, depending on which current dominates, larger CaT can prolong or shorten APD. If a larger CaT prolongs (shortens) the APD, then the coupling is positive (negative). The coupled dynamics of the membrane voltage and the intracellular Ca cycling can be categorized by the instability of membrane voltage (steep APD restitution), instability of the intracellular Ca cycling (steep relation between Ca release versus SR Ca load), and the coupling (positive or negative). If the coupling is positive, alternans is electromechanically concordant (long-short-long-short APD corresponds to large-small-large-small CaT sequence) regardless of the underlying instability mechanism. On the other hand, if the coupling is negative, alternans is electromechanically concordant in a voltage-driven regime. However, if alternans is Ca driven, alternans becomes electromechanically discordant (long-short-long-short APD corresponds to small-large-small-large CaT sequence). It is also possible to induce quasi- periodic oscillation of APD and CaT when voltage and Ca instabilities contribute equally.
Tissue level alternans in APD and CaT also occur and here we describe how the dynamical mechanism of alternans at the single cell level determines the phenomena in tissue. Spatially discordant alternans (SDA) where APDs in different regions of tissue alternate out-of-phase, is more arrhythmogenic since it causes large gradients of refractoriness and wave-break, which can initiate ventricular tachycardia and ventricular fibrillation. How is SDA induced? As the APD is a function of the previous DI, conduction velocity (CV) is also function of the previous DI (CV restitution) since the action potential propagation speed depends on the availability of the sodium channel. As the DI becomes shorter, sodium channels have less time to recover. Therefore, in general, as the DI becomes shorter, the CV becomes slower. When tissue is paced rapidly, action potentials propagate slowly near the stimulus, and thenac-celerate downstream as the DI becomes longer. This causes heterogeneity in APD (APD is shorter near the stimulus). During the following tissue excitation, APD becomes longer and the CV becomes faster at the pacing site then gradually APD becomes shorter and the CV becomes slower. The interaction between steep APD restitution and steep CV restitution creates SDA. This mechanism applies only when the cellular instability is voltage driven. When the cellular instability is Ca driven, the mechanism of SDA formation is different. If the voltage-Ca coupling is negative, SDA can form without steep APD and CV restitution. The mechanism can be understood as follows. First, when cells are uncoupled, alternans of APD and Ca are electromechanically discordant. If two cells are alternating in opposite phases, once these cells are coupled by voltage, due to electrotonic coupling, the membrane voltage of both cells is synchronized and thus APD becomes the same. This synchronization of APD amplifies the difference of CaT between two cells (Fig. 5 in). In other words it desynchronizes CaT. This instability mechanism is also found in subcellular SDA. In the case where the instability is Ca driven and the coupling is positive, there are several interesting distinctive phenomena that can occur. First, the profile of SDA of Ca contains a much steeper gradient at the node (point in space where no alternans occurs–cells downstream of the node are alternating out of phase with those upstream of the node) compared to the case of voltage driven SDA. Thus, the cellular mechanism of instability can be identified by evaluating the steepness of the alternans amplitude gradient in space around the node. When the cellular instability is voltage driven, the steady-state wavelength (separation of nodes in space) depends on electrotonic coupling between cells and the steepness of APD and CV restitution, regardless of the initial conditions. However, if the cellular instability is Ca driven, the location of nodes depends on the pacing history, which includes pacing cycle length and other parameters affected by pacing frequency. In this case, once the node is formed, the location of the node may be fixed, especially when Ca instability is strong. Such an explanation may apply to recent experimental results. Summary In this review, we described how the origin of alternans at the cellular level (voltage driven, Ca drive, coupling between voltage and Ca) affects the formation of spatially discordant alternans at the tissue level. Cardiac alternans is a multi-scale emergent phenomenon. Channel properties determine the instability mechanism at the cellular level. Alternans mechanisms at cellular level determine SDA patterns at the tissue level. In order to understand alternans and develop anti-arrhythmic drug and therapy, multi-scale modeling of the heart is useful, which is increasingly enabled by emerging technologies such as general-purpose computing on graphics processing units (GPGPU) and cloud computing.
English: Diagram of contraction of smooth muscle fiber (Photo credit: Wikipedia)
2012pharmaceutical
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