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Posts Tagged ‘Ejection Fraction’


Erythropoietin (EPO) and Intravenous Iron (Fe) as Therapeutics for Anemia in Severe and Resistant CHF: The Elevated N-terminal proBNP Biomarker

 

Co-Author of the FIRST Article: Larry H. Bernstein, MD, FCAP

Reviewer and Curator of the SECOND and of the THIRD Articles: Larry H. Bernstein, MD, FCAP

and

Article Architecture Curator: Aviva Lev-Ari, PhD, RN

This article presents Advances in the Treatment using Subcutaneous Erythropoietin (EPO) and Intravenous Iron (Fe) for IMPROVEMENT of Severe and Resistant Congestive Heart Failure and its resultant Anemia.  The Leading Biomarker for Congestive Heart Failure is an Independent Predictor identified as an Elevated N-terminal proBNP.

NT-proBNP schematic diagram-Copy.pdf_page_1

FIRST ARTICLE

Anemia as an Independent Predictor of Elevated N-terminal proBNP

Salman A. Haq, MD1, Mohammad E. Alam2, Larry Bernstein, MD, FCAP3,  LB Banko 1, Leonard Y. Lee, MD, FACS4, Barry I. Saul, MD, FACC5, Terrence J. Sacchi, MD, FACC6,  John F. Heitner, MD, FACC7
1Cardiology Fellow,  2  Clinical Chemistry Laboratories, 3 Program Director, Cardiothoracic Surgery, 4 Division of Cardiology,  Department of Medicine, New York Methodist Hospital-Weill Cornell, Brooklyn, NY

(Unpublished manuscript)  Poster Presentation

SECOND ARTICLE

The effect of correction of mild anemia in severe, resistant congestive heart failure using subcutaneous erythropoietin and intravenous iron: a randomized controlled study

Donald S Silverberg, MDa; Dov Wexler, MDa; David Sheps, MDa; Miriam Blum, MDa; Gad Keren, MDa; Ron Baruch, MDa; Doron Schwartz, MDa; Tatyana Yachnin, MDa; Shoshana Steinbruch, RNa; Itzhak Shapira, MDa; Shlomo Laniado, MDa; Adrian Iaina, MDa

J Am Coll Cardiol. 2001;37(7):1775-1780. doi:10.1016/S0735-1097(01)01248-7

http://content.onlinejacc.org/article.aspx?articleid=1127229

THIRD ARTICLE

The use of subcutaneous erythropoietin and intravenous iron for the treatment of the anemia of severe, resistant congestive heart failure improves cardiac and renal function and functional cardiac class, and markedly reduces hospitalizations

Donald S Silverberg, MDa; Dov Wexler, MDa; Miriam Blum, MDa; Gad Keren, MDa; David Sheps, MDa; Eyal Leibovitch, MDa; David Brosh, MDa; Shlomo Laniado, MDa; Doron Schwartz, MDa; Tatyana Yachnin, MDa; Itzhak Shapira, MDa; Dov Gavish, MDa; Ron Baruch, MDa; Bella Koifman, MDa; Carl Kaplan, MDa; Shoshana Steinbruch, RNa; Adrian Iaina, MDa

J Am Coll Cardiol. 2000;35(7):1737-1744. doi:10.1016/S0735-1097(00)00613-6

http://content.onlinejacc.org/article.aspx?articleid=1126474

Perspective

This THREE article sequence is related by investigations occurring by me, a very skilled cardiologist and his resident, and my premedical student at New York Methodist Hospital-Weill Cornell, in Brooklyn, NY, while a study had earlier been done applying the concordant discovery, which the team in Israel had though was knowledge neglected.  There certainly was no interest in the problem of the effect of anemia on the patient with severe congestive heart failure, even though erythropoietin was used widely in patients with end-stage renal disease requiring dialysis, and also for patients with myelofibrosis.  The high cost of EPO was only one factor, the other being a guideline to maintain the Hb concentration at or near 11 g/dl – not higher.  In the first article, the authors sought to determine whether the amino terminal pro– brain type natriuretic peptide (NT-pro BNP) is affected by anemia, and to determine that they excluded all patients who had renal insufficiency and/or CHF, since these were associated with elevated NT-proBNP.  It was already well established that this pro-peptide is secreted by the heart with the action as a urinary sodium retention hormone on the kidney nephron, the result being an increase in blood volume.  Perhaps the adaptation would lead to increased stroke volume from increased venous return, but that is not conjectured.  However, at equilibrium, one would expect there to be increased red cell production to maintain the cell to plasma volume ratio, thereby, resulting in adequate oxygen exchange to the tissues.  Whether that is always possible is uncertain because any reduction in the number of functioning nephrons would make the kidney not fully responsive at the Na+ exchange level, and the NT-pro BNP would rise.  This introduces complexity into the investigation, requiring a removal of confounders to establish the effect of anemia.

The other two articles are related studies by the same group in Israel.  They surmised that there was evidence that was being ignored as to the effect of anemia, and the treatment of anemia was essential in addition to other treatments.  They carried out a randomized trial to determine just that, a benefit to treating the anemia.  But they also conjectured that an anemia with a Hb concentration below 12 g/dl has an deleterious effect on the targeted population.  Treatment by intermittent transfusions could potentially provide the added oxygen-carrying capacity, but the fractionation of blood, the potential for transfusion-transmitted disease and transfusion-reactions, combined with the need for the blood for traumatic blood loss made EPO a more favorable alternative to packed RBCs.  The proof-of-concept is told below.  Patients randomized to receive EPO at a lower than standard dose + iron did better.

 

Introduction

In this article, Erythropoietin (EPO) and Intravenous Iron (Fe) as Therapeutics for Anemia in Severe and Resistant CHF: The Elevated N-terminal proBNP Biomarker we provides a summary of three articles on the topic and we shading new light on the role that Anemia Hb < 12 g%  plays as a Biomarker for CHF and for

  • prediction of elevated BNP, known as an indicator for the following Clinical Uses:
Clinical Use
  • Rule out congestive heart failure (CHF) in symptomatic individuals
  • Determine prognosis in individuals with CHF or other cardiac disease
  • Maximize therapy in individuals with heart failure by the use of Subcutaneous Erythropoietin (EPO) and Intravenous Iron (Fe)
Evaluation of BNP and NT-proBNP Clinical Performance
Study Sensitivity(%) Specificity(%) PPV(%) NPV(%)
Diagnose impaired LVEF3
BNP 73 77 70 79
NT-proBNP 70 73 61 80
Diagnose LV systolic dysfunction after MI2
BNP 68 69 56 79
NT-proBNP 71 69 56 80
Diagnose LV systolic dysfunction after MI12
BNP 94 40 NG 96
NT-proBNP 94 37 NG 96
Prognosis in newly diagnosed heart failure patients: prediction of mortality/survival1
BNP 98 22 42 94
NT-proBNP 95 37 47 93
Prognosis post myocardial infarction: prediction of mortality2
BNP 86 72 39 96
NT-proBNP 91 72 39 97
Prognosis post myocardial infarction: prediction of heart failure2
BNP 85 73 54 93
NT-proBNP 82 69 50 91
PPV, positive predictive value; NPV, negative predictive value; LVEF, left ventricular ejection fraction; NG, not given.
Reference Range
BNP: < 100 pg/mL13
proBNP, N-terminal: 300 pg/mL
The NT-proBNP reference range is based on EDTA plasma. Other sample types will produce higher values.
Interpretive Information
Symptomatic patients who present with a BNP or NT-proBNP level within the normal reference range are highly unlikely to have CHF. Conversely, an elevated baseline level indicates the need for further cardiac assessment and indicates the patient is at increased risk for future heart failure and mortality.BNP levels increase with age in the general population, with the highest concentrations seen in those greater than 75 years of age.14 Heart failure is unlikely in individuals with a BNP level <100 pg/mL and proBNP level ≤300 pg/mL. Heart failure is very likely in individuals with a BNP level >500 pg/mL and proBNP level ≥450 pg/mL who are <50 years of age, or ≥900 pg/mL for patients ≥50 years of age. Patients in between are either hypertensive or have mild ischemic or valvular disease and should be observed closely.15BNP is increased in CHF, left ventricular hypertrophy, acute myocardial infarction, atrial fibrillation, cardiac amyloidosis, and essential hypertension. Elevations are also observed in right ventricular dysfunction, pulmonary hypertension, acute lung injury, subarachnoid hemorrhage, hypervolemic states, chronic renal failure, and cirrhosis.NT-proBNP levels are increased in CHF, left ventricular dysfunction, myocardial infarction, valvular disease, hypertensive pregnancy, and renal failure, even after hemodialysis.Although levels of BNP and NT-proBNP are similar in normal individuals, NT-proBNP levels are substantially greater than BNP levels in patients with cardiac disease due to increased stability (half-life) of NT-proBNP in circulation. Thus, results from the two tests are not interchangeable.
References
  1. Cowie MR and Mendez GF. BNP and congestive heart failure. Prog Cardiovasc Dis. 2002;44:293-321.
  2. Richards AM, Nicholls MG, Yandle TG, et al. Plasma N-terminal pro-brain natriuretic peptide and adrenomedullin. New neurohormonal predictors of left ventricular function and prognosis after myocardial infarction. Circulation. 1998:97:1921-1929.
  3. Hammerer-Lercher A, Neubauer E, Muller S, et al. Head-to-head comparison of N-terminal pro-brain natriuretic peptide, brain natriuretic peptide and N-terminal pro-atrial natriuretic peptide in diagnosing left ventricular dysfunction. Clin Chim Acta. 2001;310:193-197.
  4. McDonagh TA, Robb SD, Murdoch DR, et al. Biochemical detection of left-ventricular systolic dysfunction. Lancet. 1998;351:9-13.
  5. Mukoyama Y, Nakao K, Hosoda K, et al. Brain natriuretic peptide as a novel cardiac hormone in humans: Evidence for an exquisite dual natriuretic peptide system, ANP and BNP. J Clin Invest. 1991;87:1402-1412.
  6. Hunt PJ, Richards AM, Nicholls MG, et al. Immunoreactive amino-terminal pro-brain natriuretic peptide (NT-PROBNP): a new marker of cardiac impairment. Clin Endocrinol. 1997;47:287-296.
  7. Davis M, Espiner E, Richards G, et al. Plasma brain natriuretic peptide in assessment of acute dyspnoea. Lancet. 1994;343:440-444.
  8. Kohno M, Horio T, Yokokawa K, et al. Brain natriuretic peptide as a cardiac hormone in essential hypertension. Am J Med. 1992;92:29-34.
  9. Bettencourt P, Ferreira A, Pardal-Oliveira N, et al. Clinical significance of brain natriuretic peptide in patients with postmyocardial infarction. Clin Cardiol. 2000;23:921-927.
  10. Jernberg T, Stridsberg M, Venge P, et al. N-terminal pro brain natriuretic peptide on admission for early risk stratification of patients with chest pain and no ST-segment elevation. J Am Coll Cardiol. 2002;40:437-445.
  11. Richards AM, Troughton RW. Use of natriuretic peptides to guide and monitor heart failure therapy. Clin Chem. 2012;58:62-71.
  12. Pfister R, Scholz M, Wielckens K, et al. The value of natriuretic peptides NT-pro-BNP and BNP for the assessment of left-ventricular volume and function. A prospective study of 150 patients.Dtsch Med Wochenschr. 2002;127:2605-2609.
  13. Siemens ADVIA Centaur® BNP directional insert; 2003.
  14. Redfield MM, Rodeheffer RJ, Jacobsen SJ, et al. Plasma brain natriuretic peptide concentration: impact of age and gender. J Am Coll Cardiol. 2002;40:976-982.
  15. Weber M, Hamm C. Role of B-type natriuretic peptid (BNP) and NT-proBNP in clinical routine.Heart. 2006;92:843-849.

SOURCE

B-type Natriuretic Peptide and proBNP, N-terminal

http://www.questdiagnostics.com/testcenter/testguide.action?dc=TS_BNP_proBNP

FIRST ARTICLE

Anemia as an Independent Predictor of Elevated N-terminal proBNP

Salman A. Haq, MD1, Mohammad E. Alam2, Larry Bernstein, MD, FCAP3,  LB Banko 1, Leonard Y. Lee, MD, FACS4, Barry I. Saul, MD, FACC5, Terrence J. Sacchi, MD, FACC6,  John F. Heitner, MD, FACC7
1Cardiology Fellow,  2  Clinical Chemistry Laboratories, 3 Program Director, Cardiothoracic Surgery, 4 Division of Cardiology,  Department of Medicine, New York Methodist Hospital-Weill Cornell, Brooklyn, NY

(Unpublished manuscript)  Poster Presentation:

Anemia as an Independent Predictor of Elevated N-Terminal proBNP Levels in
Patients without Evidence of Heart Failure and Normal Renal Function.

Haq SA, Alam ME, Bernstein L, Banko LB, Saul BI, Lee LY, Sacchi TJ, Heitner JF.

Table 1.  Patient Characteristics

Variable No Anemia(n=138) Anemia(n=80)
Median Age (years) 63 76
Men (%) 35 33
Creatinine (mg/dl) 0.96 1.04
Hemoglobin (g/dl) 13.7 10.2
LVEF (%) 67 63
Median NT-proBNP (pg/ml) 321.6 1896.0

Poster-ProBNP_final[1]

A series of slide showing the determination of the representation of normal NT-proBNP range
after removal of patient confounders.

Slide1

Slide10

Slide5

Slide8

ABSTRACT

Introduction

N-terminal proBNP (NT-proBNP) has emerged as a primary tool for diagnosing congestive heart failure (CHF). Studies have shown that the level of

  • NT-proBNP is affected by renal insufficiency (RI) and age, independent of the diagnosis of CHF.

There is some suggestion from recent studies that

  • anemia may also independently affect NT-proBNP levels.

Objective

To assess the affect of anemia on NT-proBNP independent of CHF, RI, and age.

Methods

We evaluated 746 consecutive patients presenting to the Emergency Department (ED) with shortness of breath and underwent evaluation with serum NT-proBNP.

All patients underwent a trans-thoracic echocardiogram (TTE) and clinical evaluation for CHF. Patients were included in this study if they had a normal TTE (normal systolic function, mitral inflow pattern and left ventricular (LV) wall thickness) and no evidence of CHF based on clinical evaluation. Patients were excluded if they had RI (creatinine > 2 mg/dl) or a diagnosis of sepsis. Anemia was defined using the World Health Organization (W.H.O.) definition of

  • hemoglobin (hgb) < 13 g/dl for males and hgb < 12 g/dl for females.

Results

Of the 746 consecutive patients, 218 patients (138 anemia, 80 no anemia) met the inclusion criteria. There was a markedly significant difference between

  • NT- proBNP levels based on the W.H.O. diagnosis of anemia.

Patients with anemia had a

  • mean NT- proBNP of 4,735 pg/ml compared to 1,230 pg/ml in patients without anemia (p=0.0001).

There was a markedly

  • significant difference in patients who had a hgb > 12 (median 295 pg/ml) when compared to
  • both patients with an hgb of 10.0 to 11.9 (median 2,102 pg/ml; p = 0.0001) and
  • those with a hgb < 10 (median 2,131 pg/ml; p = 0.001).

Linear regression analysis comparing hgb with log NT-proBNP was statistically significant (r = 0.395; p = 0.0001). MANOVA demonstrated that

  • elevated NT- proBNP levels in patients with anemia was independent of age.

Conclusion

This study shows that NT-proBNP is associated with anemia independent of CHF, renal insufficiency, sepsis or age.

INTRODUCTION

B-type natriuretic peptide (BNP) is secreted from the myocardium in response to myocyte stretch. 1-2 BNP is released from the myocytes as a 76 aminoacid N-terminal fragment (NT-proBNP) and a 32-amino acid active hormone (BNP). 3 These peptides have emerged as a primary non-invasive modality for the diagnosis of congestive heart failure (CHF). 4- 7 In addition, these peptides have demonstrated prognostic significance in patients with invasive modality for the diagnosis of

  • congestive heart failure (CHF). 4- 7
  • heart failure 8-9,
  • stable coronary artery disease 10, and
  • in patients with acute coronary syndromes. 11-14

Studies have shown that the level of NT- proBNP is affected by

  • age and renal insufficiency (RI) independent of the diagnosis of CHF. 15,16

There is some suggestion from the literature that

  • anemia may also independently affect NT-proBNP levels. 17-20

Willis et al. demonstrated in a cohort of 209 patients without heart failure that anemia was associated with an elevated NT- proBNP. 17 Similarly, in 217 patients undergoing cardiac catheterization, blood samples were drawn from the descending aorta prior to contrast ventriculography for BNP measurements and

  • anemia was found to be an independent predictor of plasma BNP levels. 18

The objective of this study is to assess the effect of anemia on NT-proBNP independent of CHF, sepsis, age or renal insufficiency.

METHODS

Patient population

The study population consisted of 746 consecutive patients presenting to the emergency room who underwent NT-proBNP evaluation for the evaluation of dyspnea. Transthoracic echocardiogram (TTE) was available on 595 patients. Patients were included in this study if they had a normal TTE, which was defined as normal systolic function (left ventricular ejection fraction [LVEF] > 45%), normal mitral inflow pattern and normal LV wall thickness. CHF was excluded based on thorough clinical evaluation by the emergency department attending and the attending medical physician. Patients with disease states that may affect the NT- proBNP levels were also excluded:

  1. left ventricular systolic dysfunction (LVEF < 45%),
  2. renal insufficiency defined as a creatinine > 2 mg/dl and
  3. sepsis (defined as positive blood cultures with two or more of the following systemic inflammatory response syndrome (SIRS) criteria: heart rate > 90 beats per minute;
  4. body temperature < 36 (96.8 °F) or > 38 °C (100.4 °F);
  5. hyperventilation (high respiratory rate) > 20 breaths per minute or, on blood gas, a PaCO2 less than 32 mm Hg;
  6. white blood cell count < 4000 cells/mm3 or > 12000 cells/mm³ (< 4 x 109 or > 12 x 109 cells/L), or greater than 10% band forms (immature white blood cells). 21

The study population was then divided into two groups, anemic and non- anemic. Anemia was defined using the world health organization (W.H.O.) definition of hemoglobin (hgb) < 13 g/dl for males and < 12 g/dl for females.The data was also analyzed by dividing the patients into three groups based on hgb levels i.e. hgb > 12, hgb 10 to 11.9 and hgb < 10.

Baseline patient data

Patient’s baseline data including age, gender, ethnicity, hemoglobin (hgb), hematocrit (hct), creatinine, NT- proBNP were recorded from the electronic medical record system in our institution. Chemistry results were performed on the Roche Modular System (Indianapolis, IN), with the NT- proBNP done by chemiluminescence assay. The hemogram was performed on the Beckman Coulter GenS. All TTE’s were performed on Sonos 5500 machine. TTE data collected included LVEF, mitral inflow pattern and LV wall thickness assessment.

Statistical analysis

The results are reported in the means with p < 0.05 as the measure of significance for difference between means. Independent Student’s t-tests were done comparing NT proBNP and anemia. Univariate ANOVAs and multivariate ANOVA (MANOVA) with post hoc tests using the Bonferroni method were used to compare NT- proBNP levels with varying ranges of hgb and age using SPSS 13.0 (SPSS, Chicago, IL). A linear regression analysis was performed using SYSTAT. Calculations included Wilks’Lamda, Pillai trace and Hotelling-Lawley trace. A GOLDMineR® plot was constructed to estimate the effects of age and anemia on NT- proBNP levels. The GOLDMineR® effects plot displays the odds-ratios for predicted NT-proBNP elevation versus the predictor values. Unlike the logistic regression, the ordinal regression, which the plot is derived from, can have polychotomous as well as dichotomous values, as is the case for NT-proBNP.

RESULTS

Of the 746 consecutive patients, 218 patients met the inclusion criteria (fig 1). Baseline characteristics of patients are listed in table 1. The median age for anemic patients was 76 years and 63 years for patients without anemia. One third of patients in both groups were men. The mean hemoglobin for

  • anemic patients was 10.2 g/dl as compared to 13.7 g/dl for non-anemic patients.
  • The mean LVEF of patients with anemia was 64% as compared to 67% for non-anemic patients.

Based on the WHO definition of anemia, 138 patients were determined to be anemic while 80 patients were diagnosed as non-anemic. There was a markedly  significant difference between NT-proBNP levels based on the WHO diagnosis of anemia.

Patients with anemia had a

  • mean NT-proBNP of 4,735 pg/ml compared to 1,230 pg/ml in patients without anemia (p = 0.0001).

Of the 218 patients in the study, 55 patients had a hgb of < 10 g/dl. Analysis using

  • hgb < 10 g/dl for anemia demonstrated a statistically significant difference in the NT-proBNP values.

Patients with a hgb < 10 g/dl had a mean NT- proBNP of 5,130 pg/ml

  • compared to 2,882 pg/ml in patients with a hgb of > 10 g/dl (p = 0.01)

The groups were also divided into three separate categories of hgb for subset analysis:

  • hgb > 12 g/dl,
  • hgb 10 to 11.9 g/dl and
  • hgb < 10 g/dl.

There was a markedly significant difference in

  •  the NT- ProBNP levels of patients who had a hgb > 12 g/dl (median 295 pg/ml) when
  • compared to those with a hgb range of 10.0 g/dl to 11.9 g/dl (median 2,102 pg/ml) (p = 0.0001),

and also a significant difference in

  • NT- proBNP levels of patients with a hgb > 12 g/dl (median 295 pg/ml) when
  • compared to a hgb of < 10 g/dl (median 2,131 pg/ml) (p = 0.001).

However, there was no statistically significant difference in NT-proBNP levels of patients with hgb 10 g/dl to 11.9 g/dl

  • when compared to those with a hgb of < 10 g/dl (p = 1.0).

A scatter plot comparing hgb with log NT-proBNP and fitting of a line to the data by ordinary least squares regression was significant (p = 0.0001) and demonstrated

  • a correlation between anemia and NT-proBNP levels (r = 0.395) (fig. 2).

MANOVA demonstrated that elevated NT- proBNP levels in patients with anemia was independent of age (Wilks’ Lambda [p = 0.0001]). In addition, using GOLDMineR® plots (figure 3a and 3b) with a combination of age and hb scaled as predictors of elevated NT-proBNP,

  • both age and hgb were required as independent predictors.

What about the effect of anemia? The GOLDminer analysis of ordinal regression was carried out in a database from which renal insufficiency and CHF were removed. The anemia would appear to have an independent effect on renal insufficiency. Figure 4 is a boxplot comparison of NT – proBNP, the age normalized function NKLog (NT- proBNP)/eGFR formed from taking 1000*Log(NT- proBNP) divided by the MDRD at eGFR exceeding 60 ml/min/m2 and exceeding 30 ml/min/m2. The transformed variable substantially makes the test independent of age and renal function. The boxplot shows the medians, 97.5, 75, 25 and 2.5 percentiles. There appears to be no significance in the NKLog(NT pro-BNP)/MDRD plot. Table II compares the NT-proBNP by WHO criteria at eGFR 45, 60 and 75 ml/mln/m2 using the t-test with unequal variance assumed, and the Kolmogorov-Smirnov test for nonparametric measures of significance. The significance at 60 ml/min/m2 is marginal and nonexistent at 75 ml/min/m2. This suggests that the contribution from renal function at above 60 ml/min2 can be ignored. This is consistent with the findings using the smaller, trimmed database, but there is an interaction between

  •  anemia, and
  •  eGFR at levels below 60 ml/min/m2

DISCUSSION

The findings in this study indicate that

  • anemia was associated with elevated NT-proBNP levels independent of CHF, renal insufficiency, sepsis or age.

These findings have been demonstrated with NT-proBNP in only one previous study. Wallis et al. demonstrated that after adjusting for age, sex, BMI, GFR, LVH and valvular disease;

  1. only age,
  2. valvular disease and
  3. low hemoglobin

were significantly associated with increased NT-proBNP. 18.

In our study, CHF was excluded based on both a normal TTE and a thorough clinical evaluation. In the only other study directly looking at NT- proBNP levels in anemic patients without heart failure

  • only 25% of patients had TTEs, with one patient having an LVEF of 40%. 17

BNP, the active molecule released after cleavage along with NT- proBNP, has also been studied in relation to blood hemoglobin levels. 18 In 263 patients undergoing cardiac catheterization  blood samples were drawn from the descending aorta prior to contrast ventriculography to determine the value of BNP. Anemia was present in 217 patients. Multivariate linear regression model adjusting for

  1.  age,
  2.  gender,
  3.  body mass index,
  4.  history of myocardial infarction,
  5.  estimated creatinine clearance, and
  6.  LVEF
  • found hgb to be an independent predictor of BNP levels.

In our study, patients with anemia were slightly older than those without anemia. However, both MANOVA and GOLDMineR® plot demonstrated that

  • elevated NT-proBNP levels in patients with anemia was independent of age.

Other studies have found that BNP is dependent on renal insufficiency and age. Raymond et al. randomly selected patients to complete questionnaires regarding CHF and

  1. then underwent pulse and blood pressure measurements,
  2.  electrocardiogram (ECG),
  3.  echocardiography and
  4.  blood sampling. 15

A total of 672 subjects were screened and 130 were determined to be normal, defined as

  • no CHF or ischemic heart disease,
  • normal LVEF,
  • no hypertension,
  • diabetes mellitus,
  • lung disease, and
  • not on any cardiovascular drugs.

They found

  1. older age,
  2. increasing dyspnea,
  3. high plasma creatinine and a
  4. LVEF < 45%

to be independently associated with an elevated NT-proBNP plasma level by multiple linear regression analysis. In another study, McCullough et al. evaluated the patients from the Breathing Not Properly Multinational Study

  • looking at the relationship between BNP and renal function in CHF. 16

Patients were excluded if they were on hemodialysis or had a estimated glomerular filteration rate (eGFR) of < 15 ml/min. They found that the BNP levels correlated significantly with the eGFR, especially in patients without CHF, suggesting

  1. chronic increased blood volume and
  2. increased left ventricular wall tension as a possible cause. 16

Our study was designed to exclude patients with known diseases such as CHF and renal insufficiency in order to demonstrate

  • the independent effect of anemia on elevated NT-proBNP levels.

The mechanism for elevated NT-proBNP levels in patients with anemia is unknown. Some possible mechanisms that have been reported in the literature include

  • hemodilution secondary to fluid retention in patients with CHF 18,
  • decreased oxygen carrying capacity with accompanying tissue hypoxia which
  • stimulates the cardio-renal compensatory mechanism leading to increased release of NT-proBNP. 17

The findings from our study suggest that

  •  NT-proBNP values should not be interpreted in isolation of hemoglobin levels and
  • should be integrated with other important clinical findings for the diagnosis of CHF.

Further studies are warranted

  1.  to assess the relationship between anemia and plasma natriuretic peptides, and
  2. possibly modify the NT-proBNP cutoff points for diagnosing acutely decompensated CHF in patients with anemia.

CONCLUSION

This study shows that elevated NT-proBNP levels are associated with anemia independent of

  •   CHF,
  •  renal insufficiency,
  •  sepsis and
  •  age.

NT-proBNP levels should be interpreted with caution in patients who have anemia.

 REFERENCES

1. Brunea BG, Piazza LA, de Bold AJ. BNP gene expression is specifically modulated by stretch and ET-1 in a new model of isolated rat atria.Am J Physiol  1997; 273:H2678-86.

2. Wiese S, Breyer T, Dragu A, et al. Gene expression of brain natriuretic peptide  in isolated atrial and ventricular human myocardium: influence of angiotensin II and diastolic fiber length. Circ 2000; 102:3074-79.

3. de Lemos JA, McGuire DK, Drazner MH. B-type natriuretic peptide in cardiovascular disease. Lancet 2003; 362:316-22.

4.   Dao Q, Krishnaswamy P, Kazanegra R, et al. Utility of B-type natriuretic  peptide in the diagnosis of congestive heart failure in an urgent care setting. J Am  Coll Cardiol 2001; 37:379-85.

5. Morrison LK, Harrison A, Krishnaswamy P, Kazanegra R, Clopton P, Maisel A. Utility of rapid natriuretic peptide assay in differentiating congestive heart failure from lung  disease in patients presenting with dyspnea.
J Am Coll Cardiol  2003; 39:202-09.

6.  Maisel AS, Krishnaswamy P, Nowak RM, et al.  Rapid measurement of B-type natriuretic peptide in the emergency diagnosis of heart failure. N Engl J Med 2002; 347:161-67.

7. Januzzi JL, Camargo CA, Anwaruddin S, et al. The N-terminal Pro-BNP investigation of dyspnea in the emergency department (PRIDE) study. Am J  Cardiol 2005; 95:948-954.

8.  Tsutamoto T, Wada A, Meada K, et al.   Attenuation of compensation of  endogenous cardiac natriuretic peptide system  in chronic heart failure: prognostic role  of plasma  brain natriuretic peptide concentration in patients with chronic  symptomatic  left ventricular dysfunction.
Circulation 1997; 96(2): 509-16.

9.  Anand IS, Fisher LD, Chiang YT, et al. Changes in brain natriuretic peptide and norepinephrine over time and mortality and morbidity in the Valsartan Heart Failure Trial (Val-HEFT). Circulation 2003; 107:1278-1283.

10. Omland T, Richards AM, Wergeland R and Vik-Mo H. B-type natriuretic peptide and long term survival in patients with stable coronary artery disease.
Am J Cardiol 2005; 95:24-28.

11. Omland T, Aakvaag A, Bonarjee VV. et al. Plasma brain natriuretic peptide as an indicator of left ventricular systolic dysfunction and long term prognosis after acute myocardial infarction. Comparison with plasma atrial natriuretic peptide and N-terminal proatrial natriuretic peptide.
Circulation 1996; 93:1963-1969.

12. de Lemos JA, Morrow DA, Bently JH, et al. The prognostic value of B-type natriuretic peptide in patients with acute coronary syndromes. N Engl J Med 2001; 345:1014-1021.

13. Richards AM, Nicholls MG, Espiner EA, et al. B-type natriuretic peptides and  ejection fraction for prognosis after myocardial infarction. Circulation 2003; 107:2786-2792.

14. Sabatine MS, Morrow DA, de Lemos JA, et al.  Multimarker approach to risk  stratification in non-ST elevation acute coronary syndromes: simultaneous  assessment of troponin I, C-reactive protein and B-type natriuretic peptide.
Circulation 2002; 105:1760-1763.

15. Raymond I, Groenning BA, Hildebrandt PR, Nilsson JC, Baumann M, Trawinski   J, Pedersen F.  The influence of age, sex andother variables on the plasma level of N-terminal pro brain natriureticpeptide in a large sample of the general  population. Heart 2003; 89:745-751.

16. McCollough PA, Duc P, Omland T, McCord J, Nowak RM, Hollander JE, et al. B-type natriuretic peptide and renal function in the diagnosis of heartfailure:  an analysis from the  Breathing Not Properly Multinational Study.
Am J Kidney Dis 2003; 41:571-579.

17. Willis MS, Lee ES, Grenache DG. Effect of anemia on plasma concentrations of  NT-proBNP.
Clinica Chim Acta 2005; 358:175-181.

18. Wold Knudsen C, Vik-Mo H, Omland T. Blood hemoglobin is an independent  predictor of B-type natriuretic peptide.
Clin Sci 2005; 109:69-74.

19. Tsuji H, Nishino N, Kimura Y, Yamada K, Nukui M, et al. Haemoglobin level influences plasma brain natriuretic peptide concentration. Acta Cardiol 2004;59:527-31.

20. Wu AH, Omland T, Wold KC, McCord J, Nowak RM, et al. Relationship  of B-type natriuretic peptide and anemia  in patients withand without heart failure:  A substudy from the Breathing Not Properly(BNP) Multinational Study.
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22. Bone RC, Balk RA, Cerra FB, Dellinger RP, Fein AM, et al.  Definitions for sepsis and organ failure and guidelines for theuse of innovative therapies in sepsis.  The ACCP/SCCM Consensus Conference Committee. Chest. 1992;101(6):1644-55.

Table Legends

Table I. Clinical characteristics of the study population

Table II. Comparison of NT- proBNP means under WHO criteria at different GFR

Table I
Variable No Anemia(n=80) Anemia(n=138)
Median age (years) 63 76
Gender
    Men (%) 27 (34) 47 (34)
    Women (%) 53 (66) 91 (66)
Weight (kg) 82.9 80.1
Chest Pain 21 (26) 3 (2)
Hemoglobin (g/dl) 13.7 10.2
Hematocrit (%) 40.5 30.5
Mean Corpuscular Volume 97 87
Creatinine (mg/dl) 0.99 1.07
Median NT-proBNP (pg/ml) 321 1896
Medical History
    HTN (%) 12 (15) 51 (37)
    Prior MI (%) 11 (14) 5 (4)
    ACS (%) 16 (20) 3 (2)
    CAD (%) 2 (1) 3 (2)
     DM (%) 18 (22) 11 (8)
Medication
   Clopidogrel 58 (72) 15 (11)
   Beta Blockers 68 (85) 27 (20)
   Ace Inhibitors 45 (56) 18 (13)
   Statins 57 (71) 17 (12)
   Calcium Channel Blocker 17 (21) 8 (6)
LVEF (%) 67 64

HTN: Hypertension CAD: Coronary Artery Disease
MI: Myocardial Infarction DM: Diabetes Mellitus
ACS: Acute Coronary Syndrome LVEF: Left Ventricular Ejection Fraction

Table II
GFR WHO Mean P (F) N NPar
> 45 0 3267 0.022 (4.33) 661
1 4681
> 60* 0 2593 0.031 (5.11) 456 0.018
1 4145
> 60r 0 786 0.203 (3.63) 303 0.08
1 3880
> 75 0 2773 > 0.80 320 0.043
1 3048

*AF, valve disease and elevated troponin T included
r AF, valve disease and elevated troponin T removed

FIGURE LEGENDS

FIGURE 1. Study population flow chart. (see poster)
FIGURE 2. Relationship between proBNP and hemoglobin. (see above)
FIGURE 3. NT-proBNP levels in relation to anemia (see above)

Supplementary Material

Table based on LatentGOLD Statistical Innovations, Inc., Belmont, MA., 2000: Jeroen Vermunt & Jay Magidson)

4-Cluster Model

Number of cases                                   408
Number of parameters (Npar)             24

Chi-squared Statistics
Degrees of freedom (df)                          71                     p-value
L-squared (L²)                                    80.2033                    0.21
X-squared                                            80.8313                     0.20
Cressie-Read                                        76.6761                     0.30
BIC (based on L²)                          -346.5966
AIC3 (based on L²)                        -132.7967
CAIC (based on L²)                       -417.5966

Model for Clusters
 Intercept                Cluster1      Cluster2     Cluster3     Cluster4     Wald     p-value
————–           0.1544           0.1434        0.0115        -0.3093     1.1981     0.75
Cluster Size           0.2870          0.2838       0.2487          0.1805
(across)

LogNTpr
< 1.5                       0.0843           0.2457       0.0006          0.0084
1.6-2.5                   0.6179            0.6458       0.0709          0.2809
2.5-3.5                  0.2848           0.1067         0.5319          0.5883
> 3.5                      0.0130           0.0018         0.3966         0.1224
MDRD
> 90                     0.1341             0.7919         0.0063         0.6106
61-90                  0.6019            0.2040          0.1633         0.3713
41-60                  0.2099            0.0041          0.3317         0.0175
< 41                     0.0542            0.0001         0.4987        0.0006
age
under 51           0.0668           0.5646          0.0568        0.0954
51-70                 0.3462            0.3602          0.3271         0.3880
over 70             0.5870            0.0752          0.6161         0.5166
WHO
No anemia      0.7518             0.6556          0.2041         0.0998
Anemia            0.2482             0.3444          0.7959         0.9002

———          Cluster1          Cluster2      Cluster3      Cluster4
Overall           0.2870            0.2838         0.2487        0.1805
(down)

LogNTpro
< 1.5                0.2492              0.7379           0.0013         0.0116
1.6-2.5            0.4163               0.4243           0.0427        0.1167
2.6-3.5           0.2296               0.0887          0.3723        0.3095
> 3.5              0.0328                0.0023          0.7982        0.1666
MDRD
> 90              0.1001                0.5998           0.0043        0.2958
61-90           0.5198                 0.1716           0.1136         0.1950
41-60           0.3860                 0.0055          0.5847         0.0238
< 41             0.1205                  0.0002          0.8785         0.0008
 age
< 51            0.0720                 0.7458           0.0910          0.0912
51-70         0.3036                 0.3084           0.2013          0.1867
over 70     0.3773                  0.0409          0.3633           0.2186
 WHO
No anemia 0.4589              0.3957           0.1076           0.0378
Anemia     0.1342                 0.1844            0.3742           0.3073

Hemoglobin on NT proBNP 3

SECOND ARTICLE

The effect of correction of mild anemia in severe, resistant congestive heart failure using subcutaneous erythropoietin and intravenous iron: a randomized controlled study

Donald S Silverberg, MDa; Dov Wexler, MDa; David Sheps, MDa; Miriam Blum, MDa; Gad Keren, MDa; Ron Baruch, MDa; Doron Schwartz, MDa; Tatyana Yachnin, MDa; Shoshana Steinbruch, RNa; Itzhak Shapira, MDa; Shlomo Laniado, MDa; Adrian Iaina, MDa

J Am Coll Cardiol. 2001;37(7):1775-1780. doi:10.1016/S0735-1097(01)01248-7

http://content.onlinejacc.org/article.aspx?articleid=1127229

OBJECTIVES

This is a randomized controlled study of anemic patients with severe congestive heart failure (CHF) to assess the effect of correction of the anemia on cardiac and renal function and hospitalization.

BACKGROUND

Although mild anemia occurs frequently in patients with CHF, there is very little information about the effect of correcting it with erythropoietin (EPO) and intravenous iron.

METHODS

Thirty-two patients with moderate to severe CHF (New York Heart Association [NYHA] class III to IV)
who had a left ventricular ejection fraction (LVEF) of 40% despite maximally tolerated doses of CHF medications and
  • whose hemoglobin (Hb) levels were persistently between 10.0 and 11.5 g% were randomized into two groups.
Group A (16 patients) received subcutaneous EPO and IV iron to increase the level of Hb to at least 12.5 g%. In Group B (16 patients) the anemia was not treated. The doses of all the CHF medications were maintained at the maximally tolerated levels except for oral and intravenous (IV) furosemide, whose doses were increased or decreased according to the clinical need.

RESULTS

Over a mean of 8.2 +/- 2.6 months,
  • four patients in Group B and none in Group A died of CHF-related illnesses.
  • The mean NYHA class improved by 42.1% in A and worsened by 11.4% in B.
  • The LVEF increased by 5.5% in A and decreased by 5.4% in B.
  • The serum creatinine did not change in A and increased by 28.6% in B.
  • The need for oral and IV furosemide decreased by 51.3% and 91.3% respectively in A and increased by 28.5% and 28.0% respectively in B.
  • The number of days spent in hospital compared with the same period of time before entering the study decreased by 79.0% in A and increased by 57.6% in B.

CONCLUSIONS

When anemia in CHF is treated with EPO and IV iron, a marked improvement in cardiac and patient function is seen,
  • associated with less hospitalization and renal impairment and less need for diuretics. (J Am Coll Cardiol 2001;37:1775– 80)

Anemia of any cause is known to be capable of causing congestive heart failure (CHF) (1). In patients hospitalized with CHF the 

  • mean hemoglobin (Hb) is about 12 g% (2,3),

which is considered the lower limit of normal in adults (4). Thus, anemia appears to be

common in CHF. Recently, in 142 patients in our special CHF outpatient clinic, we found that

  • as the CHF worsened, the mean Hb concentration decreased, from 13.7 g% in mild CHF (New York Heart Association [NYHA] class I) to 10.9 g% in severe CHF (NYHA 4), and
  • the prevalence of a Hb 12 g% increased from 9.1% in patients with NYHA 1 to 79.1% in those with NYHA 4 (5).
The Framingham Study has shown that anemia is an
  • independent risk factor for the production of CHF (6).
Despite this association of CHF with anemia,
  • its role is not mentioned in the 1999 U.S. guidelines for the diagnosis and treatment of CHF (7), and
  • many studies consider anemia to be only a rare contributing cause of hospitalization for CHF (8,9).
Recently, we performed a study in which the anemia of severe CHF that was resistant to maximally tolerated doses of standard medications
  • was corrected with a combination of subcutaneous (sc) erythropoietin (EPO) and intravenous iron (IV Fe) (5).
We have found this combination to be safe, effective and additive
  • in the correction of the anemia of chronic renal failure (CRF) in both
  • the predialysis period (10) and the dialysis period (11).
The IV Fe appears to be more effective than oral iron (12,13). In our previous study of CHF patients (5), the treatment resulted in
  • improved cardiac function,
  • improved NYHA functional class,
  • increased glomerular filtration rate,
  • a marked reduction in the need for diuretics and
  • a 92% reduction in the hospitalization rate
compared with a similar time period before the intervention. In the light of these positive results, a prospective randomized study was undertaken
  • to determine the effects of the correction of anemia in severe symptomatic CHF resistant to maximally tolerated CHF medication.

Abbreviations and Acronyms

CABG coronary artery bypass graft
CHF congestive heart failure
CRF chronic renal failure
EPO erythropoietin
%Fe Sat percent iron saturation
GFR glomerular filtration rate
Hb hemoglobin
Hct hematocrit
IU international units
IV intravenous
LVEF left ventricular ejection fraction
NYHA New York Heart Association
PA pulmonary artery
sc subcutaneous
SOLVD Studies Of Left Ventricular Dysfunction

MATERIALS AND METHODS

Patients.Thirty-two patients with CHF were studied. Before the study, the patients were treated for least six months in the CHF clinic with

  • maximally tolerated doses of angiotensin-converting enzyme inhibitors, the beta-blockers bisoprolol or carvedilol, aldospirone, long-acting nitrates, digoxin and oral and intravenous (IV) furosemide.

In some patients these agents could not be given because of contraindications and in others they had to be stopped because of side effects. Despite this maximal treatment

  • the patients still had severe CHF  (NYHA classIII), with  fatigue and/or shortness of breath  on even mild exertion or at rest.  All had levels of
  • Hb in the range of 10 to 11.5 g%  on at least three consecutive visits over a three-week period.
  • All had a LVEF of 40%.

Secondary causes of anemia including hypothyroidism, and folic acid and vitamin B12 deficiency were ruled out and

  • there was no clinical evidence of gastrointestinal bleeding.

The patients were randomized consecutively into two groups:

  • Group A, 16 patients, was treated with sc EPO and IV Fe to achieve a target Hb of at least 12.5 g%.
  • Group B, 16 patients, did not receive the EPO and IV Fe.

Treatment protocol for correction of anemia.

All patients in Group A received the combination of sc EPO and IV Fe. The EPO was given once a week at a starting dose of 4,000 international units (IU) per week  and
the dose was increased  to two  or  three  times a week or decreased to once every few weeks as  necessary

  • to achieve and maintain a target Hb of 12.5 g%.

The IV Fe (Venofer-Vifor International, Switzerland), a ferric sucrose product, was given in a dose of 200 mg IV in 150 ml saline over 60 min every two weeks

  • until the serum ferritin reached 400 g/l or
  • the %Fe saturation (%Fe Sat is serum iron/total iron binding capacity 100) reached 40% or
  • the Hb reached 12.5g%. 

The IV Fe was then given at longer intervals as needed to maintain these levels.

Investigations. 

Visits to the clinic were at two- to three week intervals depending on the patient’s status. This was the same frequency of visits to the CHF clinic as before then,

  • potassium and ferritin and %Fe Sat were performed on every visit.
  • blood pressure was measured by an electronic device on every visit.
  • LVEF was measured initially and at four- to six-month intervals by MUGA radioisotope ventriculography.

This technique measures

  • the amount of blood in the ventricle at the end of systole and at the end of diastole, thus giving
  • a very accurate assessment of the ejection fraction.

It has been shown to be an accurate and reproducible method of measuring the ejection fraction (14).  Hospital records were reviewed at the end of the intervention period to compare

  • the number of days hospitalized during the study with 
  • the number of days hospitalized during a similar period 
    • when the patients were treated in the CHF clinic before the initial randomization and entry into the study.

Clinic records were reviewed to evaluate the types and doses of CHF medications used before and during the study. The mean follow-up for patients was 8.2 +/-  2.7 months (range 5 to 12 months).  The study was done with the approval of the local ethics committee.Statistical analysis.

An analysis of variance with repeated measures (over time) was performed to compare the two study groups (control vs. treatment) and

  • to assess time trend and the interactions between the two factors.
  • A separate analysis was carried out for each of the outcome parameters.
  • The Mann-Whitney test was used to compare the change in NYHA class between two groups.

All the statistical analysis was performed by SPSS (version 10).

RESULTS

The mean age in Group A (EPO and Fe) was 75.3 +/-  14.6 years and in group B was 72.2 +/-  9.9 years. There were 11 and 12 men in Groups A and B, respectively.
Before the study the two groups were similar in
  1. cardiac function,
  2. comorbidities,
  3. laboratory investigations and
  4. medications
  • (Tables 1, 2 and 3), except for IV furosemide (Table 3),
which was higher in the treatment group. The mean NYHA class of Group A before the study was 3.8  0.4 and was 3.5  0.5 in Group B. The contributing factors to CHF in Groups A and B, respectively, are seen in Table 1 and were similar.
Table 1. Medical Conditions and Contributing Factors to Congestive Heart Failure in the 16 Patients Treated for the Anemia and in the 16 Controls

Table 1 medical conditions heart failure anemia

Table 2. The Effect of Correction of Anemia by Intravenous Iron and Erythropoietin Therapy on Various Parameters in 16 Patients in the Treatment (A) and 16 in the Control (B) Group

Table 2 medications to treat heart failure anemia

p values are given for analysis of variance with repeated measures and for independent t tests for comparison of baseline levels between the two groups.
BP  blood pressure; Fe Sat  iron saturation; Hb  hemoglobin; IV  intravenous; NS  not stated; Std Dev.  standard deviation.

The main contributing factors to CHF were considered to be

  • ischemic heart disease (IHD) in 11 and 10 patients respectively,
  • hypertension in two and two patients,
  • valvular heart disease in twoand two patients, and
  • idiopathic cardiomyopathy in one and two patients, respectively.

A significant change after treatment was observed in the two groups in the following parameters:

  • IV furosemide,
  • days in hospital,
  • Hb,
  • ejection fraction,
  • serum creatinine and
  • serum ferritin.
In addition, the interaction between the study group and time trend was significant in all measurements except for blood pressure and %Fe Sat. This interaction indicates that
  • the change over time was significantly different in the two groups.
Table 3. The Effect of Correction of Anemia by Intravenous Iron and Erythropoietin Therapy on Various Parameters in 16 Patients in the Treatment (A) and 16 in the Control (B) Group

Table 3  CHF aneia EPO

p values are given for analysis of variance with repeated measures and for independent t tests for comparison of baseline levels between the two groups.
BP  blood pressure; Fe Sat  iron saturation; Hb  hemoglobin; IV  intravenous; NS  not stated; Std Dev.  standard deviation.

We find in the comparisons of Tables 2 and 3:

  1. before treatment the level of oral furosemide was higher in the control group (136.2 mg/day) compared with the treatment group (132.2 mg/day).
  2. after treatment, while the dose of oral furosemide of the treated patients was reduced  to 64.4 mg/day
  • the dose of the nontreated patients was increased to 175 mg/day.

The same results of improvement in the treated group and deterioration in the control group are expressed in the following parameters:

  1. IV furosemide, days in hospital,
  2. Hb,
  3. ejection fraction and
  4. serum creatinine.

The NYHA class was

  • 3.8 +/- 0.4 before treatment and 2.2 +/- 0.7 after treatment in Group A  (delta mean = – 1.6) and
  • 3.5 +/-  0.7 before treatment and 3.9 +/- 0.3 after treatment in Group B. (delta mean = 0.4)

The improvement in NYHA class was significantly higher (p < 0.0001) in the treatment group compared with the control group (Table 4).

Table 4. Changes from Baseline to Final New York Heart Association (NYHA) Class
Initial minus final

Table 4  changes from NYHA baseline  CHF anemia

The improvement in NYHA class was statistically higher (p <  0.0001) in the treatment group compared with control.

There were no deaths in Group A and four deaths in Group B.

Case 1: A 71-year-old woman with severe mitral insufficiency and severe pulmonary hypertension  (a pulmonary artery [PA] pressure of 75 mm Hg) had persistent NYHA 4 CHF  and died during mitral valve surgery  seven months after onset of the study. She was hospitalized for 21 days  in the seven months before randomization and for 28 days  during the seven months after randomization.

Case 2:

A 62-year-old man with a longstanding history of hypertension complicated by IHD, coronary artery bypass graft (CABG) and atrial fibrillation had persistent NYHA 4 CHF  and a PA pressure of 35 mm Hg,  and died from pneumonia and septic shock eight months after onset of the study. He was hospitalized for seven days in the eight months before randomization and for 21 days during the eight months  after
randomization.

Case 3:
A 74-year old man with IHD, CABG, chronic obstructive pulmonary disease, a history of heavy smoking and diabetes had persistent NYHA 4 CHF and a PA pressure of  28 mm Hg, and died of pulmonary  edema and cardiogenic shock nine months after onset of the study. He was hospitalized for 14 days in the nine months before  randomization and for 41 days during the nine months after randomization.

Case 4:
A 74-year-old man with a history of IHD, CABG, diabetes, dyslipidemia, hypertension and atrial fibrillation, had persistent NYHA 4 CHF and a PA pressure of 30 mm Hg,  and died of pneumonia and septic shock   six months after onset of the study. He was hospitalized for five days in the six months before randomization and for 16 days during the nine months after randomization.

DISCUSSION

 Main findings.

The main finding of the present study is that the correction of

  • even mild anemia in patients with symptoms of very severe CHF despite being on maximally tolerated drug therapy
  • resulted in a significant improvement in their cardiac function and NYHA functional class.

There  was also a large

  • reduction in the number of days of  hospitalization compared with a similar period before the  intervention.
  • all this was achieved despite a marked reduction in the dose of oral and IV furosemide.

In the group in whom the anemia was not treated, four  patients died during the study. In all four cases

  • the CHF was unremitting and contributed to the deaths. 

In addition,  for the group as a whole, 

  • the LVEF, the NYHA class and  the renal function worsened.

There was also need for

  • increased oral and IV furosemide as well as increased  hospitalization.

Study limitations.

The major limitations of this study are

  1. the smallness of the sample size and
  2. the fact that randomization and treatment were not done in a blinded fashion.

Nevertheless, the two groups were almost identical in

  1. cardiac, renal and anemia status;
  2. in the types and doses of medication they were taking before and during the intervention and
  3. in the number of hospitalization days before the intervention.

Although the results of this study, like those of  our previous uncontrolled study (5), suggest that

  • anemia may play an important role in the mortality and morbidity of  CHF,
  • a far larger double-blinded controlled study should be carried out to verify our findings.

Anemia as a risk factor for hospitalization and death in CHF.

Our results are consistent with a recent analysis of 91,316 patients hospitalized with CHF (15). Anemia was found to be a stronger predictor of

  • the need for early rehospitalization than  was hypertension,  IHD or the presence of a previous CABG.  

A recent analysis of the Studies Of Left Ventricular Dysfunction (SOLVD) (16) showed that

  • the level of hematocrit (Hct) was an independent risk factor for mortality.

During a mean follow-up of 33 months the mortality was

  • 22%, 27% and 34% for those with a Hct of 40, 35 to 40 and 35 respectively.

The striking response of our patients to

  • correction of mild anemia suggests that the failing heart may be very susceptible to anemia.

It has, in fact, been found in both animal (17) and human studies (17–19) that

  • the damaged heart is more vulnerable to anemia and/or ischemia than is the normal heart.

These stimuli may result in a more marked reduction in cardiac function than occurs in the normal heart and may explain why,  in our study,

  • the patients were so resistant to high doses of CHF medications and
  • responded so well when the anemia was treated.

Our findings about the importance of anemia in CHF are not surprising when one considers that, in dialysis patients,

  • anemia has been shown to be associated with an increased prevalence and incidence of CHF (20) and that
  • correction of anemia in these patients is associated with improved
    • cardiac function (21,22),
    • less mortality (23,24) and
    • fewer hospitalizations (23,25).

Effect of improvement of CHF on CRF.

Congestive heart failure can cause progressive renal failure (26,27). Renal ischemia is found very early on

  • in patients with cardiac dysfunction (28,29), and
  • chronic ischemia may cause progression of renal failure (30). Indeed, the development of
  • CHF in patients with essential hypertension has been found to be one of the most powerful predictors of
  • the eventual development of end-stage renal disease (31).

Patients who develop CHF after a myocardial infarction experience a

  • fall in the glomerular filtration rate (GFR) of about 1 ml/min/month if the CHF is not treated (32).

In another recent analysis of the SOLVD study, treating the CHF with

  • both angiotensin-converting enzyme inhibitors and beta-blockers resulted in better preservation of the renal function than did
  • angiotensin-converting enzyme inhibitors alone (26),
suggesting that the more aggressive the treatment of the CHF, the better the renal function is preserved. In the present study, as in our previous one (5), we found that the deterioration of GFR was prevented with
  • successful treatment of the CHF, including correction of the anemia, whereas
  • the renal function worsened when the CHF remained severe

All these findings suggest that early detection and treatment of CHF and systolic and/or diastolic dysfunction from whatever cause could prevent

  • the deterioration not only of the cardiac function
  • but of the renal function as well.

This finding has very broad implications in the prevention of CRFbecause most patients with advanced CRF have

  • either clinical evidence of CHF or at least some degree of systolic dysfunction (33).

Systolic and/or diastolic dysfunction can occur early on in many  conditions, such as

  • essential hypertension (34),
  • renal disease of any cause (35,36) or
  • IHD, especially after a myocardial infarction (37).

The early detection and adequate treatment of this cardiac dysfunction, including correction of the anemia, could prevent this cardiorenal insufficiency. To detect cardiac dysfunction early on, one would need  at least an echocardiogram and MUGA radio-nucleotide ventriculography. These tests should probably be done not only in patients with signs and symptoms of CHF,   but in all patients where CHF or systolic  and/or diastolic dysfunction are suspected, such as those with a history of heart disease or suggestive changes of ischemia or hypertrophy on the electrocardiogram, or in patients with hypertension or renal disease.

Other positive cardiovascular effects of EPO treatment.

Another possible explanation for the improved cardiac function in this study may be the direct effect that EPO itself has on improving cardiac muscle function (38,39) and myocardial cell growth (39,40) unrelated to its  effect of the anemia. In fact EPO may be  crucial in the formation of the heart muscle in utero (40). It may also improve  endothelial function (41).  Erythropoietin may be superior to blood transfusions  not only  because adverse reactions to EPO are infrequent, but also because

  • EPO causes the production and release of young cells from the bone marrow into the blood.

These cells have an oxygen dissociation curve that is shifted to the right of the normal curve, causing the release of

  • much greater amounts of oxygen into the tissues than occurs normally (42).

On the other hand, transfused blood consists of older red cells with an oxygen dissociation curve that is

  • shifted to the left, causing the release of much less oxygen into the tissues than occurs normally (42).

The combination of IV Fe and EPO. The use of IV Fe along with EPO has been found to have an additive effect, 

  • increasing the Hb even more than would occur with EPO alone while at the same time
  • allowing the dose of EPO to be reduced (10 –13).
  • The lower dose of EPO will be cost-saving and also reduce the chances of hypertension developing (43).
 We used iron sucrose (Venofer) as our IV Fe medication because, in our experience, it is extremely well tolerated (10,11) and  
  • has not been  associated  with any serious side effects in more than 1,200 patients over six years.

Implications of treatment of anemia in CHF. The correction of anemia is not a substitute for the well-documented effective therapy of CHF but seems to be  an important, if not vital,  addition to the therapy. It is surprising, therefore,  that judging from  the  literature  on CHF,

  • such an obvious treatment for improving CHF is so rarely considered.

We believe that correction of the anemia will have an important role to play in

  • the amelioration of cardiorenal insufficiency, and that this improvement will have
  • significant economic  implications as well.

Acknowledgments

The authors thank Rina Issaky, Miriam Epstein, Hava Ehrenfeld and Hava Rapaport for their secretarial assistance.
Reprint requests and correspondence: Dr. D. S. Silverberg, Department of Nephrology, Tel Aviv Medical Center, Weizman 6, Tel Aviv, 64239, Israel.

 THIRD ARTICLE

The use of subcutaneous erythropoietin and intravenous iron for the treatment of the anemia of severe, resistant congestive heart failure improves cardiac and renal function and functional cardiac class, and markedly reduces hospitalizations

Donald S Silverberg, MDa; Dov Wexler, MDa; Miriam Blum, MDa; Gad Keren, MDa; David Sheps, MDa; Eyal Leibovitch, MDa; David Brosh, MDa; Shlomo Laniado, MDa; Doron Schwartz, MDa; Tatyana Yachnin, MDa; Itzhak Shapira, MDa; Dov Gavish, MDa; Ron Baruch, MDa; Bella Koifman, MDa; Carl Kaplan, MDa; Shoshana Steinbruch, RNa; Adrian Iaina, MDa

J Am Coll Cardiol. 2000;35(7):1737-1744. doi:10.1016/S0735-1097(00)00613-6

http://content.onlinejacc.org/article.aspx?articleid=1126474

OBJECTIVES

This study evaluated the prevalence and severity of anemia in patients with congestive heart failure (CHF) and

  • the effect of its correction on cardiac and renal function and hospitalization.

BACKGROUND

The prevalence and significance of mild anemia in patients with CHF is uncertain, and the role of erythropoietin with intravenous iron supplementation in treating this anemia is unknown.

METHODS

In a retrospective study, the records of the 142 patients in our CHF clinic were reviewed to find
  • the prevalence and severity of anemia (hemoglobin [Hb]12 g).
In an intervention study, 26 of these patients, despite maximally tolerated therapy of CHF for at least six months, still had had severe CHF and were also anemic. They were treated with
  • subcutaneous erythropoietin and intravenous iron sufficient to increase the Hb to 12 g%.
The doses of the CHF medications, except for diuretics, were not changed during the intervention period.

RESULTS

The prevalence of anemia in the 142 patients increased with the severity of CHF,
  • reaching 79.1% in those with New York Heart Association class IV.
In the intervention study, the anemia of the 26 patients was treated for a mean of 7.2 5.5 months.
  • The mean Hb level and mean left ventricular ejection fraction increased significantly.
  • The mean number of hospitalizations fell by 91.9% compared with a similar period before the study.
  • The New York Heart Association class fell significantly,
  • as did the doses of oral and intravenous furosemide.
  • The rate of fall of the glomerular filtration rate slowed with the treatment.

CONCLUSIONS

Anemia is very common in CHF and its successful treatment is associated with a significant improvement in
  • cardiac function,
  • functional class,
  • renal function and
  • in a marked fall in the need for diuretics and hospitalization.
Abbreviations and Acronyms
ACE Angiotensin-converting enzyme
CHF congestive heart failure
COPD chronic obstructive pulmonary disease
CRF chronic renal failure
CVA cerebrovascular accident
EPO erythropoietin
Fe iron
g% grams Hb /100 ml blood
GFR glomerular filtration rate
Hb hemoglobin
Hct hematocrit
IV intravenous
LVEF left ventricular ejection fraction
LVH left ventriculr hypertrophy
NYHA New York Heart Association
%Fe Sat percent iron saturation
sc subcutaneous
TNF tumor becrosis factor
ACE Angiotensin-converting enzyme
CHF congestive heart failure
COPD chronic obstructive pulmonary disease
CRF chronic renal failure
CVA cerebrovascular accident
EPO erythropoietin
Fe iron
g% grams Hb /100 ml blood
GFR glomerular filtration rate
Hb hemoglobin
Hct hematocrit
IV intravenous
LVEF left ventricular ejection fraction
LVH left ventriculr hypertrophy
NYHA New York Heart Association
%Fe Sat percent iron saturation
sc subcutaneous
TNF tumor becrosis factor

The mean hemoglobin (Hb) in patients with congestive heart failure (CHF) is about 12 g Hb per 100 ml blood (g%) (1–3), which is considered to be the lower limit of normal in adult men and postmenopausal women (4). Thus, many patients with CHF are anemic, and

  • this anemia has been shown to worsen as the severity of the CHF progresses (5,6).
Severe anemia of any cause can produce CHF, and treatment of the anemia can improve it (7). In patients with chronic renal failure (CRF) who are anemic,
  • treatment of the anemia with erythropoietin (EPO) has improved many of the abnormalities seen in CHF,
  • reducing left ventricular hypertrophy (LVH) (8 –10),
  • preventing left ventricular dilation (11) and,
    • in those with reduced cardiac function, increasing the left ventricular ejection fraction (LVEF)(8 –10),
    • the stroke volume (12) and
    • the cardiac output (12).
In view of the high prevalence of anemia in CHF, it is surprising that we could find no studies in which EPO was used in the treatment of the anemia of CHF, and the use of EPO is not included in U.S. Public Health Service guide-lines of treatment of the anemia of CHF (13). In fact, anemia has been considered
  • only a rare contributing factor to the worsening of CHF, estimated as contributing to
  • no more than 0% to 1.5% of all cases (14 –16).
Perhaps for this reason, recent guidelines for the prevention and treatment of CHF do not mention treatment of anemia at all (17). If successful treatment of anemia could improve cardiac function and patient function in CHF,
  • this would have profound implications, because,
  • despite all the advances made in the treatment of CHF, it is still a major and steadily increasing cause of hospitalizations, morbidity and mortality (18 –20).
The purpose of this study is to examine
  • the prevalence of anemia (Hb 12 g%) in patients with different levels of severity of CHF and
  • to assess the effect of correction of this anemia in severe CHF patients
  • resistant to maximally tolerated doses of CHF medication.
A combination of subcutaneous (SC) EPO and intravenous (IV) iron (Fe) was used. We have found this combination to be additive in improving the anemia of CRF (21,22).

METHODS 

Patients.

The medical records of the 142 CHF patients being treated in our special outpatient clinic devoted to CHF were reviewed to determine the prevalence and severity of anemia and CRF in these patients. These patients were referred to the clinic either from general practice or from the various wards in the hospital.

Intervention study.

Despite at least six months of treatment in the CHF clinic,
  • 26 of the above patients had persistent, severe CHF (New York Heart Association [NYHA] class III),
  • had a Hb level of 12 g% and were on
    • angiotensin-converting enzyme [ACE] inhibitors, the 
    • alpha-beta-blocker carvedilol,
    • long-acting nitrates,
    • digoxin, 
    • aldactone and
    • oral and IV furosemide.

These 26 patients participated in an intervention study. The mean age was 71.76  8.12 years. There were 21 men and 5 women. They  all had a

  • LVEF below 35%,
  • persistent fatigue and
  • shortness

    of breath on mild to moderate exertion and often at rest, and had

  • required hospitalizations at least once during their follow-up in the CHF clinic for pulmonary edema.
In 18 of the 26 patients, the CHF was associated with ischemic heart disease either
  • alone in four patients, or
  • with hypertension in six,
  • diabetes in four,
  • the two together in three, or with
  • valvular heart disease in one.
Of the remaining eight patients,
  • four had valvular heart disease alone and
  • four had essential hypertension alone.
Secondary causes of anemia including
  • gastrointestinal blood loss (as assessed by history and by three negative stool occult blood examinations),
  • folic acid and vitamin B12 deficiency and
  • hypothyroidism were ruled out.
Routine gastrointestinal endoscopy was not carried out. The study passed an ethics committee.
Table 1. Initial Characteristics of the 142 Patients With CHF Seen in the CHF Clinic
Age, yearsMale/female,  %Associated conditionsDiabetesHypertensionDyslipidemiaSmoking

Main cardiac diagnosis
Ischemic heart disease

Dilated CMP

Valvular heart disease

Hypertension

LVEF,  %

Left atrial area (n 15 cm2)

Pulmonary artery pressure  (15 mm Hg)

Previous hospitalizations/year

Serum Na, mEq/liter

Serum creatinine, mg%

Hemoglobin, g%

70.1 +/- 11.1

79/21

28%

64%

72%

40%

74%

15%

6%

5%

32.5 +/- 12.2

31.3  +/- 10.3

43.1  +/-14.9

3.2  +/- 1.5

139.8  +/- 4.0

1.6   +/-  1.1

11.9   +/- 1.5

CMP  cardiomyopathy; LVEF  left ventricular ejection fraction; NYHA  New York Heart Association class.

Correction of the anemia.

All patients received the combination of SC EPO and IV Fe. The EPO was given once a week at a starting dose of 2,000 IU per week subcutaneously, and the dose was increased or decreased as necessary to achieve and maintain a target Hb of 12 g%. The IV Fe (Venofer-Vifor International, St. Gallen, Switzerland), a ferric sucrose product, was given in a dose of 200 mg IV in 150 ml saline over 60 min every week until the serum ferritin reached 400  g/liter or the percent Fe saturation (%Fe Sat: serum iron/total iron binding capacity   100) reached 40% or until the Hb reached 12 g%. The IV Fe was then given at longer intervals as needed to maintain these levels.

Medication dose.

Except for oral and IV furosemide therapy, the doses of all the other CHF medications, which were used in the maximum tolerated doses before the intervention, were kept unchanged during the intervention period.

Duration of the study.

The study lasted for a mean of 7.2  5.5 months (range four to 15 months).

Investigations.

Visits were at weekly intervals initially and then at two- to three-week intervals depending on the patient’s status. This was the same frequency of visits to the CHF clinic as before the intervention study.
  • A complete blood count, serum creatinine, serum ferritin and % Fe Sat were performed on every visit.
  •  An electronic device measured the blood pressure on every visit.
  • The LVEF was measured by a multiple gated ventricular angiography heart scan initially and at four- to six-month intervals.
Hospital records were reviewed to compare the number of hospitalizations during the time the patients were treated for the anemia with the number of hospitalizations
  • during a similar period of time that they were treated in the CHF clinic 
    before the anemia was treated.
Clinic records were reviewed to evaluate the types and doses of CHF medications used 
before and during the study.

Period of time that they were treated in the CHF clinic before the anemia was treated.

Clinic records were reviewed to evaluate the types and doses of CHF medications used before and during the study.  The glomerular filtration rate (GFR) was calculated from the serum creatinine by the formula: 1/serum creatinine in mg% x 100 GFR in ml/min. The rate of change of the GFR before and during the intervention period was calculated by comparing the change in GFR per month in the year before the intervention with that during the intervention.

Statistical analysis.

Mean standard deviation was calculated. One-way analysis of variance (ANOVA) was performed to compare parameter levels between the four NYHA groups. Hochberg’s method of multiple comparisons (23) was used for pair-wise comparison between two groups. A p value of less than 0.05 was considered statistically significant. In the intervention study, the significance of the difference between the initial values and those at the end of the study for the individual parameters in the 26 treated patients was assessed by paired student’s t test; p < 0.05 was considered statistically significant. All the statistical analysis was performed by the SPSS program (Version 9, Chicago, Illinois).

 RESULTS

CHF: the whole study group.

The clinical, biochemical and hematological characteristics of the 142 patients seen in the clinic are shown in Tables 1 and 2.

  • Sixty-seven patients (47%) had severe CHF as judged by a NYHA class of IV (Table 2).
  • Seventy- nine of the 142 patients (55.6%) were anemic (Hb  12 g%).

The mean Hb level fell progressively from 13.73 +/- 0.83 g% in class I NYHA to 10.90 +/- 1.70 g% in class IV NYHA (p  0.01). The percentage of patients with Hb  12 g% increased from 9.1% in class I to 79.1% in class IV.
Fifty eight patients (40.8%) had CRF as defined as a serum creatinine  1.5 mg%. The mean serum creatinine increased from 1.18 +/_  0.38 mg% in class I NYHA, to 2.0 +/-    1.89 mg% in class IV NYHA, p  0.001. The percentage of patients with an elevated serum creatinine ( 1.5 mg%)      increased from 18.2% in class I to 58.2% in class IV.

The mean ejection fraction fell from 37.67 +/-  15.74% in class I to 27.72 +/-  9.68% (p  0.005) in class IV.

Table 2. LVEF and Biochemical and Hematological Parameters by NYHA Class in 142 Patients With CHF 
NYHA Class I II III IV  Significantly Different Pairs*

 *p  0.05 at least between the two groups by pair-wise comparison between groups.

†p  0.05 at least between the groups by ANOVA.

No. of patients

11

26  

38

67

(total 142) (%)

    (7.7)    (18.3)    (26.8)    (47.2)

Hb, g%†

13.73 (0.83)

13.38 (1.26)

11.95 (1.48)

10.90 (1.70) 

1–3, 1–4, 2–3, 2–4

Serum creatinine,

1.18

1.22

1.32

2.00

1–2, 1–3, 1–4

mg%†

    (0.38)     (0.29)      (0.38)     (1.89)

LVEF, %†

37.67 (15.74)

32.88 (12.41)

32.02 (10.99)

27.72 (9.68)

1–4, 2–4

Hb 12 g%,  (%)

1
(9.1)

5 (19.2) 

20 (52.6) 

53 (79.1)

Serum creatinine

    2      5     12     39

1.5 mg%,  (%) 

 (18.2)

(19.2)

(31.6)

 (58.2)

The intervention study: medications.

The percentage of patients receiving each CHF medication before and after the intervention period and the reasons for not receiving  them are seen in Table 3.

Table 3. Number (%) of the 26 Patients Taking Each Type of Medication Before and During the Intervention Period and the Reason Why the Medication Was Not Used

Medication    No. of Patients  (%)         Reason for Not Receiving the Medications (No. of Patients)
BP  blood pressure; CRF  chronic renal failure; IV  intravenous.

The main reason for not receiving:

  • 1) ACE inhibitors was the presence of reduced renal function;
  • 2) carvedilol was the presence of chronic obstructive pulmonary disease (COPD);
  • 3) nitrates was low blood pressure and aortic stenosis and
  • 4) aldactone was hyperkalemia.
Table 4. Mean Dose of Each Medication Initially and at the End of the Intervention Period in the 26 Patients

                                       No. of Patients                                 Initial Dose ^                 Final Dose^
Carvedilol (mg/day)                      20                                                        26.9 15.5                                   28.8 14.5
Captopril (mg/day)                          7                                                        69.6 40.0                                 70.7 40.4
Enalapril (mg/day)                        13                                                        25.7 12.5                                   26.9 12.6
Digoxin (mg/day)                          25                                                       0.10 0.07                                    0.10 0.07
Aldactone (mg/day)                       19                                                        61.2 49.2                                   59.9 47.1
Long-acting nitrates                      23                                                        53.2 13.2                                   54.1 14.4
Oral furosemide (mg/day)           26                                                      200.9 120.4                                78.3 41.3*
IV furosemide (mg/month)         26                                                      164.7 178.9                                  19.8 47.0*
*p  0.05 at least vs. before by paired Student’s t test.
^  +/-

The mean doses of the medications are shown in Table 4. 

The mean dose of oral furosemide was 200.9 +/-  120.4 mg/day before and 78.3 +/-  41.3 mg/day after the intervention (p   0.05). The dose of IV furosemide was 164.7 +/-  19.8,  178.9 mg/month before and  7.0 mg/month after the intervention (p  0.05).  

The doses of the other CHF medications were almost identical in the two periods.

Clinical results.

DEATHS.
There were three deaths during the intervention period. An 83-year-old man died after eight months of respiratory failure after many years of COPD, a 65-year-old man at eight months of a CVA with subsequent pneumonia and septic shock and a 70-year-old man at four months of septicemia related to an empyema that developed after aortic valve replacement.
HEMODIALYSIS.
Three patients, a 76-year-old man, an 85-year-old woman and a 72-year-old man, required chronic hemodialysis after six, 16 and 18 months, respectively. The serum creatinines of these three patients at onset of the anemia treatment were 4.2, 3.5 and 3.6 mg%, respectively. All three had improvement in their NYHA status but
  • their uremia worsened as the renal function deteriorated, demanding the initiation of dialysis.

In no cases, however, was pulmonary congestion an indication for starting dialysis.

Functional results (Table 5).

During the treatment period, the NYHA class fell from a mean of 3.66 +/- 0.47 to 2.66 +/- 0.70 (p 0.05), and
  • 24 had some improvement in their functional class.
The mean LVEF increased from 27.7 +/- 4.8 to 35.4  +/- 7.6% (p 0.001), an increase of 27.8%.
Compared with a similar period of time before the onset of the anemia treatment, the mean number of hospitalizations fell from 2.72 +/-  1.21 to 0.22 +/-  0.65 per patient (p   0.05)a decrease of 91.9%.
No significant changes were found in the mean systolic/diastolic blood pressure.

Hematological results (Table 5).

  • The mean hematocrit (Hct) increased from 30.14 +/- 3.12%) to 35.9  +/- 4.22% (p < 0.001).
  • The mean Hb increased from 10.16 +/- 0.95 g%) to 12.10 +/-  1.21 g% (p <  0.001).
  • The mean serum ferritin increased from 177.07 +/-  113.80  g/liter to 346.73 +/- 207.40 g/liter (p  0.005).
  • The mean serum Fe increased from 60.4 +/- 19.0 g% to 74 +/- .80  20.7 g% (p  0.005). 
  • The mean %Fe Sat increased from 20.05   6.04% to 26.14 =/- 5.23% (p  0.005).
  • The mean dose of EPO used throughout the treatment period was 5,227  +/- 455 IU per week, and
  • the mean dose of IV Fe used was 185.1 +/- 57.1 mg per month.
In four of the patients, the target Hb of 12 g% was maintained despite stopping the EPO for at least four months.

Renal results (Table 5).

The changes in serum creatinine were not significant. The estimated creatinine clearance fell at a rate of 0.95 + 1.31 ml/min/month before the onset of treatment of the anemia and increased at a rate of 0.85 + 2.77 ml/min/month during the treatment period.
Table 5. The Hematological and Clinical Data of the 26 CHF Patients at Onset and at the End of the Intervention Period

————–                                         Initial ^                                    Final^
Hematocrit, vol%                              30.14 3.12                            35.90 4.22*
Hemoglobin, g%                                10.16 0.95                              2.10 1.21*
Serum ferritin, g/liter                    177.07 113.80                       346.73  207.40*
Serum iron, g%                                  60.4 19.0                               74.8  20.7*
% iron saturation                              20.5 6.04                               26.14 5.23*
Serum creatinine, mg%                   2.59 0.77                                 2.73 1.55
LVEF, %                                              27.7 4.8                                   35.4  7.6*
No. hospitalizations/patient          2.72 1.21                                 0.22   0.65*
Systolic BP, mm Hg                       127.1 19.4                                128.9  26.4
Diastolic BP, mm Hg                       73.9 9.9                                   74.0   12.7
NYHA (0–4)                                     3.66 0.47                                2.66 0.70*
*p  0.05 at least vs before by paired Student’s t test.     ^ +/-
BP  blood pressure; LVEF  left ventricular ejection fraction; NYHA  New York Heart Association.

DISCUSSION

The main findings in the present study are that anemia is common in CHF patients and becomes progressively more prevalent and severe as CHF progresses. In addition, for patients with resistant CHF, the treatment of the associated anemia causes a marked improvement in their

  1. functional status,
  2. ejection fraction and
  3. GFR.
        • All these changes were associated with a markedly
            • reduced need for hospitalization and
            • for oral and IV furosemide.

The effect of anemia on the ischemic myocardium.

We used the IV Fe together with EPO to avoid the Fe deficiency caused by the use of EPO alone (38,39).
The Fe deficiency will cause

  • a resistance to EPO therapy and
  • increase the need for higher and higher doses to maintain the Hb level (39,40).

These high doses will not only be expensive but may increase the blood pressure excessively (41). The IV Fe reduces the dose of EPO needed to correct the anemia, because

  • the combination of SC EPO and IV Fe has been shown to have an additive effect on correction of the anemia of CRF (21,22,39,42).

Oral Fe, however, has no such additive effect (39,42). The relatively low dose of EPO needed to control the anemia in our study may explain why

  • the blood pressure did not increase significantly in any patient.

We used Venofer, an Fe sucrose product, as our IV Fe supplement because, in our experience (21,22,43), it has very few side effects and, indeed, no side effects with its use were encountered in this study.

The Effect of Anemia Correction on Renal Function.

Congestive heart failure is often associated with some degree of CRF (1–3,27–29), and

  • this is most likely due to renal vasoconstriction and ischemia (28,29).

When the anemia is treated and the cardiac function improves,

  • an increase in renal blood flow and glomerular filtration is seen (7,28).

In the present study, renal function decreased as the CHF functional class worsened (Table 2). The rate of deterioration of renal function was slower during the intervention period. Treatment of anemia in CRF has been associated with

  • a rate of progression of the CRF that is either unchanged (30) or is slowed (31–33).

It is possible, therefore, that adequate treatment of the anemia in CHF may, in the long term, help slow down the progression of CRF.

Possible Adverse Effects of Correction of the Anemia.

There has been concern, in view of the recent Amgen study (34), that correction of the Hct to a mean 42% in hemodialysis patients might increase cardiovascular events in those receiving EPO compared with those maintained at a Hct of 30%. Although there is much uncertainty about how to interpret this study (35), there is a substantial body of evidence that shows

  • correction of the anemia up to a Hb of 12 g% (Hct 36%) in CRF on dialysis is safe and desirable (35–38), and
  • results in a reduction in mortality, morbidity and in the number and length of hospitalizations.

The same likely holds true for the anemia of CHF with or without associated CRF. Certainly, our patients’ symptoms were strikingly improved, as was their cardiac function (LVEF) and need for hospitalization and diuretics. It remains to be established

  • if correction of the anemia up to a normal Hb level of 14 g% might be necessary in order to further improve the patient’s clinical state.

The Role of Fe Deficiency and its Treatment in the Anemia of CHF.

We used the IV Fe together with EPO to avoid the Fe deficiency caused by the use of EPO alone (38,39). The Fe deficiency will cause

  • a resistance to EPO therapy and increase the need for higher and higher doses to maintain the Hb level (39,40).

These high doses will not only be expensive but may

  • increase the blood pressure excessively (41).

The IV Fe reduces the dose of EPO needed to correct the anemia, because the combination of SC EPO and IV Fe has been shown to have an additive effect on correction of the anemia of CRF (21,22,39,42). Oral Fe,  however, has no such additive effect (39,42). The relatively low dose of EPO needed to control the anemia in our study may explain

  • why the blood pressure did not increase significantly in any patient.

We used Venofer, an Fe sucrose product, as our IV Fe supplement because, in our experience (21,22,43), it has very few side effects and, indeed, no side effects with its use were encountered in this study.

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Intracoronary Transplantation of Progenitor Cells after Acute MI

Curators: Larry H. Bernstein, MD, FCAP and Aviva Lev-Ari, PhD, RN

 

Transcoronary Transplantation of Progenitor Cells after Myocardial Infarction

Birgit Assmus, M.D., Jörg Honold, M.D., Volker Schächinger, M.D., Martina B. Britten, M.D., Ulrich Fischer-Rasokat, M.D., et al.
From the Division of Cardiology and Mo­lecular Cardiology, Department of Medi­cine III (B.A., J.H., V.S., M.B.B., U.F.-R., R.L., C.T., K.P., S.D., A.M.Z.), Division of He­matology, Department of Medicine II (H.M.), and the Department of Diagnos­tic and Interventional Radiology (N.D.A.), Johann Wolfgang Goethe University; and the Institute for Transfusion Medicine and Immunohematology, Red Cross Blood Donor Service, Baden–Württem-berg–Hessen (T.T.) — both in Frankfurt, Germany.

N Engl J Med 2006;355:1222-32.

Background

Pilot studies suggest that intracoronary transplantation of progenitor cells derived from bone marrow (BMC) or circulating blood (CPC) may improve left ventricular function after acute myocardial infarction. The effects of cell transplantation in patients with healed myocardial infarction are unknown.

METHODS

After an initial pilot trial involving 17 patients, we randomly assigned, in a controlled crossover study, 75 patients with stable ischemic heart disease who had had a myo­cardial infarction at least 3 months previously to receive either no cell infusion (23 patients) or infusion of CPC (24 patients) or BMC (28 patients) into the patent coro­nary artery supplying the most dyskinetic left ventricular area. The patients in the control group were

  • subsequently randomly assigned to receive CPC or BMC, and
  • the patients who initially received BMC or CPC crossed over to receive CPC or BMC, respectively, at 3 months’ follow-up.

RESULTS

The absolute change in left ventricular ejection fraction was significantly greater among patients receiving BMC (+2.9 percentage points) than among those receiving CPC (−0.4 percentage point, P = 0.003) or no infusion (−1.2 percentage points, P<0.001). The increase in global cardiac function was related to significantly

  • en­hanced regional contractility in the area targeted by intracoronary infusion of BMC.

The crossover phase of the study revealed that intracoronary infusion of BMC was associated with a significant increase in global and regional left ventricular func­tion, regardless of whether patients crossed over from control to BMC or from CPC to BMC.

CONCLUSIONS

Intracoronary infusion of progenitor cells is safe and feasible in patients with healed myocardial infarction. Transplantation of BMC is associated with moderate but significant improvement in the left ventricular ejection fraction after 3 months. (ClinicalTrials.gov number, NCT00289822.)

Introduction

HRONIC HEART FAILURE IS COMMON, and its prevalence continues to increase.1 Ischemic heart disease is the principal cause of heart failure.2 Although myocardial salvage due to early reperfusion therapy has significantly re­duced early mortality rates,3

  • postinfarction heart failure resulting from ventricular remodeling re­mains a problem.4

One possible approach to re­versing postinfarction heart failure is

  • enhance­ment of the regeneration of cardiac myocytes as well as
  • stimulation of neovascularization within the infarcted area.

Initial clinical pilot studies have suggested that

  • intracoronary infusion of pro­genitor cells is feasible and may
  • beneficially af­fect postinfarction remodeling processes in pa­tients with acute myocardial infarction.5-9

However, it is currently unknown whether such a treatment strategy may also be associated with

  • improvements in cardiac function in patients with persistent left ventricular dysfunction due to healed myocardial infarction with established scar formation.

Therefore, in the prospective TOPCARE-CHD (Transplantation of Progenitor Cells and Recovery of LV [Left Ventricular] Function in Patients with Chronic Ischemic Heart Disease) trial, we inves­tigated

  • whether intracoronary infusion of pro­genitor cells into the infarct-related artery at least 3 months after myocardial infarction improves global and regional left ventricular function.

Patient Outcome Criteria

The primary end point of the study was the absolute change in global left ventricular ejection fraction (LVEF) as measured by quantitative left ventricular angiography 3 months after cell infu­sion. Secondary end points included quantitative variables relating to the regional left ventricular function of the target area, as well as left ven­tricular volumes derived from serial left ventric­ular angiograms. In addition, functional status was assessed by NYHA classification. Finally, event-free survival was defined as freedom from death, myocardial infarction, stroke, or rehospi­talization for worsening heart failure. Causes of rehospitalization during follow-up were verified by review of the discharge letters or charts of hospital stays.

DETECTION OF VIABLE MYOCARDIUM

All patients underwent low-dose dobutamine stress echocardiography, combined thallium sin­gle-photon-emission computed tomography and [18F]fluorodeoxyglucose positron-emission tomog­raphy, or both, as previously described.6 It was pos­sible to analyze regional left ventricular viability in 80 patients (87%).

RESULTS

BASELINE CHARACTERISTICS OF THE PATIENTS

A total of 92 patients were enrolled in the study. Of these, 35 patients received BMC as their ini­tial treatment (in phases 1 and 2 of the trial), 34 patients received CPC (in phases 1 and 2), and 23 patients received no intracoronary cell infu­sion (in phase 2, as the control group). Table 1 illustrates that the three groups of patients were well matched.

EFFECTS OF PROGENITOR-CELL INFUSION

Quantitative Characteristics of Left Ventricular Function

Patients with an adverse clinical event (six), sub­total stenosis of the target vessel at follow-up (three), an intraventricular thrombus precluding performance of left ventricular angiography (one), or atrial flutter or fibrillation at follow-up (one) were excluded from the exploratory analysis. In addition, of the 81 eligible patients, left ventricu­lar angiograms could not be quantitatively ana­lyzed in 4 because of inadequate contrast opaci-fication, in 1 because of ventricular extrasystoles, and in 4 because of the patients’ refusal to un­dergo invasive follow-up. Thus, a total of 72 of 81 serial paired left ventricular angiograms were available for quantitative analysis (28 in the BMC group, 26 in the CPC group, and 18 in the control group).

Table 2 summarizes the angiographic charac­teristics of the 75 patients included in the ran­domized phase of the study. At baseline, the three groups did not differ with respect to global LVEF, the extent or magnitude of regional left ventricu­lar dysfunction, left ventricular volumes, or stroke volumes.

The absolute change in global LVEF from base­line to 3 months did significantly differ among the three groups of patients. Patients receiving BMC had a significantly larger change in LVEF than patients receiving CPC (P = 0.003) and those in the control group (P<0.001). Similar results were ob­tained when patients from the first two phases of the study (the pilot phase and the randomized phase) were pooled. The results did not differ when patients without evidence of viable myo­cardium before inclusion were analyzed sepa­rately. The change in LVEF was −0.3±3.4 percent­age points in the control group (9 patients), +0.4±3.0 percentage points in the CPC group (18 patients), and +3.7±4.0 percentage points in the BMC group (18 patients) (P = 0.02 for the com­parison with the control group and P = 0.02 for the comparison with the CPC group).

In the subgroup of 35 patients who underwent serial assessment of left ventricular function by MRI, MRI-derived global LVEF increased signifi­cantly, by 4.8±6.0% (P = 0.03) among those receiv­ing BMC (11 patients) and by 2.8±5.2% (P = 0.02) among those receiving CPC (20 patients), where­as no change was observed in 4 control patients (P = 0.14). Thus, MRI-derived assessment of left ventricular function further corroborated the re­sults obtained from the total patient population.

Analysis of regional left ventricular function revealed that BMC treatment significantly in­creased contractility in the center of the left ven­tricular target area (Table 2). Likewise, MRI-derived regional analysis of left ventricular function re­vealed that the number of hypocontractile seg­ments was significantly reduced, from 10.1±3.6 to 8.7±3.6 segments (P = 0.02), and the number of normocontractile segments significantly in­creased, from 3.8±4.5 to 5.4±4.6 segments (P = 0.01), in the BMC group, whereas no significant changes were observed in the CPC group. MRI-derived infarct size, as measured by late enhance­ment volume normalized to left ventricular mass, remained constant both in the CPC group (25± 18% at baseline and 23±14% at 3 months,13 patients) and in the BMC group (20±10% at both time points, 9 patients). Thus, taken together, the data suggest that intracoronary infusion of BMC is associated with significant improvements in global and regional left ventricular contractile function among patients with persistent left ven­tricular dysfunction due to prior myocardial in­farction.

To identify independent predictors of improved global LVEF, a stepwise multivariate regression analysis was performed; it included classic deter­minants of LVEF as well as various baseline characteristics of the three groups (Table 3). The multivariate analysis identified the type of pro­genitor cell infused and the baseline stroke vol­ume as the only statistically significant indepen­dent predictors of LVEF recovery.

Functional Status

The functional status of the patients, as assessed by NYHA classification, improved significantly in the BMC group (from 2.23±0.6 to 1.97±0.7, P = 0.005). It did not improve significantly either in the CPC group (class, 2.16±0.8 at baseline and 1.93±0.8 at 3 months; P = 0.13) or in the control group (class, 1.91±0.7 and 2.09±0.9, respectively; P = 0.27).

RANDOMIZED CROSSOVER PHASE

Of the 24 patients who initially were randomly assigned to CPC infusion, 21 received BMC at the time of their first follow-up examination. Likewise, of the 28 patients who initially were randomly assigned to BMC infusion,

  • 24 received CPC after 3 months.

Of the 23 patients of the control group, 10 patients received CPC and 11 received BMC at their reexamination at 3 months (Fig. 1). As illustrated in Figure 2, regardless of whether patients received BMC as initial treatment, as crossover treatment after CPC infusion, or as crossover treatment after no cell infusion,

  • glob­al LVEF increased significantly after infusion of BMC. In contrast,
  • CPC treatment did not significantly alter LVEF when given either before or after BMC.

Thus, the intrapatient comparison of the dif­ferent treatment strategies not only documents the superiority of intracoronary infusion of BMC over the infusion of CPC for improving global left ventricular function, but also corroborates our findings in the analysis of data according to initial treatment assignment. The

  • preserved im­provement in cardiac function observed among patients who initially received BMC treatment and
  • then crossed over to CPC treatment demon­strates that the initially achieved differences in cardiac function persisted for at least 6 months after intracoronary infusion of BMC.
 Table 1. Baseline Characteristics of the Patients.* (not copied)  

Table 2. Quantitative Variables Pertaining to Left Ventricular Function, as Assessed by Left Ventricular Angiography.*

copy protected

Figure 2. Absolute Change in Quantitative Global Left Ventricular Ejection Fraction (LVEF) during the Crossover Phase of the Trial.

Data at 3 and 6 months are shown for all patients crossing over from BMC to CPC infusion (18 patients), from CPC to BMC infusion
(18 patients), and from no cell infusion to either CPC infusion (10 patients) or BMC infusion (11 patients). I bars represent standard
errors.

Table 3. Stepwise Linear Regression Analysis for Predictors of Improvement in Global Left Ventricular Ejection Fraction.*

Variable Nonstandardized Coefficient B

95% CI for B

P Value

Treatment group

1.49

0.53 to 2.46

0.003
Baseline stroke volume

−0.13

−0.22 to –0.05

0.002
No. of cardiovascular risk factors 0.76
Time since most recent MI 0.48
Concomitant PCI 0.60
Age 0.82
Baseline ejection fraction 0.72
Baseline end-diastolic volume 0.88

* Values are shown only for significant differences. MI denotes myocardial infarc­tion, and PCI percutaneous coronary intervention. For the overall model, the ad­justed R2 was 0.29; P<0.001 by analysis of variance.

 

DISCUSSION

Intrapatient comparison in the crossover phase of the trial rules out the possibility that differences in the patient populations studied may have affected outcomes. However, the mechanisms involved in mediating improved contractile function after intracoronary progenitor-cell infusion are not well understood.

Experimentally, although there is no definitive proof that cardiac myocytes may be regenerated, BMC were shown to contribute to functional re­covery of left ventricular contraction when in­jected into freshly infarcted hearts,13-15 whereas CPC profoundly stimulated ischemia-induced neovascularization.16,17 Both cell types were shown to prevent cardiomyocyte apoptosis and reduce the development of myocardial fibrosis and there­by improve cardiac function after acute myocar­dial infarction.18,19 Indeed, in our TOPCARE-AMI (Transplantation of Progenitor Cells and Regen­eration Enhancement in Acute Myocardial Infarc­tion) studies,6,7,9 intracoronary infusion of CPC was associated with functional improvements similar to those found with the use of BMC im­mediately after myocardial infarction. In the cur­rent study, however, which involved patients who had had a myocardial infarction at least 3 months before therapy,

  • transcoronary adminis­tration of CPC was significantly inferior to administration of BMC in altering global left ven­tricular function.

CPC obtained from patients with chronic ischemic heart disease show pro­found functional impairments,20,21 which might limit their recruitment, after intracoronary infu­sion, into chronically reperfused scar tissue many months or years after myocardial infarction. Thus, additional studies in which larger numbers of functionally enhanced CPC are used will be re­quired to increase the response to intracoronary infusion of CPC.

The magnitude of the improvement after in-tracoronary infusion of BMC, with absolute increases in global LVEF of approximately 2.9 percentage points according to left ventricular angiography and 4.8 percentage points accord­ing to MRI, was modest. However, it should be noted that the improvement in LVEF occurred in the setting of full conventional pharmacologic treatment: more than 90% of the patients were receiving beta-blocker and angiotensin-convert-ing–enzyme inhibitor treatment. Moreover, results from trials of contemporary reperfusion for the treatment of acute myocardial infarction, which is regarded as the most effective treatment strat­egy for improving left ventricular contractile per­formance after ischemic injury, have reported in­creases in global LVEF of 2.8% (in the CADILLAC [Controlled Abciximab and Device Investigation to Lower Late Angioplasty Complications] trial) and 4.1% (in the ADMIRAL [Abciximab before Direct Angioplasty and Stenting in Myocardial Infarction Regarding Acute and Long-Term Fol­low-up] trial).22,23

The number of patients, as well as the dura­tion of follow-up, is not sufficient to address the question of whether the moderate improvement in LVEF associated with one-time intracoronary BMC infusion is associated with reduced mortal­ity and morbidity among patients with heart fail­ure secondary to previous myocardial infarction. We conclude that intracoronary infusion of BMC is associated with persistent improvements in regional and global left ventricular function and improved functional status among patients who have had a myocardial infarction at least 3 months previously. Given the reasonable short-term safety profile of this therapeutic ap­proach, studies on a larger scale are warranted to examine its potential effects on morbidity and mortality among patients with postinfarction heart failure.

REFERENCES (1-8/23)

  1. 2001 Heart and stroke statistical up­date. Dallas: American Heart Association, 2000.
  2. Braunwald E. Cardiovascular medicine at the turn of the millennium: triumphs, concerns, and opportunities. N Engl J Med 1997;337:1360-9.
  3. Lange RA, Hillis LD. Reperfusion ther­apy in acute myocardial infarction. N Engl J Med 2002;346:954-5.
  4. Sutton MG, Sharpe N. Left ventricular remodeling after myocardial infarction: pathophysiology and therapy. Circulation 2000;101:2981-8.
  5. Strauer BE, Brehm M, Zeus T, et al. Re­pair of infarcted myocardium by autologous intracoronary mononuclear bone marrow cell transplantation in humans. Circula­tion 2002;106:1913-8.
  6. Assmus B, Schachinger V, Teupe C, et al. Transplantation of Progenitor Cells and Regeneration Enhancement in Acute Myo­cardial Infarction (TOPCARE-AMI). Circu­lation 2002;106:3009-17.
  7. Britten MB, Abolmaali ND, Assmus B, et al. Infarct remodeling after intra-coronary progenitor cell treatment in pa­tients with acute myocardial infarction (TOPCARE-AMI): mechanistic insights from serial contrast-enhanced magnetic resonance imaging. Circulation 2003;108: 2212-8.
  8. Wollert KC, Meyer GP, Lotz J, et al. In-tracoronary autologous bone-marrow cell transfer after myocardial infarction: the BOOST randomised controlled clinical trial. Lancet 2004;364:141-8.

 

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Pacemakers, Implantable Cardioverter Defibrillators (ICD) and Cardiac Resynchronization Therapy (CRT)

Curators: Justin D Pearlman, MD, PhD, FACC and Aviva Lev-Ari, PhD, RN

Updated on 2/16/2015

Mild, non-ischemic heart failure might be more deadly than thought, an Austrian group found, calling for broader ICD use.

SOURCE

http://www.medpagetoday.com/Cardiology/Strokes/50048?isalert=1&uun=g99985d3527R5099207u&utm_source=breaking-news&utm_medium=email&utm_campaign=breaking-news&xid=NL_breakingnews_2015-02-16

 

The voice of our Series A Content Consultant: Justin D Pearlman, MD, PhD, FACC

Pacemakers place one or more wires into heart muscle to trigger electro-mechanically coupled contraction. A single wire to the right atrium is called an AAI pacemaker (atrial sensing, atrial triggering, inhibit triggering if sensed). A single wire to the right ventricle is called a VVI pacemaker (ventricular sensing, ventricular triggering, inhibit if sensed). With two wires to the heart more combinations are possible, including atrial-ventricular sequential activation, a closer mimic to normal function (DDDR pacemaker: dual sensing, dual triggering, dual functions, and rate-responsive to mimic exercise adjustment of heart rate). Three wires are used for synchronization: one to the right atrium, one to the right ventricle apex, and a third lead into a distal branch of the coronary sinus to activate the far side of the left ventricle. Resynchronization is used to compensate for a dilated ventricle, especially one with conduction delays, where the timing of activation is so unbalanced that the heart contraction approaches a wobbling motion rather than a well coordinated contraction. Adjusting timing of activation of the right ventricle and left ventricle can offset dysynchrony (unbalanced timing) and thereby increase the amount of blood ejected by each heart beat contraction (ejection fraction). Patients with dilated cardiomyopathy and significant conduction delays can improve the ejection fraction by 10 or more percentage points, which offers a significant improvement in exertion tolerance and heart failure symptoms.

Patients with ejection fraction below 35%, among others, have an elevated risk of life-ending arrhythmias such as ventricular tachycardia. Ventricular tachycardia is an extreme example of a wobbling heart in which the electrical activation sequence circles around the heart sequentially activating a portion and blocking its ability to respond until the electric signal comes around again. Whenever a portion of the heart is activated, ions shift location, and further activation of that region is not possible until sufficient time passes so that the compartmentalized ion concentrations can be restored (repolarization). Pacing can interrupt ventricular tachycardia by depolarizing a region that supported the circular activation pattern. Failing that, an electric shock can stop an ineffective rhythm. After all regions stop activation, they will generally reactivate in the normal pulsatile synchronous manner. An implanted cardiac defibrillator is a device designed to apply an internal electric shock to pause all activation and thereby interrupt ventricular tachycardia.
UPDATED on 12/31/2013

Published on Friday, 27 December 2013

S-ICD – Subcutaneous Implantable Cardioverter Defibrillator – Boston Scientific

Boston Scientific Subcutaneous Implantable Cardiodefibrillator Device S-ICD

S-ICD – Subcutaneous Implantable Cardioverter Defibrillator – Boston Scientific

Boston Scientific Subcutaneous Implantable Cardiodefibrillator Device S-ICD

‘Regular’ Pacemaker/ICD with Leads and a ‘Can’
When we think of Pacemakers and ICD’s we naturally think of a ‘Can’ and Leads that track down into the heart. Whilst these devices work fantastically well and will continue to do so. Unfortunately the ‘lead’ part of the device opens the door for a few complications to possibly arise. Those who have a Pacemaker or ICD will probably be familiar with concerns over;
  1. Systemic Infection – Infections travelling down the Leads into the Heart
  2. Lead Displacement – The Lead moving away from the heart tissue and thus becoming pretty useless.
  3. Vascular/Organ Injury – Damage to the blood vessels being used for access or perforation of heart wall.
  4. Pneumothorax (damage to the lining around the Lung), Haemothorax (build up of blood in the chest cavity), and air embolism (air bubble trapped in a blood vessel).
These complications are one of the key motivations behind developing ‘leadless’ devices the first of which the St Jude Nanostim, a small VVI Pacemaker that fits directly into the heart.
Another device to address these issues is the Boston Scientific S-ICD

What is the Boston Scientific S-ICD?

The S-ICD is what is sometimes referred to as a ‘shock box’ it does not have the pacemaker functionality that many other ICD’s do have. It is ONLY there to terminate dangerous Arrhythmias.
*It does not have the pacing functionality of traditional ICD‘s because it DOES NOT HAVE A LEAD THAT ENTERS THE HEART.*
It is not a Pacemaker!
 
Without the lead(s) ENTERING the heart via a blood vessel there is a reduction in the risks mentioned previously that are associated traditional device. Another of the benefits is that the S-ICD is positioned and implanted using anatomical landmarks (visible parts of your body) and not Fluoroscopy (video X-Ray) which reduces radiation exposure to the patient.

Positioning of the S-ICD.

Boston Scientific Subcutaneous Implantable Cardiodefibrillator Device S-ICD

The ‘Can‘ (metal box that contains all the circuitry and battery), is buried under the skin on the outside of the ribs. Put your arms down by your sides, the device would go where your ribs meet the middle of your bicep. A lead is then run under the skin to the centre of your chest where its is anchored and then north, under the skin again until the tip of the lead is roughly at the top of the sternum.
For you physicians out there the ‘can’ is positioned at the mid-axillary line between the 5th and 6th intercostal spaces, the lead is then tunnelled to a small Xiphoid incision and then tunnelled north to a superior incision.

How is an S-ICD Implanted?

VIEW VIDEO
Having spoken to Boston Scientific it is becoming more apparent that the superior incision (cut at the top of the chest) may actually be removed from the procedure guidance as simply tunnelling the lead and ‘wedging’ the tip at that point is satisfactory – THIS IS NOT CONFIRMED AT THE MOMENT AND IS THEREFORE NOT PROCEDURE ADVICE.
Boston Scientific Subcutaneous Implantable Cardiodefibrillator Device S-ICD
Image Courtesy of
http://www.bostonscientific.com/

How does the S-ICD Work?

A ‘Shock Box’ basically needs to do 2 things. Firstly be able to SENSE if the heart has entered a Dangerous Arrhythmia and Secondly, be able to treat it.
The treatment part of the functionality is the easy bit – it delivers an electric shock across a ‘circuit’ that involves a large amount of the tissue in the heart. The lead has two ‘electrodes’ and the ‘Can’ is a third electrode allowing you different shocking ‘vectors’. By vectors we mean directions and area through which the electricity travels during a shock. This gives us extra options when implanting a device as some vectors will work better than others for the treatment of dangerous arrhythmias.

Shocking Vectors?

This is a concept you are familiar with without even thinking about it… when you are watching ER or another TV program and they Defibrillate the patient using the metal paddles, where do they position them? One either side of the heart? Precisely!! this is creating a ‘vector’ across the heart to involve the cardiac tissue. The paddles would be a lot less effective if you put one on the knee and one on the foot!

Boston Scientific Subcutaneous Implantable Cardiodefibrillator Device S-ICD

Now because the ‘Vectors’ used by the S-ICD are over a larger area than those with a traditional device – more energy has to be delivered to have the same desired affect. The upshot of this is that a larger battery is required to deliver the 80J! Bigger Battery = Bigger Box. This image shows a demo device but this is the exact size compared to a One Pound Coin! Now yes it is big but because of the extra room where they place the device it is pretty discrete and hidden in even slender patients.
STAT ATTACK!
The S-ICD System delivers up to 5 shocks per episode at 80 J with up to 128 seconds of ECG storage per episode and storage of up to 45 episodes.
The heart rate that the S-ICD is told to deliver therapy is programable between 170 and 250 bpm. Quite cleverly the device is able to also deliver a small amount of ‘pacing’ after a shock, when the heart can often run slowly. This is external pacing and will be felt!! It can run for 30s.

Sensing in an S-ICD.

 
The S-ICD uses its electrodes to produce an ECG similar to a surface ECG. 
 
Now the Sensing functionality is the devices ability to determine what Rhythm the heart is in! Without a lead in the heart to give us really accurate information the device is using a large area of heart, ribs and muscle. This means there is more potential for ‘artefact’. Artefact is the electrical interference and confusion – that could potentially lead to a patient being shocked when they do not require it – or not being shocked when they do…
Boston Scientific have come up with a very clever software/algorithm called ‘Insight’. Insight uses 3 separate methods to determine the nature of a heart rhythm.
  • Normal Sinus Rhythm Template (Do your heart beats look as they should)
  • Dynamic Morphology Analysis (A live comparison of heart beat to previous heart beat, do they all look the same or do they keep changing?)
  • QRS Width analysis (Are the tall ‘peaks’ on your ECG, the QRS’, wider than they normally are?)
These questions (with some very complex maths) and the rate of a rhythm are used to decide whether to ‘shock’ or not.
Insight Algorithm S-ICD

Image Courtesy of  http://www.bostonscientific.com/

How does Insight and the S-ICD compare to other ICD Devices?

The statistics for treatment success and inappropriate shocks (an electrocuted patient that did not need to be) actually compare very similarly if not favourably compared to other devices on the market – these two studies are well worth a read if you have the time 🙂
1. Burke M, et al. Safety and Efficacy of a Subcutaneous Implantable-Debrillator (S-ICD System US IDE Study). Late-Breaking Abstract Session. HRS 2012.
2. Lambiase PD, et al. International Experience with a Subcutaneous ICD; Preliminary Results of the EFFORTLESS S-ICD Registry. Cardiostim 2012.
3. Gold MR, et al. Head-to-head comparison of arrhythmia discrimination performance of subcutaneous and transvenous ICD arrhythmia detection algorithms: the START study. J Cardiovasc Electrophysiol. 2012;23;4:359-366.
Who qualifies?
Template S-ICD Eligibility

Template used to assess eligibility!
Image Courtesy of
http://www.bostonscientific.com/
Well essentially anyone who qualifies for a normal ‘shock box’ ICD but with one other requirement. The Insight Software requires that a person has certain characteristics on their ECG. This is essentially showing that they have tall enough and narrow enough complexes to allow the algorithm to perform effectively. A simple 12 lead ECG Laying and Standing will be obtained and then a ‘Stencil’ is passed over the Print out – If the complexes fit within the boundaries marked on the ‘stencil’ then you potentially qualify. If your ECG does not meet requirements then it will not be recommended for you to have the S-ICD.

There you have it a quick overview of the Boston Scientific S-ICD.

Thanks for Reading

Cardiac Technician

SOURCE

http://www.thepad.pm/2013/12/boston-scientific-s-icd.html#!

UPDATED on 10/15/2013

Frequency and Determinants of Implantable Cardioverter Defibrillator Deployment Among Primary Prevention Candidates With Subsequent Sudden Cardiac Arrest in the Community

  1. Kumar Narayanan, MD;
  2. Kyndaron Reinier, PhD;
  3. Audrey Uy-Evanado, MD;
  4. Carmen Teodorescu, MD, PhD;
  5. Harpriya Chugh, BS;
  6. Eloi Marijon, MD;
  7. Karen Gunson, MD;
  8. Jonathan Jui, MD, MPH;
  9. Sumeet S. Chugh, MD

+Author Affiliations


  1. From The Heart Institute, Cedars-Sinai Medical Center, Los Angeles, CA (K.N., K.R., A.U.-E., C.T., H.C., E.M., S.S.C.); and Departments of Pathology (K.G.) and Emergency Medicine (J.J.), Oregon Health and Science University, Portland, OR.
  1. Correspondence to Sumeet S. Chugh, MD, Cedars-Sinai Medical Center, The Heart Institute, AHSP Suite A3100, 127 S. San Vicente Blvd., Los Angeles, CA 90048, Los Angeles, CA 90048. E-mail sumeet.chugh@cshs.org

Abstract

Background—The prevalence rates and influencing factors for deployment of primary prevention implantable cardioverter defibrillators (ICDs) among subjects who eventually experience sudden cardiac arrest in the general population have not been evaluated.

Methods and Results—Cases of adult sudden cardiac arrest with echocardiographic evaluation before the event were identified from the ongoing Oregon Sudden Unexpected Death Study (population approximately 1 million). Eligibility for primary ICD implantation was determined from medical records based on established guidelines. The frequency of prior primary ICD implantation in eligible subjects was evaluated, and ICD nonrecipients were characterized. Of 2093 cases (2003–2012), 448 had appropriate pre– sudden cardiac arrest left ventricular ejection fraction information available. Of these, 92 (20.5%) were eligible for primary ICD implantation, 304 (67.9%) were ineligible because of left ventricular ejection fraction >35%, and the remainder (52, 11.6%) had left ventricular ejection fraction ≤35% but were ineligible on the basis of clinical guideline criteria. Among eligible subjects, only 12 (13.0%; 95% confidence interval, 6.1%–19.9%) received a primary ICD. Compared with recipients, primary ICD nonrecipients were older (age at ejection fraction assessment, 67.1±13.6 versus 58.5±14.8 years, P=0.05), with 20% aged ≥80 years (versus 0% among recipients, P=0.11). Additionally, a subgroup (26%) had either a clinical history of dementia or were undergoing chronic dialysis.

Conclusions—Only one fifth of the sudden cardiac arrest cases in the community were eligible for a primary prevention ICD before the event, but among these, a small proportion (13%) were actually implanted. Although older age and comorbidity may explain nondeployment in a subgroup of these cases, other determinants such as socioeconomic factors, health insurance, patient preference, and clinical practice patterns warrant further detailed investigation.

Key Words:

  • Received March 11, 2013.
  • Accepted August 21, 2013

http://circ.ahajournals.org/content/128/16/1733.abstract

UPDATED on 9/15/2013

based on 9/6/2013 Trials and Fibrillations — The Heart.org

http://www.theheart.org/columns/trials-and-fibrillations-with-dr-john-mandrola/new-post-39.do#!

Echo-CRT trial: Most important study released at ESC 2013

Cardiac resynchronization therapy (CRT) is a multilead pacing device that can extend lives and improve the quality of life of selected patients who suffer from reduced performance of the heart due to adverse timing of contraction (wobbling motion from conduction delays that cause asynchrony or  delayed activation of one portion of the left ventricle compared to others reducing net blood ejection).

The degree of benefit in CRT responders depends not only on the degree of asynchrony, but also on the delayed activity location in relation to the available locations for lead placement. CRT is an adjustment in the timing of muscle activiation to improve the concerted impact on blood ejection. Only patients likely to improve should be exposed to the risks and costs of CRT.

The Echo-CRT trial, presented September 3, 2013 at the European Society of Cardiology (ESC) 2013 Congressand simultaneously published in the New England Journal of Medicine, helps identify which patients may benefit from CRT devices. (See Steve Stiles’ report on heartwire),

Echo-CRT trial summary

Background is important

Previous CRT studies enrolled patients with QRS duration >120 or >130 ms for synchronizing biventricular pacing. Additional work confirmed the greatest benefit occurred in patients with QRS durations >150 ms and typical left bundle branch block (LBBB). Conflicting observational and small randomized trials were less clear for patients with shorter QRS durations—the majority of heart-failure patients. What’s more, most cardiologists have seen patients with “modest” QRS durations respond to CRT. In theory, wide QRS is only expected if the axis of significant delay projects onto the standard ECG views, whereas significant opportunity for benefit can be missed if the axis of significant delay is not wide in the standard views. CRT implanters have heard of patients with normal-duration QRS where echo shows marked dyssynchrony. This raised the  question: Are there CHF patients with mechanical dyssynchrony (determined by echo) but no electrical delay (as measured by the ECG) benefit from CRT?Unfortunately, echo does not resolve the issue either. Thus there is the residual question of who should be evaluated by a true 3D syncrhony assessment by cardiac MRI.

Echocardiographic techniques held promise to identify mechanical dyssynchrony, but like the standard 12 lead ECG, they also utilize limited orientations of views of the heart and hence the directions in which delays can be detected. Cardiac MRI Research (not limited in view angle) by JDPearlman showed that the axis of maximal delay in patients with asynchrony is within 30 degrees of the ECG and echo views in a majority of patients with asynchrony, but it can be 70-110 degrees away from the views used by echocardiography and by ECG in 20% of cases. Hence some patients who may benefit can be missed by ECG or Echo criteria.

Methodology

Echo-CRT was an industry-sponsored (Biotronik) investigator-initiated prospective international randomized controlled trial. All patients had mechanical dyssynchrony by echo, QRS <130 ms, and an ICD indication. CRT-D devices were implanted in all patients. Blinded randomization to CRT-on (404 patients) vs CRT-off (405 patients) was performed after implantation. Programming in the CRT-off group was set to minimize RV pacing. The primary outcome was a composite of all-cause mortality or hospitalization.

Six key findings

1. Although entry criteria for the trial was a QRS duration <130 ms, the mean QRS duration of both groups was 105 ms.

2. The data safety monitoring board terminated the trial prematurely because of an increased death rate in the CRT group.

3. No differences were noted in the primary outcome.

4. More patients died in the CRT group (hazard ratio=1.8).

5. The higher death rate in the CRT group was driven by cardiovascular death.

6. More patients in the CRT group were hospitalized, due primarily to device-related issues.

These findings send clear and simple messages to all involved with treating patients with heart failure. My interpretation of Echo-CRT is as follows:

Do not implant CRT devices in patients with “narrow” QRS complexes.

The signal of increased death was strong. A hazard ratio of 1.8 translates to an almost doubling of the risk of death. This finding is unlikely to be a statistical anomaly, as it was driven by CV death. The risks of CRT in nonresponders are well-known and include: increased RV pacing, possible proarrhythmia from LV pacing, and the need for more device-related surgery. Patients who do not respond to CRT get none of the benefits but all the potential harms—an unfavorable ratio indeed.

Echo is not useful for assessing dyssynchrony in patients with narrow QRS complexes.

Dr Samuel Asirvatham explains the concept of electropathy in a review article in the Journal of Cardiovascular Electrophysiology. He teaches us that the later the LV lateral wall is activated relative to the RV, the more the benefit of preexciting the lateral wall with an LV lead. That’s why the benefit from CRT in many cases increases with QRS duration, because—in a majority—a wide QRS means late activation of the lateral LV.

Simple triumphs over complicated—CRT response best estimated with the old-fashioned ECG.

In a right bundle branch block, the left ventricle is activated first; in LBBB, the LV lateral wall is last, and with a nonspecific ICD, there’s delayed conduction in either the His-Purkinje system or in ventricular muscle. What does a normal QRS say? It says the wave front of activation as projected onto the electric views obtained activates the LV and RV simultaneously. If those views capture the worst delay then they can eliminate the  need for resynchrony.

CRT benefit with mild-moderate QRS prolongation still not settled

Dr Robert Myerburg (here and here) teaches us to make a distinction between trial entry criteria and the actual values of the cohort.

Consider how this applies to QRS duration:  COMPANION and CARE-HF are clinical trials that showed definitive CRT benefit. Entry required a QRS duration >120 ms (130 ms in CARE-HF). But the actual mean QRS duration of enrolled patients was 160 ms. A meta-analysis of CRT trials confirmed benefit at longer QRS durations and questioned it below 150 ms. CRT guideline recommendations incorporate study entry criteria, not the mean values of actual patients in the trial. Patients enrolled in Echo-CRT had very narrow QRS complexes (105 ms). What to recommend in the common situation when a patient with a typical LBBB has a QRS duration straddling 130 ms is not entirely clear. The results of Echo-CRT might have been different had the actual QRS duration values been closer to 130 ms.

Conclusion

Echo-CRT study reinforces expectations based on cardiac physiology. In the practice of medicine, it’s quite useful to know when not to do something.

The trial should not dampen enthusiasm for CRT. Rather, it should focus our attention to patient selection—and the value of the 12-lead ECG.

 References

Rethinking QRS Duration as an Indication for CRT

SMITA MEHTA M.D.1 and SAMUEL J. ASIRVATHAM M.D., F.A.C.C.2,3

Author Information

  1. Department of Pediatric Cardiology, Cleveland Clinic, Cleveland, Ohio, USA
  2. Division of Cardiovascular Diseases, Department of Medicine, Mayo Clinic, Rochester, Minnesota, USA
  3. Department of Pediatrics and Adolescent Medicine, Mayo Clinic, Rochester, Minnesota, USA

*Samuel J. Asirvatham, M.D., Division of Cardiovascular Diseases, Department of Internal Medicine and Division of Pediatric Cardiology, Department of Pediatric and Adolescent Medicine, Mayo Clinic College of Medicine, 200 First Street SW, Rochester, MN 55905, USA. E-mail: asirvatham.samuel@mayo.edu

J Cardiovasc Electrophysiol, Vol. 23, pp. 169-171, February 2012.

http://onlinelibrary.wiley.com/doi/10.1111/j.1540-8167.2011.02163.x/full

Indications for Implantable Cardioverter-Defibrillators Based on Evidence and Judgment FREE

Robert J. Myerburg, MD; Vivek Reddy, MD; Agustin Castellanos, MD
J Am Coll Cardiol. 2009;54(9):747-763. doi:10.1016/j.jacc.2009.03.078

Implantable Cardioverter–Defibrillators after Myocardial Infarction

Robert J. Myerburg, M.D.

Division of Cardiology, University of Miami Miller School of Medicine, Miami.

N Engl J Med 2008; 359:2245-2253 November 20, 2008DOI: 10.1056/NEJMra0803409

END OF UPDATE

Electrical conduction of the Human Heart

  • Physiology and
  • Genetics

were explained by us in the following articles:

Genetics of Conduction Disease: Atrioventricular (AV) Conduction Disease (block): Gene Mutations – Transcription, Excitability, and Energy Homeostasis

On Devices and On Algorithms: Prediction of Arrhythmia after Cardiac Surgery and ECG Prediction of an Onset of Paroxysmal Atrial Fibrillation

Dilated Cardiomyopathy: Decisions on implantable cardioverter-defibrillators (ICDs) using left ventricular ejection fraction (LVEF)

Reduction in Inappropriate Therapy and Mortality through ICD Programming

Below, we present the following complementary topics:

Options for Cardiac Resynchronization Therapy (CRT) to Arrhythmias:

  • Implantable Pacemaker
  • Insertable Programmable Cardioverter Defibrillator (ICD)

UPDATED 8/6/2013

Medtronic Pacemaker Recall

 

17/07/2013

Australia’s regulatory authority, the Therapeutic Goods Administration (TGA) has issued a hazard alert pertaining to one of Medtronic’s pacing devices, the Consulta® Cardiac Resynchronization Therapy Pacemaker (CRT-P). The alert coincides somewhat with Medtronic’s own issuance of a field safety notice concerning Consulta and Syncra® CRT-P devices.

Background

Consulta and Syncra CRT-Ps are implantable medical devices used to treat heart failure. The devices provide pacing to help coordinate the heart’s pumping action and improve blood flow.

The two devices are the subject of a global manufacturer recall after Medtronic had identified an issue with a subset of both during production, although as yet there had been no reported or confirmed device failures. However, because of the potential for malfunction, Medtronic is requiring the return of non-implanted devices manufactured between April 1 and May 13, 2013 for re-inspection.

Seemingly this manufacturing issue could compromise the sealing of the device. Should an out-of-spec weld fail this could result in body fluids entering the device, which could cause it to malfunction leading to loss of pacing output. This could potentially see the return of symptoms including

  • fainting or lightheadedness,
  • dyspnoea (shortness of breath),
  • fatigue and
  • oedema.

Medtronic’s recall is thought to relate to 265 devices, 44 of which have been implanted in the US.

The Australian warning letter, issued by the TGA states that only one “at risk” Consulta CRT-P device has been implanted in the country and there have been no reports of device failures or patient injuries relating to this issue.

Neither Medtronic nor the TGA are suggesting any specific patient management measures other than routine follow-up in accordance with labelling instructions.

Pacemaker/Implantable Cardioverter Defibrillator (ICD) Insertion

Procedure Overview

What is a pacemaker/implantable cardioverter defibrillator (ICD) insertion?

A pacemaker/implantable cardioverter defibrillator (ICD) insertion is a procedure in which a pacemaker and/or an ICD is inserted to assist in regulating problems with the heart rate (pacemaker) or heart rhythm (ICD).

Pacemaker

When a problem develops with the heart’s rhythm, such as a slow rhythm, a pacemaker may be selected for treatment. A pacemaker is a small electronic device composed of three parts: a generator, one or more leads, and an electrode on each lead. A pacemaker signals the heart to beat when the heartbeat is too slow.

Illustration of a single-chamber pacemaker
Click Image to Enlarge

A generator is the “brain” of the pacemaker device. It is a small metal case that contains electronic circuitry and a battery. The lead (or leads) is an insulated wire that is connected to the generator on one end, with the other end placed inside one of the heart’s chambers.

The electrode on the end of the lead touches the heart wall. In most pacemakers, the lead senses the heart’s electrical activity. This information is relayed to the generator by the lead.

If the heart’s rate is slower than the programmed limit, an electrical impulse is sent through the lead to the electrode and the pacemaker’s electrical impulse causes the heart to beat at a faster rate.

When the heart is beating at a rate faster than the programmed limit, the pacemaker will monitor the heart rate, but will not pace. No electrical impulses will be sent to the heart unless the heart’s natural rate falls below the pacemaker’s low limit.

Pacemaker leads may be positioned in the atrium or ventricle or both, depending on the condition requiring the pacemaker to be inserted. An atrial dysrhythmia/arrhythmia (an abnormal heart rhythm caused by a dysfunction of the sinus node or the development of another atrial pacemaker within the heart tissue that takes over the function of the sinus node) may be treated with an atrial pacemaker.

Illustration of a dual-chamber pacemaker
Click Image to Enlarge

A ventricular dysrhythmia/arrhythmia (an abnormal heart rhythm caused by a dysfunction of the sinus node, an interruption in the conduction pathways, or the development of another pacemaker within the heart tissue that takes over the function of the sinus node) may be treated with a ventricular pacemaker whose lead wire is located in the ventricle.

It is possible to have both atrial and ventricular dysrhythmias, and there are pacemakers that have lead wires positioned in both the atrium and the ventricle. There may be one lead wire for each chamber, or one lead wire may be capable of sensing and pacing both chambers.

A new type of pacemaker, called a biventricular pacemaker, is currently used in the treatment of congestive heart failure. Sometimes in heart failure, the two ventricles (lower heart chambers) do not pump together in a normal manner. When this happens, less blood is pumped by the heart.

A biventricular pacemaker paces both ventricles at the same time, increasing the amount of blood pumped by the heart. This type of treatment is called cardiac resynchronization therapy.

Implantable cardioverter defibrillator (ICD)

An implantable cardioverter defibrillator (ICD) looks very similar to a pacemaker, except that it is slightly larger. It has a generator, one or more leads, and an electrode for each lead. These components work very much like a pacemaker. However, the ICD is designed to deliver an electrical shock to the heart when the heart rate becomes dangerously fast, or €œfibrillates.”

An ICD senses when the heart is beating too fast and delivers an electrical shock to convert the fast rhythm to a normal rhythm. Some devices combine a pacemaker and ICD in one unit for persons who need both functions.

The ICD has another type of treatment for certain fast rhythms called anti-tachycardia pacing (ATP). When ATP is used, a fast pacing impulse is sent to correct the rhythm. After the shock is delivered, a “back-up” pacing mode is used if needed for a short while.

The procedure for inserting a pacemaker or an ICD is the same. The procedure generally is performed in an electrophysiology (EP) lab or a cardiac catheterization lab.

Other related procedures that may be used to assess the heart include resting and exercise electrocardiogram (ECG), Holter monitor, signal-averaged ECG, cardiac catheterization, chest x-ray, computed tomography (CT scan) of the chest, echocardiography, electrophysiology studies, magnetic resonance imaging (MRI) of the heart, myocardial perfusion scans, radionuclide angiography, and ultrafast CT scan.

The heart’s electrical conduction system

Illustration of the anatomy of the heart, view of the electrical system
Click Image to Enlarge

The heart is, in the simplest terms, a pump made up of muscle tissue. Like all pumps, the heart requires a source of energy in order to function. The heart’s pumping energy comes from an indwelling electrical conduction system.

An electrical stimulus is generated by the sinus node (also called the sinoatrial node, or SA node), which is a small mass of specialized tissue located in the right atrium (right upper chamber) of the heart.

The sinus node generates an electrical stimulus regularly at 60 to 100 times per minute under normal conditions. This electrical stimulus travels down through the conduction pathways (similar to the way electricity flows through power lines from the power plant to your house) and causes the heart’s chambers to contract and pump out blood.

The right and left atria (the two upper chambers of the heart) are stimulated first and contract a short period of time before the right and left ventricles (the two lower chambers of the heart).

The electrical impulse travels from the sinus node to the atrioventricular (AV) node, where it stops for a very short period, then continues down the conduction pathways via the “bundle of His” into the ventricles. The bundle of His divides into right and left pathways to provide electrical stimulation to both ventricles.

What is an ECG?

This electrical activity of the heart is measured by an electrocardiogram (ECG or EKG). By placing electrodes at specific locations on the body (chest, arms, and legs), a tracing of the electrical activity can be obtained. Changes in an ECG from the normal tracing can indicate one or more of several heart-related conditions.

Dysrhythmias/arrhythmias (abnormal heart rhythms) are diagnosed by methods such as EKG, Holter monitoring, signal-average EKG, or electrophysiological studies. These symptoms may be treated with medication or procedures such as a cardiac ablation (removal of a location in the heart that is causing a dysrhythmia by freezing or radiofrequency).

Reasons for the Procedure

A pacemaker may be inserted in order to provide stimulation for a faster heart rate when the heart is beating too slowly, and when other treatment methods, such as medication, have not improved the heart rate.

An ICD may be inserted in order to provide fast pacing (ATP), cardioversion (small shock), or defibrillation (larger shock) when the heart beats too fast.

Problems with the heart rhythm may cause difficulties because the heart is unable to pump an adequate amount of blood to the body. If the heart rate is too slow, the blood is pumped too slowly.

If the heart rate is too fast or too irregular, the heart chambers are unable to fill up with enough blood to pump out with each beat. When the body does not receive enough blood, symptoms such as fatigue, dizziness, fainting, and/or chest pain may occur.

Some examples of rhythm problems for which a pacemaker or ICD might be inserted include:

  • atrial fibrillation – occurs when the atria beat irregularly and too fast
  • ventricular fibrillation – occurs when the ventricles beat irregularly and too fast
  • bradycardia – occurs when the heart beats too slow
  • tachycardia – occurs when the heart beats too fast
  • heart block – occurs when the electrical signal is delayed after leaving the SA node; there are several types of heart blocks, and each one has a distinctive ECG tracing

There may be other reasons for your physician to recommend a pacemaker or ICD insertion.

Risks of the Procedure

Possible risks of pacemaker or ICD insertion include, but are not limited to, the following:

  • bleeding from the incision or catheter insertion site
  • damage to the vessel at the catheter insertion site
  • infection of the incision or catheter site
  • pneumothorax – air becomes trapped in the pleural space causing the lung to collapse

If you are pregnant or suspect that you may be pregnant, you should notify your physician. If you are lactating, or breastfeeding, you should notify your physician.

Patients who are allergic to or sensitive to medications or latex should notify their physician.

For some patients, having to lie still on the procedure table for the length of the procedure may cause some discomfort or pain.

There may be other risks depending upon your specific medical condition. Be sure to discuss any concerns with your physician prior to the procedure.

Before the Procedure

  • Your physician will explain the procedure to you and offer you the opportunity to ask any questions that you might have about the procedure.
  • You will be asked to sign a consent form that gives your permission to do the test. Read the form carefully and ask questions if something is not clear.
  • You will need to fast for a certain period of time prior to the procedure. Your physician will notify you how long to fast, usually overnight.
  • If you are pregnant or suspect that you are pregnant, you should notify your physician.
  • Notify your physician if you are sensitive to or are allergic to any medications, iodine, latex, tape, or anesthetic agents (local and general).
  • Notify your physician of all medications (prescription and over-the-counter) and herbal supplements that you are taking.
  • Notify your physician if you have heart valve disease, as you may need to receive an antibiotic prior to the procedure.
  • Notify your physician if you have a history of bleeding disorders or if you are taking any anticoagulant (blood-thinning) medications, aspirin, or other medications that affect blood clotting. It may be necessary for you to stop some of these medications prior to the procedure.
  • Your physician may request a blood test prior to the procedure to determine how long it takes your blood to clot. Other blood tests may be done as well.
  • You may receive a sedative prior to the procedure to help you relax. If a sedative is given, you will need someone to drive you home afterwards.
  • The upper chest may be shaved or clipped prior to the procedure.
  • Based upon your medical condition, your physician may request other specific preparation.

During the Procedure

Picture of a chest X-ray, showing a single-chamber implanted pacemaker
Chest X-ray with Implanted Pacemaker

A pacemaker or implanted cardioverter defibrillator may be performed on an outpatient basis or as part of your stay in a hospital. Procedures may vary depending on your condition and your physician’s practices.

Generally, a pacemaker or ICD insertion follows this process:

  1. You will be asked to remove any jewelry or other objects that may interfere with the procedure.
  2. You will be asked to remove your clothing and will be given a gown to wear.
  3. You will be asked to empty your bladder prior to the procedure.
  4. An intravenous (IV) line will be started in your hand or arm prior to the procedure for injection of medication and to administer IV fluids, if needed.
  5. You will be placed in a supine (on your back) position on the procedure table.
  6. You will be connected to an electrocardiogram (ECG or EKG) monitor that records the electrical activity of the heart and monitors the heart during the procedure using small, adhesive electrodes. Your vital signs (heart rate, blood pressure, breathing rate, and oxygenation level) will be monitored during the procedure.
  7. Large electrode pads will be placed on the front and back of the chest.
  8. You will receive a sedative medication in your IV before the procedure to help you relax. However, you will likely remain awake during the procedure.
  9. The pacemaker or ICD insertion site will be cleansed with antiseptic soap.
  10. Sterile towels and a sheet will be placed around this area.
  11. A local anesthetic will be injected into the skin at the insertion site.
  12. Once the anesthetic has taken effect, the physician will make a small incision at the insertion site.
  13. A sheath, or introducer, is inserted into a blood vessel, usually under the collarbone. The sheath is a plastic tube through which the pacer/ICD lead wire will be inserted into the blood vessel and advanced into the heart.
  14. It will be very important for you to remain still during the procedure so that the catheter placement will not be disturbed and to prevent damage to the insertion site.
  15. The lead wire will be inserted through the introducer into the blood vessel. The physician will advance the lead wire through the blood vessel into the heart.
  16. Once the lead wire is inside the heart, it will be tested to verify proper location and that it works. There may be one, two, or three lead wires inserted, depending on the type of device your physician has chosen for your condition. Fluoroscopy, (a special type of x-ray that will be displayed on a TV monitor), may be used to assist in testing the location of the leads.
  17. Once the lead wire has been tested, an incision will be made close to the location of the catheter insertion (just under the collarbone). You will receive local anesthetic medication before the incision is made.
  18. The pacemaker/ICD generator will be slipped under the skin through the incision after the lead wire is attached to the generator. Generally, the generator will be placed on the non-dominant side. (If you are right-handed, the device will be placed in your upper left chest. If you are left-handed, the device will be placed in your upper right chest).
  19. The ECG will be observed to ensure that the pacer is working correctly.
  20. The skin incision will be closed with sutures, adhesive strips, or a special glue.
  21. A sterile bandage/dressing will be applied.

After the Procedure

In the hospital

After the procedure, you may be taken to the recovery room for observation or returned to your hospital room. A nurse will monitor your vital signs for a specified period of time.

You should immediately inform your nurse if you feel any chest pain or tightness, or any other pain at the incision site.

After the specified period of bed rest has been completed, you may get out of bed. The nurse will assist you the first time you get up, and will check your blood pressure while you are lying in bed, sitting, and standing. You should move slowly when getting up from the bed to avoid any dizziness from the period of bedrest.

You will be able to eat or drink once you are completely awake.

The insertion site may be sore or painful, but pain medication may be administered if needed.

Your physician will visit with you in your room while you are recovering. The physician will give you specific instructions and answer any questions you may have.

Once your blood pressure, pulse, and breathing are stable and you are alert, you will be taken to your hospital room or discharged home.

If the procedure is performed on an outpatient basis, you may be allowed to leave after you have completed the recovery process. However, if there are concerns or problems with your ECG, you may stay in the hospital for an additional day (or longer) for monitoring of the ECG.

You should arrange to have someone drive you home from the hospital following your procedure.

At home

You should be able to return to your daily routine within a few days. Your physician will tell you if you will need to take more time in returning to your normal activities. In addition, you should not do any lifting or pulling on anything for a few weeks. You may be instructed not to lift your arms above your head for a period of time.

You will most likely be able to resume your usual diet, unless your physician instructs you differently.

It will be important to keep the insertion site clean and dry. Your physician will give you specific bathing instructions.

Your physician will give you specific instructions about driving. If you had an ICD, you will not be able to drive until your physician gives you approval. Your physician will explain these limitations to you, if they are applicable to your situation.

You will be given specific instructions about what to do if your ICD discharges a shock. For example, you may be instructed to dial 911 or go to the nearest emergency room in the event of a shock from the ICD.

Ask your physician when you will be able to return to work. The nature of your occupation, your overall health status, and your progress will determine how soon you may return to work.

Notify your physician to report any of the following:

  • fever and/or chills
  • increased pain, redness, swelling, or bleeding or other drainage from the insertion site
  • chest pain/pressure, nausea and/or vomiting, profuse sweating, dizziness and/or fainting
  • palpitations

Your physician may give you additional or alternate instructions after the procedure, depending on your particular situation.

Pacemaker/ICD precautions

The following precautions should always be considered. Discuss the following in detail with your physician, or call the company that made your device:

  • Always carry an ID card that states you are wearing a pacemaker or an ICD. In addition, you should wear a medical identification bracelet that states you have a pacemaker or ICD.
  • Use caution when going through airport security detectors. Check with your physician about the safety of going through such detectors with your type of pacemaker. In particular, you may need to avoid being screened by hand-held detector devices, as these devices may affect your pacemaker.
  • You may not have a magnetic resonance imaging (MRI) procedure. You should also avoid large magnetic fields.
  • Abstain from diathermy (the use of heat in physical therapy to treat muscles).
  • Turn off large motors, such as cars or boats, when working on them (they may temporarily €œconfuse” your device).
  • Avoid certain high-voltage or radar machinery, such as radio or television transmitters, electric arc welders, high-tension wires, radar installations, or smelting furnaces.
  • If you are having a surgical procedure performed by a surgeon or dentist, tell your surgeon or dentist that you have a pacemaker or ICD, so that electrocautery will not be used to control bleeding (the electrocautery device can change the pacemaker settings).
  • You may have to take antibiotic medication before any medically invasive procedure to prevent infections that may affect the pacemaker.
  • Always consult your physician if you have any questions concerning the use of certain equipment near your pacemaker.
  • When involved in a physical, recreational, or sporting activity, you should avoid receiving a blow to the skin over the pacemaker or ICD. A blow to the chest near the pacemaker or ICD can affect its functioning. If you do receive a blow to that area, see your physician.
  • Always consult your physician when you feel ill after an activity, or when you have questions about beginning a new activity.

SOURCE

http://stanfordhospital.org/healthLib/greystone/heartCenter/heartProcedures/pacemakerImplantableCardioverterDefibrillatorICDInsertion.html

In Summary: Who Needs a Pacemaker?

Doctors recommend pacemakers for many reasons. The most common reasons are bradycardia and heart block.

Bradycardia is a heartbeat that is slower than normal. Heart block is a disorder that occurs if an electrical signal is slowed or disrupted as it moves through the heart.

Heart block can happen as a result of aging, damage to the heart from a heart attack, or other conditions that disrupt the heart’s electrical activity. Some nerve and muscle disorders also can cause heart block, including muscular dystrophy.

Your doctor also may recommend a pacemaker if:

  • Aging or heart disease damages your sinus node’s ability to set the correct pace for your heartbeat. Such damage can cause slower than normal heartbeats or long pauses between heartbeats. The damage also can cause your heart to switch between slow and fast rhythms. This condition is called sick sinus syndrome.
  • You’ve had a medical procedure to treat an arrhythmia called atrial fibrillation. A pacemaker can help regulate your heartbeat after the procedure.
  • You need to take certain heart medicines, such as beta blockers. These medicines can slow your heartbeat too much.
  • You faint or have other symptoms of a slow heartbeat. For example, this may happen if the main artery in your neck that supplies your brain with blood is sensitive to pressure. Just quickly turning your neck can cause your heart to beat slower than normal. As a result, your brain might not get enough blood flow, causing you to feel faint or collapse.
  • You have heart muscle problems that cause electrical signals to travel too slowly through your heart muscle. Your pacemaker may provide cardiac resynchronization therapy (CRT) for this problem. CRT devices coordinate electrical signaling between the heart’s lower chambers.
  • You have long QT syndrome, which puts you at risk for dangerous arrhythmias.

Doctors also may recommend pacemakers for people who have certain types ofcongenital heart disease or for people who have had heart transplants. Children, teens, and adults can use pacemakers.

Before recommending a pacemaker, your doctor will consider any arrhythmia symptoms you have, such as dizziness, unexplained fainting, or shortness of breath. He or she also will consider whether you have a history of heart disease, what medicines you’re currently taking, and the results of heart tests.

Diagnostic Tests

Many tests are used to detect arrhythmias. You may have one or more of the following tests.

EKG (Electrocardiogram)

An EKG is a simple, painless test that detects and records the heart’s electrical activity. The test shows how fast your heart is beating and its rhythm (steady or irregular).

An EKG also records the strength and timing of electrical signals as they pass through your heart. The test can help diagnose bradycardia and heart block (the most common reasons for needing a pacemaker).

A standard EKG only records the heartbeat for a few seconds. It won’t detect arrhythmias that don’t happen during the test.

To diagnose heart rhythm problems that come and go, your doctor may have you wear a portable EKG monitor. The two most common types of portable EKGs are Holter and event monitors.

Holter and Event Monitors

A Holter monitor records the heart’s electrical activity for a full 24- or 48-hour period. You wear one while you do your normal daily activities. This allows the monitor to record your heart for a longer time than a standard EKG.

An event monitor is similar to a Holter monitor. You wear an event monitor while doing your normal activities. However, an event monitor only records your heart’s electrical activity at certain times while you’re wearing it.

For many event monitors, you push a button to start the monitor when you feel symptoms. Other event monitors start automatically when they sense abnormal heart rhythms.

You can wear an event monitor for weeks or until symptoms occur.

Echocardiography

Echocardiography (echo) uses sound waves to create a moving picture of your heart. The test shows the size and shape of your heart and how well your heart chambers and valves are working.

Echo also can show areas of poor blood flow to the heart, areas of heart muscle that aren’t contracting normally, and injury to the heart muscle caused by poor blood flow.

Electrophysiology Study

For this test, a thin, flexible wire is passed through a vein in your groin (upper thigh) or arm to your heart. The wire records the heart’s electrical signals.

Your doctor uses the wire to electrically stimulate your heart. This allows him or her to see how your heart’s electrical system responds. This test helps pinpoint where the heart’s electrical system is damaged.

Stress Test

Some heart problems are easier to diagnose when your heart is working hard and beating fast.

During stress testing, you exercise to make your heart work hard and beat fast while heart tests, such as an EKG or echo, are done. If you can’t exercise, you may be given medicine to raise your heart rate.

SOURCE

http://www.nhlbi.nih.gov/health/health-topics/topics/pace/whoneeds.html

What Are the Risks of Pacemaker Surgery?

Pacemaker surgery generally is safe. If problems do occur, they may include:

  • Swelling, bleeding, bruising, or infection in the area where the pacemaker was placed
  • Blood vessel or nerve damage
  • A collapsed lung
  • A bad reaction to the medicine used during the procedure

Talk with your doctor about the benefits and risks of pacemaker surgery.

How Does a Pacemaker Work?

A pacemaker consists of a battery, a computerized generator, and wires with sensors at their tips. (The sensors are called electrodes.) The battery powers the generator, and both are surrounded by a thin metal box. The wires connect the generator to the heart.

A pacemaker helps monitor and control your heartbeat. The electrodes detect your heart’s electrical activity and send data through the wires to the computer in the generator.

If your heart rhythm is abnormal, the computer will direct the generator to send electrical pulses to your heart. The pulses travel through the wires to reach your heart.

Newer pacemakers can monitor your blood temperature, breathing, and other factors. They also can adjust your heart rate to changes in your activity.

The pacemaker’s computer also records your heart’s electrical activity and heart rhythm. Your doctor will use these recordings to adjust your pacemaker so it works better for you.

Your doctor can program the pacemaker’s computer with an external device. He or she doesn’t have to use needles or have direct contact with the pacemaker.

Pacemakers have one to three wires that are each placed in different chambers of the heart.

  • The wires in a single-chamber pacemaker usually carry pulses from the generator to the right ventricle (the lower right chamber of your heart).
  • The wires in a dual-chamber pacemaker carry pulses from the generator to the right atrium (the upper right chamber of your heart) and the right ventricle. The pulses help coordinate the timing of these two chambers’ contractions.
  • The wires in a biventricular pacemaker carry pulses from the generator to an atrium and both ventricles. The pulses help coordinate electrical signaling between the two ventricles. This type of pacemaker also is called a cardiac resynchronization therapy (CRT) device.

Cross-Section of a Chest With a Pacemaker

The image shows a cross-section of a chest with a pacemaker. Figure A shows the location and general size of a double-lead, or dual-chamber, pacemaker in the upper chest. The wires with electrodes are inserted into the heart's right atrium and ventricle through a vein in the upper chest. Figure B shows an electrode electrically stimulating the heart muscle. Figure C shows the location and general size of a single-lead, or single-chamber, pacemaker in the upper chest.

The image shows a cross-section of a chest with a pacemaker. Figure A shows the location and general size of a double-lead, or dual-chamber, pacemaker in the upper chest. The wires with electrodes are inserted into the heart’s right atrium and ventricle through a vein in the upper chest. Figure B shows an electrode electrically stimulating the heart muscle. Figure C shows the location and general size of a single-lead, or single-chamber, pacemaker in the upper chest.

Types of Pacemaker Programming

The two main types of programming for pacemakers are

  • demand pacing and
  • rate-responsive pacing.

A demand pacemaker monitors your heart rhythm. It only sends electrical pulses to your heart if your heart is beating too slow or if it misses a beat.

A rate-responsive pacemaker will speed up or slow down your heart rate depending on how active you are. To do this, the device monitors your

  • sinus node rate,
  • breathing,
  • blood temperature, and
  • other factors to determine your activity level.

Your doctor will work with you to decide which type of pacemaker is best for you.

SOURCE

http://www.nhlbi.nih.gov/health/health-topics/topics/pace/howdoes.html

What To Expect During Pacemaker Surgery

Placing a pacemaker requires minor surgery. The surgery usually is done in a hospital or special heart treatment laboratory.

Before the surgery, an intravenous (IV) line will be inserted into one of your veins. You will receive medicine through the IV line to help you relax. The medicine also might make you sleepy.

Your doctor will numb the area where he or she will put the pacemaker so you don’t feel any pain. Your doctor also may give you antibiotics to prevent infection.

First, your doctor will insert a needle into a large vein, usually near the shoulder opposite your dominant hand. Your doctor will then use the needle to thread the pacemaker wires into the vein and to correctly place them in your heart.

An x-ray “movie” of the wires as they pass through your vein and into your heart will help your doctor place them. Once the wires are in place, your doctor will make a small cut into the skin of your chest or abdomen.

He or she will slip the pacemaker’s small metal box through the cut, place it just under your skin, and connect it to the wires that lead to your heart. The box contains the pacemaker’s battery and generator.

Once the pacemaker is in place, your doctor will test it to make sure it works properly. He or she will then sew up the cut. The entire surgery takes a few hours.

SOURCE

http://www.nhlbi.nih.gov/health/health-topics/topics/pace/during.html

What To Expect After Pacemaker Surgery

Expect to stay in the hospital overnight so your health care team can check your heartbeat and make sure your pacemaker is working well. You’ll likely have to arrange for a ride to and from the hospital because your doctor may not want you to drive yourself.

For a few days to weeks after surgery, you may have pain, swelling, or tenderness in the area where your pacemaker was placed. The pain usually is mild; over-the-counter medicines often can relieve it. Talk to your doctor before taking any pain medicines.

Your doctor may ask you to avoid vigorous activities and heavy lifting for about a month after pacemaker surgery. Most people return to their normal activities within a few days of having the surgery.

SOURCE

http://www.nhlbi.nih.gov/health/health-topics/topics/pace/after.html

How Will a Pacemaker Affect My Lifestyle?

Once you have a pacemaker, you have to avoid close or prolonged contact with electrical devices or devices that have strong magnetic fields. Devices that can interfere with a pacemaker include:

  • Cell phones and MP3 players (for example, iPods)
  • Household appliances, such as microwave ovens
  • High-tension wires
  • Metal detectors
  • Industrial welders
  • Electrical generators

These devices can disrupt the electrical signaling of your pacemaker and stop it from working properly. You may not be able to tell whether your pacemaker has been affected.

How likely a device is to disrupt your pacemaker depends on how long you’re exposed to it and how close it is to your pacemaker.

To be safe, some experts recommend not putting your cell phone or MP3 player in a shirt pocket over your pacemaker (if the devices are turned on).

You may want to hold your cell phone up to the ear that’s opposite the site where your pacemaker is implanted. If you strap your MP3 player to your arm while listening to it, put it on the arm that’s farther from your pacemaker.

You can still use household appliances, but avoid close and prolonged exposure, as it may interfere with your pacemaker.

You can walk through security system metal detectors at your normal pace. Security staff can check you with a metal detector wand as long as it isn’t held for too long over your pacemaker site. You should avoid sitting or standing close to a security system metal detector. Notify security staff if you have a pacemaker.

Also, stay at least 2 feet away from industrial welders and electrical generators.

Some medical procedures can disrupt your pacemaker. These procedures include:

  • Magnetic resonance imaging, or MRI
  • Shock-wave lithotripsy to get rid of kidney stones
  • Electrocauterization to stop bleeding during surgery

Let all of your doctors, dentists, and medical technicians know that you have a pacemaker. Your doctor can give you a card that states what kind of pacemaker you have. Carry this card in your wallet. You may want to wear a medical ID bracelet or necklace that states that you have a pacemaker.

Physical Activity

In most cases, having a pacemaker won’t limit you from doing sports and exercise, including strenuous activities.

You may need to avoid full-contact sports, such as football. Such contact could damage your pacemaker or shake loose the wires in your heart. Ask your doctor how much and what kinds of physical activity are safe for you.

Ongoing Care

Your doctor will want to check your pacemaker regularly (about every 3 months). Over time, a pacemaker can stop working properly because:

  • Its wires get dislodged or broken
  • Its battery gets weak or fails
  • Your heart disease progresses
  • Other devices have disrupted its electrical signaling

To check your pacemaker, your doctor may ask you to come in for an office visit several times a year. Some pacemaker functions can be checked remotely using a phone or the Internet.

Your doctor also may ask you to have an EKG (electrocardiogram) to check for changes in your heart’s electrical activity.

Battery Replacement

Pacemaker batteries last between 5 and 15 years (average 6 to 7 years), depending on how active the pacemaker is. Your doctor will replace the generator along with the battery before the battery starts to run down.

Replacing the generator and battery is less-involved surgery than the original surgery to implant the pacemaker. Your pacemaker wires also may need to be replaced eventually.

Your doctor can tell you whether your pacemaker or its wires need to be replaced when you see him or her for followup visits.

SOURCE

http://www.nhlbi.nih.gov/health/health-topics/topics/pace/lifestyle.html

Clinical Trial on Pace Makers

clinical trials related to pacemakers, talk with your doctor. You also can visit the following Web sites to learn more about clinical research and to search for clinical trials:

For more information about clinical trials for children, visit the NHLBI’s Children and Clinical Studies Web page.

SOURCE

http://www.nhlbi.nih.gov/health/health-topics/topics/pace/trials.html

RESOUCES on PaceMakers

Links to Other Information About Pacemakers

NHLBI Resources

Non-NHLBI Resources

Clinical Trials

SOURCE

 

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iElastance: Calculates Ventricular Elastance, Arterial Elastance and Ventricular-Arterial Coupling using Echocardiographic derived values in a single beat determination

Reporter: Aviva Lev-Ari, PhD, RN

 

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First iElastance release for Android!

iElastance is an application designed for calculate Ventricular Elastance, Arterial Elastance and Ventricular-Arterial Coupling using Echocardiographic derived values in a single beat determination.
This application is extremely useful to a variety of health care givers such as Cardiologists, Intensivists, Anesthesiologist and more who want to calculate ventricular arterial coupling even in the Critical Care setting and, above all, bedside.

The variables needed for the calculator to work are:

Systolic Blood Pressure (mmHg)
Diastolic Blood Pressure (mmHg)
Stroke Volume (ml)
Ejection Fraction (0-1)
Total Ejection Time (msec)
Pre Ejection Time (msec)

Formulas are validated and extracted from the article by Chen CH et Al J Am Coll Cardiol. 2001 Dec;38(7):2028-34.

DISCLAIMER: The calculator provided is not meant to be a substitute for professional advice and is not to be used for medical diagnosis. Extensive effort has been exerted to make this software as accurate as possible; however the accuracy of information provided by this software cannot be guaranteed. Health care professionals should use clinical judjement and individualize therapy to each patient care situation.

All rights reserved – 2013 Pietro Bertini – Department of Cardiothoracic Anesthesia and Intensive Care Medicine – University Hospital of Pisa – Dr. Fabio Guarracino, Head of Department

FULL NETWORK ACCESS
Allows the app to create network sockets and use custom network protocols. The browser and other applications provide means to send data to the internet, so this permission is not required to send data to the internet.

https://play.google.com/store/apps/details?id=air.iElastance

 

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Reporter: Aviva Lev-Ari, PhD, RN

Preliminary Communication | April 17, 2013

Effect of Shock Wave–Facilitated Intracoronary Cell Therapy on LVEF in Patients With Chronic Heart Failure The CELLWAVE Randomized Clinical Trial

Birgit Assmus, MD; Dirk H. Walter, MD; Florian H. Seeger, MD; David M. Leistner, MD; Julia Steiner; Ina Ziegler; Andreas Lutz, MD; Walaa Khaled, MD; Jens Klotsche, PhD; Torsten Tonn, MD; Stefanie Dimmeler, PhD; Andreas M. Zeiher, MD
JAMA. 2013;309(15):1622-1631. doi:10.1001/jama.2013.3527.

ABSTRACT

Importance  The modest effects of clinical studies using intracoronary administration of autologous bone marrow–derived mononuclear cells (BMCs) in patients with chronic postinfarction heart failure may be attributed to impaired homing of BMCs to the target area. Extracorporeal shock wave treatment has been experimentally shown to increase homing factors in the target tissue, resulting in enhanced retention of applied BMCs.

Objective  To test the hypothesis that targeted cardiac shock wave pretreatment with subsequent application of BMCs improves recovery of left ventricular ejection fraction (LVEF) in patients with chronic heart failure.

Design, Setting, and Participants  The CELLWAVE double-blind, randomized, placebo-controlled trial conducted among patients with chronic heart failure treated at Goethe University Frankfurt, Germany, between 2006 and 2011.

Interventions  Single-blind low-dose (n = 42), high-dose (n = 40), or placebo (n = 21) shock wave pretreatment targeted to the left ventricular anterior wall. Twenty-four hours later, patients receiving shock wave pretreatment were randomized to receive double-blind intracoronary infusion of BMCs or placebo, and patients receiving placebo shock wave received intracoronary infusion of BMCs.

Main Outcomes and Measures  Primary end point was change in LVEF from baseline to 4 months in the pooled groups shock wave + placebo infusion vs shock wave + BMCs; secondary end points included regional left ventricular function assessed by magnetic resonance imaging and clinical events.

Results  The primary end point was significantly improved in the shock wave + BMCs group (absolute change in LVEF, 3.2% [95% CI, 2.0% to 4.4%]), compared with the shock wave + placebo infusion group (1.0% [95% CI, −0.3% to 2.2%]) (P = .02). Regional wall thickening improved significantly in the shock wave + BMCs group (3.6% [95% CI, 2.0% to 5.2%]) but not in the shock wave + placebo infusion group (0.5% [95% CI, −1.2% to 2.1%]) (P = .01). Overall occurrence of major adverse cardiac events was significantly less frequent in the shock wave + BMCs group (n = 32 events) compared with the placebo shock wave + BMCs (n = 18) and shock wave + placebo infusion (n = 61) groups (hazard ratio, 0.58 [95% CI, 0.40-0.85]; P = .02).

Conclusions and Relevance  Among patients with postinfarction chronic heart failure, shock wave–facilitated intracoronary administration of BMCs vs shock wave treatment alone resulted in a significant, albeit modest, improvement in LVEF at 4 months. Determining whether the increase in contractile function will translate into improved clinical outcomes requires confirmation in larger clinical end point trials.

Trial Registration  clinicaltrials.gov Identifier: NCT00326989

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Cardiotoxicity and Cardiomyopathy Related to Drugs Adverse Effects

Curator: Larry H Bernstein, MD, FCAP

Introduction
This is the second part of a series on toxicities of therapeutic medications, the first being on the impact on drug development of early phase failure to identify toxicities that are found in late stage trials and result in withdrawal.  This portion will go into details of identifying the effects clinically and give some examples.  In the future, the design of therapies, the identification of high probability successful genomic targets, and more accurate patient selection will transform the approach to development, clinical trials, and clinical use of pharmaceuticals in patients.

Cardiotoxicity and Cardiomyopathy

refer to: What are cardiotoxicity and cardiomyopathy?

The Scott Hamilton Cares Initiative
Cardiotoxicity is a condition of heart muscle functional impairment from toxicity as an
  • adverse secondary effect of taking an essential medication, or
  • as a result of interactions between prescribed medications that result in heart damage,
  • usually dose and time related.
If severe, the adverse effect of chemotherapy may lead to cardiomyopathy.  While cardiomyopathy might be a result of treatments, such as chemotherapeutic medications, it may also caused by a group of diseases or disorders, leading to
  • damaged myocardiocytes, and the injury leads to
  • insufficient cardiac output, referred to as
  • heart failure.
Cardiomyopathy has many causes, singly or in combination:
  • viruses – such as,
    • coxsackie B,
    • human immunodeficiency virus (HIV)
  • systemic inflammatory disorder
    • systemic lupus erythematosis
  • Amyloidosis – amyloid protein deposits in the myocardium alone, and/or other organs
  • Infection –
    • bacterial (tetanus),
    • parasitic (Chaga’s disease)
    • Rheumatic fever
  •  high blood pressure
  • Chronic or long-term alcohol use (B vitamin deficiency)
  • Endocrine disease, such as hyperthyroidism
  • Thiamine and Vitamin B deficiency
  • Radiation therapy
  • Medications – anthracyclines.

Anthracyclines may be used to treat leukemia, lymphoma, multiple myeloma, breast cancer, and sarcoma. A commonly used anthracycline is called doxorubicin (Adriamycin®).

  • cardiomyopathy may also result from genetic defects
  • illegal drugs and toxic substances, cocaine, may also produce serious myocardial damage

With certain drugs, such as doxorubicin, there is a dose at which these cardiotoxic effects on the heart may occur.
An echocardiogram, or a radionuclide ventriculography scan, is performed

  • prior to initiating a cardiotoxic medication
  • to determine baseline cardiac function., and
  • repeated at intervals to monitor heart function while receiving cardiotoxic medications.

The ejection fraction (EF) is a percentage of blood pumped out into the body during each heartbeat. An EF of 50%-75% is considered normal.

  • The lower the ejection fraction, the more severe the heart failure may be.
This may determine if the cardiotoxic drug has caused cardiomyopathy.

Symptoms of cardiomyopathy:

  • fatigue
  •  shortness of breath
  •  fever and aching of the joints,
      • all characteristic of a flu-like illness.
  • Or, sudden heart failure or sudden cardiac death without any prior symptoms.
    • swollen feet and ankles
    • distended neck veins
    • tachycardia
    • dyspnea while reclining

Diagnosis:

  • history & physical examination
  • laboratory tests
  • EKG
  • Chest x-ray
  • Echocardiography
  • Cardiac cath
  • Angiography

Treatment:

  • Dexraoxane HCL –  doxorubicin
  • ACE inhibitors
  • Beta-blockers
  • Diuretics
  • Digoxin

 Biomolecular Screening for Drug Toxicity

Multiparameter In Vitro Assessment of Compound Effects on Cardiomyocyte Physiology Using iPSC Cells

O Sirenko, C Crittenden, N Callamaras, J Hesley, Yen-Wen Chen, et al.
 A sufficient percentage of drugs fail in clinical studies due to cardiac toxicity that the development of new, sensitive in vitro assays that can evaluate potential adverse effects on cardiomyocytes is needed. Cell-based models are more clinically relevant than those used in practice. Human-induced pluripotent stem cell–derived cardiomyocytes are especially attractive because
  • they express ion channels and
  • demonstrate spontaneous mechanical and electrical activity
    • similar to adult cardiomyocytes.
This study introduces techniques for measuring the impact of pharmacologic compounds on the beating rate of cardiomyocytes with ImageXpress Micro and FLIPR Tetra systems. The assays employ
calcium-sensitive dyes to monitor changes in Ca2+ fluxes
  • synchronous with cell beating,
This method allows monitoring of the
  • beat rate
  • amplitude, and
  • other parameters.
The system detects
  • concentration-dependent atypical patterns caused by
  • hERG inhibitors and other ion channel blockers.
In addition,
  • both positive and negative chronotropic effects on cardiac rate can be observed and
  • IC50 values determined.
This methodology is well suited for safety testing and can be used to estimate efficacy and dosing of drug candidates prior to clinical studies.
J Biomol Screen Jan 2013;18(1): 39-53  http://dx.doi.org/10.1177/1087057112457590

Estimating the risk of drug-induced proarrhythmia using human induced pluripotent stem cell-derived cardiomyocytes.

L Guo, RMC Abrams, JE Babiarz, JD Cohen, S Kameoka, et al.
 Early prediction of drug-induced toxicity is needed in the pharmaceutical and biotechnology industries to decrease late-stage drug attrition.
  • Cardiotoxicity accounts for about one third of safety-based withdrawn pharmaceuticals.
This study reports a high-throughput functional assay,  detailing a model that accurately detects
  • drug-induced cardiac abnormalities.
It employs
  • induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs).
  • Using 96-well plates with interdigitated electrode arrays  detect
    • assess impedance,
    • the rhythmic, synchronous contractions of the iPSC-CMs
Treatment of the iPSC-CMs with 28 different compounds with known cardiac effects resulted in
  • compound-specific changes in the beat rate and/or
  • the amplitude of the impedance measurement.
Changes in impedance for the compounds tested were comparable with the results from a related technology,
  • electric field potential assessment obtained from microelectrode arrays.
Using the results from the set of compounds,
  • an index of drug-induced arrhythmias was calculated,
  • which enabled the determination of a drug’s proarrhythmic potential.
This system of interrogating human cardiac function in vitro opens new opportunities for predicting cardiac toxicity and studying cardiac biology.
Toxicol Sci. Sep 2011; 123 (1):281-9  21693436

Determination of the Human Cardiomyocyte mRNA and miRNA Differentiation Network by Fine-Scale Profiling.

JE Babiarz, M Ravon, S Sridhar, P Ravindran, B Swanson,  et al.
This study is a detailed comparison of the mRNA and miRNA transcriptomes
  • across differentiating human-induced pluripotent stem cell (hiPSC)-derived cardiomyocytes and
  • biopsies from fetal, adult, and hypertensive human hearts
Gene ontology analysis of the mRNA expression levels of the hiPSCs differentiating into cardiomyocytes
revealed 3 distinct groups of genes:
  • pluripotent specific,
  • transitional cardiac specification, and
  • mature cardiomyocyte specific.
Hierarchical clustering of the mRNA data revealed that the transcriptome of hiPSC cardiomyocytes
  • stabilizes 20 days after initiation of differentiation.
But analysis of cells continuously cultured for 120 days indicated that
  • the cardiomyocytes continued to mature toward a more adult-like gene expression pattern.
Analysis of cardiomyocyte-specific miRNAs (miR-1, miR-133a/b, and miR-208a/b) revealed
  • an miRNA pattern indicative of stem cell to cardiomyocyte specification.
A biostatistitical approach integrated the miRNA and mRNA expression profiles revealing a
  • cardiomyocyte differentiation miRNA network and
  • identified putative mRNAs targeted by multiple miRNAs.
Together, these data reveal the
miRNA network in human heart development and
  • support the notion that overlapping miRNA networks
  • re-enforce transcriptional control during developmental specification.
Stem Cells Dev. 2012 Jul 20;21 (11):1956-65  22050602

Comparative Gene Expression Profiling in Human Induced Pluripotent Stem Cell Derived Cardiocytes and Human and Cynomolgus Heart Tissue.

D Puppala, LP Collis, SZ Sun, V Bonato, X Chen, B Anson, et al.  Compound Safety Prediction.
Cardiotoxicity is one of the leading causes of drug attrition. Current in vitro models insufficiently predict cardiotoxicity.  The authors describe
  • the gene expression profile of human induced pluripotent stem cell derived cardiocytes (iCC)
  • post-thaw over a period of 42 days in culture and
  • compare this profile to human fetal and adult as well as
  • adult cynomolgus nonhuman primate (NHP: Macaca fascicularis) heart tissue.
The results indicate that iCC express relevant cardiac markers such as
  • ion channels (SCN5A, KCNJ2, CACNA1C, KCNQ1 and KCNH2),
  • tissue specific structural markers (MYH6, MYLPF, MYBPC3, DES, TNNT2 and TNNI3),
  • transcription factors (NKX2.5, GATA4 and GATA6), and
  • lack the expression of stem cell markers (FOXD3, GBX2, NANOG, POU5F1, SOX2, and ZFP42).

A functional evaluation of contractility of the iCC showed

  • functional and pharmacological correlations with myocytes isolated from adult NHP hearts.
The results suggest that stem cell derived cardiocytes may represent
  • a novel in vitro model to study human cardiac toxicity with potential ex vivo and in vivo translation.
Toxicol Sci. Sep 14 2012;:   22982684

Characterization of Human Induced Pluripotent Stem Cell Derived Cardiomyocytes:
Bioenergetics and Utilization in Safety Screening.

P Rana, B Anson, S Engle, Y Will.   Compound Safety Prediction. Pfizer Global R&D, Groton CT.
Cardiotoxicity remains the number one reason for drug withdrawal from the market and FDA issued black box warnings; thus
  • demonstrating the need for more predictive preclinical safety screening,
  • especially early in the drug discovery process.
Whereas hERG screening has become routine to mitigate proarrhythmic risk,
  • the development of in vitro assays predicting additional on- and off-target biochemical toxicities
  • will benefit from cellular models exhibiting true cardiomyocyte characteristics
    • such as, native tissue-like mitochondrial activity.
An hypothesis was tested  for using human stem cell derived tissue cells by using a combination of
  • flux analysis,
  • gene and protein expression, and
  • toxicity-profiling techniques
    • to characterize mitochondrial function
    • in induced pluripotent stem cell (iPSC)-derived human cardiomyocytes
      • in the presence of differing carbon sources
      • over extended periods in cell culture.
Functional analyses demonstrate that iPSC-derived cardiomyocytes:
1) are capable of utilizing anaerobic or aerobic respiration depending upon the available carbon substrate,
2) are bioenergetically closest to adult heart tissue cells when cultured in galactose or galactose supplemented with fatty acids, and
3) show a dose dependent toxicity profile to a variety of kinase inhibitors with known clinical cardiac liabilities.
Furthermore, gene and protein expression analyses revealed that in comparison to adult cardiac tissue,
  • iPSCs-derived cardiomyocytes possess a qualitatively similar expression pattern of mitochondrial genes,
  • an up-regulation of apoptotic and antioxidant genes, and
  • a mitochondrial transcription pattern that is similar across different carbon substrates
  • despite showing changes in protein levels and functional bioenergetic adaptation.
Toxicol Sci. 2012 Jul 27;:   22843568

Decreasing cardiac chamber sizes and associated heart dysfunction in COPD – role of hyperinflation.

H Watz, B Waschki, T Meyer, G Kretschmar, A Kirsten, M Claussen, H Magnussen
This study examined the relationship of
  • lung function with heart size and heart dysfunction and
  • associated consequences for 6-minute walk distance (6MWD)
    • in patients with COPD of different severity.
METHODS:   138 patients with COPD (GOLD I-IV)
  • the size of all cardiac chambers,
  • left ventricular diastolic dysfunction (relaxation and filling), and
  • global right ventricular dysfunction (Tei-index)
    • were measured by echocardiography .
  • lung function (spirometry, bodyplethysmography, diffusion capacity) and
  • 6MWD …. were measured.
RESULTS: Size of all cardiac chambers decreased with GOLD stages. Overall,
moderate relationships existed between
  • variables of lung function and cardiac chamber sizes.
  • Static hyperinflation (inspiratory-to-total lung capacity ratio [IC/TLC],
  • functional residual capacity, and residual volume)
showed stronger associations with
  • cardiac chamber sizes than
  • airway obstruction or diffusion capacity.
IC/TLC ratio correlated best with cardiac chamber sizes and was
  • an independent predictor of cardiac chamber sizes
    • after adjustment for body surface area.
Patients with an IC/TLC ratio <!–= 0.25 had a significantly–>
  • impaired left ventricular diastolic filling pattern and
  • a significantly impaired Tei-index
    • compared to patients with an IC/TLC ratio > 0.25.
An impaired left ventricular diastolic filling pattern was independently associated with
  • a reduced 6MWD.
An increasing severity of COPD is associated with a decreasing heart size.
Hyperinflation in patients with COPD might have an important role with respect to
  • heart size and
  • cardiac dysfunction
Chest. Feb 26 2010;:   20190002  Cit:4

Cardiovascular Events After Clarithromycin Use in Lower Respiratory Tract Infections
Analysis of Two Prospective Cohort Studies

S Schembri, PA Williamson, PM Short, A Singanayagam, A Akram, et al. British Medical Journal
Acute exacerbations of chronic obstructive pulmonary disease and community acquired pneumonia are common causes of admission to a hospital.
Antibiotics, including clarithromycin, are commonly prescribed during acute exacerbations of chronic obstructive pulmonary disease, especially
  • in the presence of increased breathlessness,
  • sputum volume, and
  • purulence.
 Use of macrolide antibiotics in community acquired pneumonia has been consistently associated with improved short term mortality in observational studies,
and national and international guidelines therefore recommend their use in combination with β lactams for patients admitted to hospital.

Widespread use of macrolide antibiotics has been accompanied by concerns about adverse effects on cardiovascular morbidity and mortality.
A retrospective study of erythromycin use in 1,249,943 patients identified an increase in deaths from cardiovascular disease.
Azithromycin was shown to have a similar association with increased cardiovascular deaths

  • during the time of administration.

CLARICOR (Effect of Clarithromycin on Mortality and Morbidity in Patients with Ischemic Heart Disease trial) was a double blind, placebo controlled trial
showing that a two week course of clarithromycin administered to patients with coronary heart disease 

  • increased cardiovascular and all cause mortality
The increased mortality rate (clear of pulmonary infection)
  • persisted for three years after discontinuation of the drug.

A recent meta-analysis of 17 trials of antibiotics in coronary heart disease showed

  • increased long term mortality after macrolides, primarily due
  • to increased deaths from cardiovascular disease.

However, no studies have examined the long term effect of clarithromycin on cardiovascular events and mortality in patients

  • after acute exacerbations of chronic obstructive pulmonary disease or community acquired pneumonia.

Therefore, this prospective cohort study was undertaken to examine the association of clarithromycin with cardiovascular events

  • in the setting of acute exacerbations of chronic obstructive pulmonary disease and community acquired pneumonia.

Population.

  • 1343 patients admitted to hospital with acute exacerbations of chronic obstructive pulmonary disease
  • and 1631 patients admitted with community acquired pneumonia.

Main Outcome Measures.

Hazard ratios for cardiovascular events at one year (defined as hospital admissions with

  • acute coronary syndrome, decompensated cardiac failure, serious arrhythmia, or sudden cardiac death) and
  • admissions for acute coronary syndrome (acute ST elevation myocardial infarction, non-ST elevation myocardial infarction, and unstable angina).

Secondary outcomes were all cause and cardiovascular mortality at one year.

Results.

  •  268 cardiovascular events occurred in the acute exacerbations of chronic obstructive pulmonary disease cohort and
  • 171 in the community acquired pneumonia cohort over one year.

After multivariable adjustment, clarithromycin use in acute exacerbations of chronic obstructive pulmonary disease

  • was associated with an increased risk of cardiovascular events and acute coronary syndrome—
  • hazard ratios 1.50 (95% confidence interval 1.13 to 1.97) and 1.67 (1.04 to 2.68).
After multivariable adjustment, clarithromycin use in community acquired pneumonia
  •  was associated with increased risk of cardiovascular events (hazard ratio 1.68, 1.18 to 2.38)
  • but not acute coronary syndrome (1.65, 0.97 to 2.80).
This association was found between clarithromycin use in acute exacerbations of COPD and
  • cardiovascular mortality (adjusted hazard ratio 1.52, 1.02 to 2.26)
  • but not all cause mortality (1.16, 0.90 to 1.51) .

No association was found between clarithromycin use in community acquired pneumonia and all cause mortality or cardiovascular mortality.
Use of β lactam antibiotics or doxycycline was not associated with increased cardiovascular events in patients with

  • acute exacerbations of chronic obstructive pulmonary disease, suggesting an effect specific to clarithromycin.

 Timing of Cardiovascular Events

The study found no significantly increased risk of cardiovascular events while patients were taking clarithromycin in the COPD cohort
(hazard ratio 1.73, 0.71 to 4.25), but
  • an increased risk was present after the clarithromycin course ended (1.41, 1.05 to 1.89).
In the community acquired pneumonia cohort, the hazard ratio for association between clarithromycin use and cardiovascular events
was 1.84 (0.75 to 4.51) during clarithromycin use and 1.66 (1.14 to 2.43) after the antibiotic was stopped.

Association With Duration of Antibiotic Use

Longer courses of clarithromycin were associated with more cardiovascular events. The median duration of treatment was seven days in both cohorts.
Less than three days of clarithromycin treatment was not associated with cardiovascular events in the chronic obstructive pulmonary disease cohort
(hazard ratio 0.89, 0.50 to 1.57) or the community acquired pneumonia cohort (0.63, 0.15-2.65), compared with patients who did not receive clarithromycin.

Effect of Age and Cardiovascular Risk Status

The hazard ratios of the effect of clarithromycin on cardiovascular events in such patients were
  • 1.35 (0.94 to 1.95) in those with a high cardiovascular risk and 0.88 (0.20 to 3.96) in those with a low risk.

The lowest hazard ratios for cardiovascular events were in patients aged 60 or below (1.01, 0.36 to 2.91).
The hazard ratio was 1.47 (1.01 to 2.14) for patients aged 60-79, and a higher risk was associated with

  • clarithromycin use in patients aged over 80 (hazard ratio 1.68, 1.05 to 2.69).

Use of Other Antibiotics

Use of β lactam or doxycycline was not associated with increased cardiovascular events
  • (hazard ratios 1.06 (0.83 to 1.37) and 0.96 (0.61 to 1.51), respectively)
in the chronic obstructive pulmonary disease cohort compared with patients not receiving antibiotics.

Possible Explanations for Findings

There was a strong association between prolonged (more than seven days) courses of clarithromycin and
  • cardiovascular events,
    • which strengthens the case for a true biological cause.

The association between duration of antibiotic treatment and cardiovascular events

  • could also represent residual confounding by severity of illness.

How do the results point to the effect on outcome after cessation of the drug?  The authors support an ischaemic mechanism.
Clarithromycin may activate macrophages, leading to an inflammatory cascade resulting in more vulnerable plaques that

  • over time may lead to acute coronary syndromes or sudden cardiac death by plaque rupture.

 Conclusion

Prolonged courses of clarithromycin (more than seven days) may be associated with

  • increased risk of cardiovascular events,
  • especially in patients with a pre-existing history of coronary heart disease.

This may be of particular importance given recent data supporting long term macrolide use

  • to prevent exacerbations of chronic obstructive pulmonary disease.

Biomarkers Role in Drug Development

Biomarkers: An indispensible addition to the drug development toolkit

Biomarkers are becoming an essential part of clinical development. In this white paper, Thomson Reuters explores
the role of biomarkers as evaluative tools in improving clinical research and the challenges this presents.
The potential of biomarkers to

  • improve decision making,
  • accelerate drug development and
  • reduce development costs

is discussed with insights into a faster alternative to the conventional drug development approach and the promise of

  • safer drugs,
  • in greater numbers,
  • approved more quickly.
The attrition rate for drugs in clinical development is high: the percentage of tested products
  • entering phase I trials that eventually gain regulatory approval has been estimated at a paltry 8%.
Many of these failures happen late in clinical trials, with the consequence that expenditure in clinical drug development is increasing.
One study calculated that the cost of developing a drug increased by over 50% between 2002 and 2007. The related concern is that
very few drugs are making it out of the clinical research pipeline.
In 2007, the FDA approved just 17 new molecular entities and 2 biologic licenses, the lowest number since 1983.
The problem is mainly due to a gap in the industry’s ability to predict a drug candidate’s performance early, and with a large degree of certainty.
The convention in clinical research has been to measure the performance of novel therapies using clinical outcomes. This approach is
laborious, inexact and, as the US Food and Drug Administration (FDA ) puts it, decades old.

Why and what kinds of biomarkers do we determine are ESSENTIAL?

Biomarkers — a measure of
  • a normal biological process in the body,
  • a pathological process, or
  • the response of the body to a therapy —
may offer information about
  • the mechanism of action of the drug,
  • its efficacy, its safety and
  • its metabolic profile.
They feature heavily in the FDA ’s Critical Path Opportunities List for their potential
  • to speed the development and approval of medical products.
  • Moreover, they can predict drug efficacy more quickly than conventional clinical endpoints.
The first three examples are measures of drug efficacy and treatment response, but are not indicators of TOXICITY.

In 1960, researchers discovered that some patients with chronic myelogenous leukemia (CML), a form of adult leukemia

  • in which there is a proliferation of myeloid cells in the bone marrow,
  • have a specific genetic change associated with their cancer, a shortened version of chromosome.

The Philadelphia chromosome is caused by a translocation between chromosomes 9 and 22. The consequence of this genetic swap

  • is the creation of the BCR-ABL ‘oncogene’;
  • this cancer-causing gene produces a protein with elevated tyrosine kinase activity
  • that induces the onset of leukemia.

Researchers were able to use the Philadelphia chromosome as a biomarker

  • to indicate which patients would benefit from drug candidates (tyrosine-kinase inhibitors)
    • specifically targeting the rogue protein.

The drug imatinib (Gleevec) is a Tyr kinase inhibitor and

  • decreases the proliferation of Philadelphia chromosome+ cells,
  • slowing the progression of the disease.

Specific mutations in the BCR–ABL gene were biomarkers that predicted resistance to imatinib,

  • leading to the development of newer tyrosine-kinase inhibitors dasatinib and nilotinib.

In the late 1980’s, scientists discovered that HIV viral load could be used as a marker of disease progression
Viral load was used to show that patients receiving combination therapy had

  • a higher reduction in viral load than those on monotherapy.

Eventually, the viral load biomarker was used in the development and assessment of Highly Active Antiretroviral Therapy (HAART)
treatment regimens taken by many people living with HIV today.

The HER-2 gene and receptor was also discovered in the mid 1980’s. Between 20–30% of breast cancer patients show an

  • over-expression of the HER-2 receptor on their cancer cells (usually postmenopausal).

This biomarker indicates a higher risk of adverse outcomes, but it gave clinicians a new target for novel therapies, and

  • the antibody trastuzumab (Herceptin) was developed
  • to target HER-2 receptors in these ‘overexpressing’ patients.

 Preventing Drug Development Disasters

The need for biomarkers to guide clinical research is perhaps best highlighted in the stories of recent drug development failures.
Between 1995 and 2005, at least 34 drugs were withdrawn from the market, mainly as a result of hepatotoxic or cardiotoxic effects.

Many of us are familiar with the withdrawal in 2004 of the anti-inflammatory drug rofecoxib (Vioxx) due to concerns about its

  • increased risk of heart attack and stroke, and more recently with
  • the extremely serious adverse effects in the phase I clinical trial and subsequent failure of the monoclonal antibody, TGN1412.

TG N1412, a ‘superagonist’, produced by the firm TeGenero, stimulates an immune response. While originally intended to treat B cell
chronic lymphocytic leukemia and rheumatoid arthritis, it had been tested pre-clinically with no toxic or pro-inflammatory effects.
In 2006, six healthy male volunteers took part in a phase I clinical trial to test the safety of the candidate. Within 90 minutes of receiving the drug,

  • all six men were experiencing the beginnings of a ‘cytokine storm’, a term that describes
  • a cascade of proinflammatory cytokine release
  • leading to organ failure due to hypotension.

Although all the men survived, they required weeks of hospitalization. The cost of a failure, such as TGN1412,

  • in terms of patient health and lost resources is huge.

The TGN1412 trial failure highlighted a need for improved preclinical safety testing. It has been suggested that had procedures using safety biomarkers to

  • guide dosing and predict the toxicity of this drug been used, the disaster may not have occurred.

Biomarkers today

Today you “would not even conceive” of developing a new drug without simultaneously looking for biomarkers for
  • efficacy,
  • safety, and
  • to measure the pharmacodynamics of the drug,
says Dr Jeffrey Ross, Head of Pathology at the Albany Medical Center in New York, involved in the original work on HER-2.
The field of oncology is leading the way in the use of biomarkers in drug development. “Clinical trials are designed upon biomarker assays,”
“abstracts of phase II and III cancer trials talk about what biomarkers were selected.
  • In vivo biomarkers,
  • imaging biomarkers,
  • blood and tissue based biomarkers,

One example of a biomarker in use in oncology is circulating tumor cells (CTCs), a biomarker present in the blood of cancer patients.
At the moment, CTCs are used in the development of anti-cancer drugs as

  • an objective and direct measurement of the response of the cancer to a novel agent.

The way that clinical trials had been done previously was to enroll all patients

  • with a given disease independent of gene or phenotypic makers.
  • By selecting a population with the particular gene which is predicted
  • to be important for response to a novel therapeutic, then
    • a smaller clinical trial should be sufficient to see whether it works or not.

The chemotherapy drug irinotecan (Camptosar) is an example of personalized medicine,

  • using a biomarker to guide both clinical practice and subsequent clinical trials.

Irinotecan is used to treat advanced colorectal cancer. Once administered, irinotecan is

  • activated to the metabolite SN-38, and then
  • eventually inactivated in the body by the UGT1A1 enzyme.

In 2005, the US Food and Drug Administration added a warning to the label of the drug, stating that patients

  • homozygous for a particular a version of the UGT1A1 gene — the UGT1A1*28 allele,
  • associated with decreased UGT1A1 enzyme activity —
    • should be given a reduced dose.
Because patients with this allele clear the drug less quickly from their body than the rest of the population,
  • they effectively receive a greater exposure to the drug from the same dose.
As a consequence, they are at higher risk of potentially life-threatening side effects such as neutropenia (a decrease in white blood cells) and diarrhea.
The toxicity of irinotecan has long been a concern, and this biomarker now allows clinicians to better identify those patients who are at high risk of
  • serious side-effects (about 10% of the population are homozygous for UGT1A1*28).
And while this pharmacogenomics information has helped improve the clinical use and efficacy of irinotecan, it has also fed back into
the development of other drugs; this new understanding prompted the use of the UGT1A1 biomarker to guide other studies,
including several new irinotecan and oxaliplatin-based chemotherapy regimens.

Using preclinical biomarkers as evidence of efficacy

  • biomarkers can accelerate research by substituting for clinical symptoms as a measure of efficacy.
  • biomarkers can also replace clinical symptoms when it comes to measuring drug safety
  • an efficacy biomarker plus a safety biomarker will define not just whether a drug will work, but also what kind of dose might be relevant in humans

 Improving efficacy in cardiology

Consider the role of inflammatory marker C-reactive-protein (CRP) in cardiovascular disease. CRP is released by inflamed atherosclerotic plaques in the arteries
of individuals with coronary heart disease, and increased levels of CRP are associated with a greater risk of plaque rupture, but also of a silent heart attack.
CRP is being used as a biomarker to measure drug efficacy, in particular whether rosuvastatin (Crestor)

  • reduces the risk of cardiovascular morbidity and mortality
  • in apparently healthy individuals with low LDL-cholesterol levels but elevated CRP.

The JUPITER study (Justification for the Use of Statins in Primary Prevention: an Intervention Trial Evaluating Rosuvastatin) was halted in March 2008

  • due to firm evidence that the drug is indeed more beneficial than placebo and
  • improves the prognosis of individuals with high CRP levels.
A related biomarker of cardiovascular risk called neopterin. Just as CRP is produced by inflamed atherosclerotic plaques at risk of rupture,
neopterin is produced by activated macrophages in this inflammatory process. Circulating neopterin levels are higher in patients with ACS and may be
a marker of coronary disease activity. In addition, “Neopterin could also potentially be a marker of drug efficacy because
if you reduce the number of active macrophages in the plaque or the circulation, the levels of neopterin also decrease,” says Dr Juan Carlos Kaski,
Professor of Cardiovascular Science and Director of the Cardiovascular Biology Research Centre at St George’s University of London.

Other uses of biomarkers

These types of biomarkers can be used to drive critical ‘go/no go’ decision in drug development
Mechanistic or ‘target’ biomarkers can be used in pre-clinical or phase I trials to measure the pharmacological effect of the drug, i.e.
  • whether the drug interacts with its receptor, enzyme, or protein target,
  • whether it is distributed to the site where it needs to act,whether there is some
    • form of downstream pharmacology, and
  • the dose ranges in which the drug is pharmacologically active.
Drugs such as 5-HT4 receptor agonists (e.g. cisapride, mosapride), used in gastro-esophageal reflux disease (GERD), stimulate
  • the secretion of aldosterone as a side-effect.
Although aldosterone is not linked to GERD (and can’t be used as a biomarker of the disease), the hormone can be used
  • as a mechanistic biomarker in drug development to assess whether
    • novel 5-HT4 agonists in development have a pharmacological effect.

Discovering new biomarkers

The fundamental issue we have to deal with, both with target selection and developing better biomarkers,
  • is a better understanding of pathophysiology.
The clinical need is huge, not least in diseases like chronic obstructive pulmonary disease (COPD), an illness about which we know very little.

“COPD has very few markers to indicate severity and disease progression,” says Dr Trevor Hansel, Medical Director of the National Heart &
Lung Institute Clinical Studies Unit in London. Many pharmaceutical companies have begun to invest in ‘omics’ —

  • genomics,
  • proteomics,
  • metabonomics —

to begin to sort through this mountain of molecules and characterize biomarkers based on a molecular understanding of disease.

The ‘omics’ approach enables
  • the detection of small changes in tissue composition through protein profiling technologies such as
  • mass spectrometry and gel electrophoresis.

Essentially, it is about capturing a molecular profile from a clinical sample and converting this into

  • information about a clinical condition — for example the stage of disease or
  • what players are involved in the disease pathways.
“We will be able to look at diseases and catagorize them based on
  • biochemical or physiological findings, rather than just on symptoms” …  David Roblin, Pfizer

Companion Diagnostics and the Drug–Diagnostic Codevelopment Model

 Jan Trøst Jørgensen   Drug Development Research Nov 2012; 73(7):390-397.   http://dx.doi.org/10.1002/ddr.21029

The concept of using a predictive or selective diagnostic assay in relation to drug development goes back to the 1970s when

  • the selective estrogen receptor modulator, tamoxifen (AstraZeneca) was developed for metastatic breast cancer.
Clinical data showed that the estrogen receptor status correlated well with the clinical outcome when the patients were treated with tamoxifen.
It is only within the last decade that this model has gained widespread acceptance. The drug and the diagnostic are interdependent, and
if the development project proves successful, the companion diagnostic assay (CoDx) will end up determining the conditions for the use of the drug.
This gatekeeper role obviously requires that the CoDx assays adhere to the same strict rules and regulations that are known from the development of drugs.
For any CoDx assay, it must be documented that it is robust and reliable and that it possesses clinical utility. The article focus on some of the most important
aspects of the CoDx development process with emphasis on the clinical validation and clinical utility but also other critical issues, such as,
  • the biomarker selection process,
  • determination of the cut-off value, and
  • the analytical validation.

 Detecting Potential Toxicity in Mitochondria

 Brad Larson, Principal Scientist; Peter Banks, Scientific Director; BioTek Instruments, Winooski, Vt.
Mitochondrial dysfunction may be
  • inherited,
  • arise spontaneously, or
  • develop as a result of drug toxicity.
Mitochondrial toxicity as a result of pharmaceutical use may damage key organs, such as the liver and heart. For example,
  • nefazodone—a depression treatment—was withdrawn from the U.S. market after it was shown to
significantly inhibit mitochondrial respiration in liver cells, leading to liver failure. Troglitazone, an anti-diabetic and anti-inflammatory,
was withdrawn from all markets after research concluded that it caused acute mitochondrial membrane depolarization, also leading to liver failure.
Drug recalls are costly to a manufacturer’s bottom line and reputation, and more importantly, can be harmful or even fatal to users. As drug
discovery continues to evolve, much lead compound research now includes careful review of its interaction and potential toxicity with mitochondria.
Cytotoxicity and ATP production are measured in cancerous and normal hepatocytes using a known inducer of cellular necrosis. (All figures: BioTek Instruments)
Cell-based mitochondrial assays in microplate format may include
  • mitochondrial membrane potential,
  • total energy metabolism,
  • oxygen consumption, and
  • metabolic activity;
and offer a truer environment for mitochondrial function in the presence of drug compounds compared to isolated mitochondria-based tests.
Combining more than one assay in a multiplex format increases the amount of data per well while decreasing data variability arising from running the assays separately.
The aggregated data also provides a more encompassing analysis of the drug’s effect on mitochondria than a single test.
Human cardiac muscle

Human cardiac muscle (Photo credit: Carolina Biological Supply Company)

English: Non-sustained run of ventricular tach...

English: Non-sustained run of ventricular tachycardia on telemonitoring from a patient with chemotherapy-induced cardiomyopathy. (Photo credit: Wikipedia)

English: Doxorubicin 3D model Русский: Трёхмер...

English: Doxorubicin 3D model Русский: Трёхмерная модель молекулы доксорубицина (Photo credit: Wikipedia)

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Accurate Identification and Treatment of Emergent Cardiac Events


Accurate Identification and Treatment of Emergent Cardiac Events

Author: Larry H Bernstein, MD, FCAP
In the immediately preceding article, I discussed the difficulties in predicting long-term safety for developing drugs, and the cost of failure in early identification.

It is not the same scale of issue as for the patient emergently presenting to the ED. Despite enormous efforts to reduce the development of and the complications of acute ischemia related cardiac events, the accurate diagnosis of the patient presenting to the emergency room is still, as always, reliant on clinical history, physical examination, effective use of the laboratory, and increasingly helpful imaging technology. The main issue that we have a consensus agreement that PLAQUE RUPTURE is not the only basis for a cardiac ischemic event. The introduction of  high sensitivity troponin tests has made it no less difficult after throwing out the receiver-operator characteristic curve (ROC) and assuming that any amount of cardiac troponin released from the heart is pathognomonic of an acute ischemic event.  This has resulted in a consensus agreement that

  • ctn measurement at a coefficient of variant (CV) measurement in excess of 2 Std dev of the upper limit of normal is a “red flag”
  • signaling AMI? or other cardiomyopathic disorder

This is the catch.  The ROC curve established AMI in ctn(s) that were accurate for NSTEMI – (and probably not needed with STEMI or new Q-wave, not previously seen) –

  1. ST-depression
  2. T-wave inversion
    • in the presence of other findings
    • suspicious for AMI

Wouldn’t it be nice if it was like seeing a robin on your lawn after a harsh winter?  Life isn’t like that.  When acute illness hits the patient may well present with ambiguous findings.   We are accustomed to relying on

  1. clinical history
  2. family history
  3. co-morbidities, eg., diabetes, obesity, limited activity?, diet?
    1. stroke and/or peripheral vascular disease
    2. hypertension and/or renal vascular disease
    3. aortic atherosclerosis or valvular heart disease
      • these are evidence, and they make up syndromic classes
  4. Electrocardiogram – 12 lead EKG (as above)
  5. Laboratory tests
    1. isoenzyme MB of creatine kinase (CK)… which declines after 12-18 hours
    2. isoenzyme-1 of LD if the time of appearance is > day-1 after initial symptoms (no longer used)
    3. cardiac troponin cTnI or cTnT
      • genome testing
      • advanced analysis of EKG

This may result in more consults for cardiologists, but it lays the ground for better evaluation of the patient, in the long run.  When you look at the amount of information that has to be presented to the physician, there is serious need for improvement in the electronic medical record to benefit the patient and the caregivers.  Recently, we have a publication on a new test that has been evaluated, closely related to the C-reactive protein (CRP), a test that has generated much discussion over the effect of treatment for patients who have elevated CRP in the absence of increased LDL cholesterol, diabetes, or obvious atherosclerotic comorbidities.  The serum pentraxin 3 test is related to cell mediated immunity, and an evaluation has been published in the Journal of Investigative Medicine.

Journal of Investigative Medicine Feb 2013; 61 (2): 278–285.
http://dx.doi.org/10.231/JIM.0b013e31827c2971

Serum Pentraxin 3 Levels Are Associated With the Complexity and Severity of Coronary Artery Disease in Patients With Stable Angina Pectoris
Karakas, Mehmet Fatih MD*; Buyukkaya, Eyup MD*; Kurt, Mustafa MD*; et al.
From the Departments of Cardiology and,Clinical Biochemistry, Mustafa Kemal University, Tayfur Ata Sokmen Medical School, Hatay, Turkey.
Reprints: Mehmet Fatih Karakas, MD, Antakya 31005, Turkey. E-mail: mfkarakas@hotmail.com.

Abstract
Background: Atherosclerosis is a complex inflammatory process. Although pentraxin 3 (PTX-3), a newly identified inflammatory marker, was associated with adverse outcomes in stable angina pectoris,

  • an association between PTX-3 and the complexity of coronary artery disease (CAD) has not been reported.

The aim of the present study is to assess

  • the association between the level of PTX-3 and
  • the complexity and severity of CAD assessed with
  • SYNTAX and Gensini scores in patients with stable angina pectoris.

Methods: The study population is 2 groups:

  • 161 patients with anginal symptoms and evidence of ischemia
    • who underwent coronary angiography and
  • 50 age- and sex- matched control subjects without evidence of ischemia .

Patients were grouped into 3 groups according to the complexity and severity of coronary lesions

  • assessed by the SYNTAX score (30 patients with a SYNTAX score of 0 were excluded).

Serum PTX-3 and high-sensitivity C-reactive protein (hs-CRP) levels were measured in both groups.

Results: The PTX-3 levels demonstrated

  • an increase from low to high SYNTAX groups (r = 0.72, P < 0.001).

Whereas the low SYNTAX group had statistically significantly higher PTX-3 levels when compared with the control group (0.50 ± 0.01 vs 0.24 ± 0.01 ng/mL, P < 0.001),

  • the hs-CRP levels were not different (0.81 ± 0.42 vs 0.86 ± 0.53 mg/dL, P = 0.96).
  • but  the intermediate SYNTAX group had higher hs-CRP levels compared with the low SYNTAX group (1.3 ± 0.66 vs 0.86 ± 0.53 mg/dL, P = 0.002).

Serum PTX-3 levels and hs-CRP levels were both correlated with the SYNTAX scores and Gensini scores (for SYNTAX: r = 0.87 [P < 0.001] and r = 0.36 [P = 0.01]; for Gensini: r = 0.75 [P < 0.001] and r = 0.27 [P = 0.002], respectively), and

  • according to the results of univariate and multivariate analyses, for “intermediate and high” SYNTAX scores, age, diabetes mellitus, low-density lipoprotein cholesterol, hs-CRP, and PTX-3
  • were found to be independent predictors, whereas
  • for the presence of “high” SYNTAX score only PTX-3 was found to be an independent predictor.
  • The receiver operating characteristic curve analysis further revealed that the PTX-3 level was
    • a strong indicator of high SYNTAX score with an area under the curve of 0.91 (95% confidence interval, 0.86–0.96).

Conclusions: Pentraxin 3, a novel inflammatory marker, was more tightly associated with the complexity and severity of CAD than hs-CRP and

    • it was found to be an independent predictor for high SYNTAX score.

The association between atherosclerosis and inflammation has been more understood during recent years. Currently, atherosclerosis is considered as a complex inflammatory process in which

    • leukocytes and inflammatory markers are involved.1

Several inflammatory markers

  1.  high-sensitivity C-reactive protein (hs-CRP),
  2. fibrinogen, and
  3. complement C3…. are associated with cardiovascular events.1–5

Pentraxin 3 (PTX-3), that resembles CRP both in structure and function,1 is produced both by

  • hematopoietic cells such as macrophages, dendritic cells, neutrophils, and by
  • nonhematopoietic cells such as fibroblasts and vascular endothelial cells.2

Plasma PTX-3 levels may be elevated in patients with

  1. vasculitis,6
  2. acute myocardial infarction,7,8 and
  3. systemic inflammation or sepsis,9
  4. psoriasis,
  5. unstable angina pectoris, and
  6. heart failure.10–13

Dubin et al14 reported that PTX-3 levels are associated with with adverse outcomes in stable angina pectoris (SAP). Despite reports about the association of PTX-3 and coronary artery disease (CAD),

an association between the level of PTX-3 and the complexity and severity of CAD is not established.15,16 Thus, the aim of this study was

  • to assess the association between the level of PTX-3 and the complexity and severity of CAD assessed with SYNTAX and Gensini scores in SAP patients.

MATERIALS AND METHODS

Of 211 patients were prospectively recruited,  161 SAP patients with evidence of ischemia (positive treadmill or myocardial perfusion scan) underwent coronary angiography for suspected CAD, and 50 age- and sex- matched outpatient subjects with a negative treadmill or myocardial perfusion scan test were taken as the control group. Patients were excluded if they had

  •  acute coronary syndrome
  • history of previous myocardial infarction;
  • coronary artery bypass grafting or percutaneous coronary intervention;
  • secondary hypertension (HT);
  • renal failure;
  • hepatic failure;
  • chronic obstructive lung disease and/or
  • manifest heart disease, such as
    • cardiac failure (left ventricular ejection fraction <50%),
    • atrial fibrillation, and
    • moderate to severe cardiac valve disease; and
    • SYNTAX score of zero

Similarly, patients were excluded with

  • infection,
  • acute stress, or chronic systemic inflammatory disease and
  • those who had been receiving medications affecting the number of leukocytes .

Thirty patients were excluded from the study because the coronary angiograms revealed normal coronary arteries (SYNTAX score of 0). All the participants included in the study were informed about the study, and they voluntarily consented to participate. The Serum PTX-3 level was measured on blood samples collected after 12-hour fast just prior to coronary angiography and kept at −80°C until the assays were performed. PTX3 was measured by enzyme immunoassay (EIA) using quantitative kit (human PTX-3/TSG-14 immunoassay, DPTX30; R&D Systems, Inc, Minneapolis, MN). The intra-assay and interassay coefficients of variation ranged from 3.8% to 4.4% and 4.1% to 6.1%, respectively (minimum detectable concentration, 0.025 ng/mL). High-sensitivity CRP was measured in serum by EIA (Immage hs-CRP EIA Kit; Beckman Coulter Inc, Brea, CA). Transthoracic echocardiography was performed, and biplane Simpson’s ejection fraction (%) was calculated before coronary angiography. Hypertension was defined as having at least 2 blood pressure measurements greater than 140/90 mm Hg or using antihypertensive drugs, whereas diabetes mellitus (DM) was defined as having at least 2 fasting blood sugar measurements greater than 126 mg/dL or using antidiabetic drugs. Smoking was categorized into current smokers and nonsmokers. Nonsmokers included ex-smokers who had quit smoking for at least 6 months before the study. Body mass index (BMI) values were calculated based on the height and weight of each patient. Medications used before the coronary angiography were noted. The study was approved by the local ethics committee.
SYNTAX and Gensini Scores
To grade the complexity of CAD, the SYNTAX score was used. Each coronary lesion with a stenosis diameter of 50% or greater in vessels of 1.5 mm or greater was scored. Parameters used in the SYNTAX scoring are shown in Table 1. The latest online updated version (2.11) was used in the calculation of the SYNTAX scores (www.syntaxscore.com).17 The SYNTAX score was classified as follows:

  1. low SYNTAX score (≤22),
  2. intermediate SYNTAX score (23–32)
  3. high SYNTAX score (≥33).

Table 1   http://images.journals.lww.com/jinvestigativemed/LargeThumb.00042871-201302000-00007.TT1.jpeg

The severity of CAD was determined by the Gensini score, which

  • measures the extent of coronary stenosis according to degree and location.18

In the Gensini scoring system,

  • larger segments are more heavily weighted ranging from 0.5 to 5.0
    • left main coronary artery × 5;
    • proximal segment of the left anterior descending coronary artery [LAD] × 2.5;
    • proximal segment of the circumflex artery × 2.5;
    • midsegment of the LAD × 1.5;
    • right coronary artery distal segment of the LAD,
    • posterolateral artery, and obtuse marginal artery × 1;
    • and others × 0.5.

The narrowing of the coronary artery lumen is rated

  1. 2 for 0% to 25% stenosis,
  2. 4 for 26% to 50%,
  3. 8 for 51% to 75%,
  4. 16 for 76% to 90%,
  5. 32 for 91% to 99%,
  6. 64 for 100%.

The Gensini index is the sum of the total weights for each segment. All angiographic variables of the SYNTAX and Gensini score were computed by

  • 2 experienced cardiologists who were blinded to the procedural data and clinical outcomes.

The final decision was reached by consensus when a conflict occurred.The number of diseased vessels with

  • greater than 50% luminal stenosis was scored from 1 to 3 (namely, 1-, 2-, or 3-vessel disease), and
  • a lesion greater than 50% in the left main coronary artery was regarded as a 2-vessel disease.

Statistical Analyses

Statistical analyses were conducted with SPSS 17 (SPSS Inc, Chicago, IL) software package program.
Continuous variables were expressed as mean ± SD or median ± interquartile range values, whereas categorical variables were presented as percentages.
The differences between normally distributed numeric variables were evaluated by Student t test or 1-way analysis of variance, whereas

  • non–normally distributed variables were analyzed by Mann-Whitney U test or Kruskal-Wallis variance analysis as appropriate.

χ2 Test was used for the comparison of categorical variables. Pearson test was used for correlation analysis.
To determine the independent predictors of “intermediate and high” SYNTAX scores and only “high” SYNTAX scores,

  • 2 different sets of univariate and multivariate analyses were performed
    • (in the first model SYNTAX cutoff was 22, whereas
    • in the second model SYNTAX cutoff was 33).

The standardized parameters that were found to have a significance (P < 0.10) in the univariate analysis were evaluated by stepwise logistic regression analysis.
Ninety-five percent confidence interval (CI) and odds ratio (OR) per SD increase were presented together. Interobserver and intraobserver variability for SYNTAX scores

  • was done by Bland-Altman analysis.

An exploratory evaluation of additional cut points was performed using the receiver operating characteristic (ROC) curve analysis.
All the P values were 2-sided, and a P < 0.05 was considered as statistically significant.
RESULTS
Baseline Characteristics
In total, 181 patients (50.2 ± 6.5 years, 52.5% were composed of males) were included in the study. Baseline clinical, angiographic, and laboratory characteristics of the patients
relative to SYNTAX score groups are shown in Table 2. Age, sex, HT, DM, BMI, and medication were not different between the groups. Baseline clinical and laboratory characteristics
of patients according to PTX-3 quartiles are shown in Table 3. The Bland-Altman analysis revealed that the degrees of intraobserver and interobserver variability for SYNTAX score
and Gensini score readings were 5% and 6% for SYNTAX and 8% and 9% for Gensini,
respectively.
Table 2   http://images.journals.lww.com/jinvestigativemed/Original.00042871-201302000-00007.TT2.jpeg
Table 3   http://images.journals.lww.com/jinvestigativemed/Original.00042871-201302000-00007.TT3.jpeg

The PTX-3 levels demonstrated an increase from the low SYNTAX group to the high SYNTAX group (r = 0.87, P < 0.001).
The low SYNTAX group had statistically significantly higher PTX-3 levels when compared with the control group (0.50 ± 0.01 vs 0.24 ± 0.01 ng/mL, P < 0.001); similarly,
the PTX-3 levels were higher in the high SYNTAX group than in both

  • the intermediate SYNTAX group (0.84 ± 0.08 vs 0.55 ± 0.01 ng/mL, P < 0.001) and
  • the low SYNTAX group (0.84 ± 0.08 vs 0.50 ± 0.01 ng/mL, P < 0.001).
  • there was no difference in levels of PTX-3 between the low and the intermediate SYNTAX group (0.50 ± 0.01 vs 0.55 ± 0.01 ng/mL, P = 0.09).

On the other hand, there was no difference in levels of hs-CRP between the control and the low SYNTAX group (0.81 ± 0.42 vs 0.86 ± 0.53 mg/dL, P = 0.96).
The intermediate SYNTAX group had statistically significantly higher hs-CRP levels

  • compared with the low SYNTAX group (1.3 ± 0.66 vs 0.86 ± 0.53 mg/dL, P = 0.002);
  • the hs-CRP levels were not different between the high SYNTAX group
    • and the intermediate SYNTAX group. (1.3 ± 0.66 vs 1.3 ± 0.43 mg/dL, P = 0.99).

Univariate correlation analysis revealed a positive correlation between serum PTX-3 levels and hs-CRP levels with

  • the SYNTAX and Gensini scores
    • for SYNTAX: r = 0.87 [P < 0.001] and r = 0.36 [P = 0.01];
    • for Gensini: r = 0.75 [P < 0.001] and r = 0.27 [P = 0.002],  (Fig. 1).

In addition to that, the Gensini and SYNTAX scores are found to be well correlated with each other (r = 0.80, P < 0.001).
When the SYNTAX score was taken as continuous variable, multivariate linear regression analysis revealed that

  • the SYNTAX score was correlated with PTX-3 and hs-CRP (for PTX-3: β = 0.84 [P < 0.001]; hs-CRP: β =0.08 [P = 0.032]).

Figure 1   http://images.journals.lww.com/jinvestigativemed/Original.00042871-201302000-00007.FF1.jpeg

For determining the predictors of intermediate and high SYNTAX scores and only-high SYNTAX scores,

  • 2 different sets of univariate and multivariate analyses were performed among the patients who underwent coronary angiography.

For predicting the intermediate and high SYNTAX scores, the SYNTAX score was dichotomized into

  • high (score ≥22) and
  • low (<22) groups,

whereas for predicting the only-high SYNTAX scores, the SYNTAX score was dichotomized into

  • 2 groups with a score of 33 or greater and a score of less than 33.

In the first multivariate analysis (where SYNTAX cutoff was 22), the parameters showing significance in the univariate analysis

  • age,
  • sex,
  • HT,
  • DM,
  • low-density lipoprotein cholesterol [LDL-C],
  • hs-CRP,
  • PTX-3

were evaluated by multivariate analysis to determine the

  • independent predictors of intermediate and high SYNTAX scores.

In the univariate analysis, higher values of

  • age (OR, 1.5 [95% CI, 1.1–2.0]; P = 0.01),
  • LDL-C (OR, 1.3 [95% CI, 0.98–1.8]; P = 0.068),
  • hs-CRP (OR, 2.6 [95% CI, 1.8–3.8]; P < 0.001), and
  • PTX-3 (OR, 13.6 [95% CI, 6.4–28.9]; P < 0.001)
    • were associated with higher SYNTAX scores,
  • HT (OR, 0.44 [95% CI, 0.24–0.80]; P = 0.008) and
  • DM (OR, 0.48 [95% CI, 0.25–0.91]; P = 0.02)
    • were associated with lower SYNTAX scores.

In the multivariate analysis – age, DM, LDL-C, hs-CRP, and PTX-3 – were found to be

  • independent predictors of “intermediate to high” SYNTAX score (Table 4).

Increased

  • age (OR, 2.5 [95% CI, 1.3–4.8]; P = 0.007),
  • LDL-C (OR, 2.8 [95% CI, 1.5–5.2]; P = 0.001),
  • hs-CRP (OR, 3.3 [95% CI, 1.8–6.1]; P < 0.001), and
  • PTX-3 (OR, 35.4 [95% CI, 10.1–123.6]; P < 0.001)
    • were associated with increased SYNTAX scores,

whereas DM (OR, 0.08 [95% CI, 0.02–0.33]; P < 0.001) was associated with lower SYNTAX score (Table 4).

In the second univariate and multivariate analyses (where SYNTAX cutoff was 33),

  • the parameters that showed significance in the univariate analysis were age, LDL-C, glucose, hs-CRP, and PTX-3.
  • In the univariate analysis, increased
    • age (OR, 1.5 [95% CI, 1.0–2.3]; P = 0.05),
    • LDL-C (OR, 1.5 [95% CI, 0.97–2.2]; P = 0.07),
    • hs-CRP (OR, 1.4 [95% CI, 0.97–2.1]; P = 0.072), and
    • PTX-3 (OR, 18.5 [95% CI, 6.6–51.8]; P < 0.001)
      • were found to be associated with increased SYNTAX scores.

When these parameters were evaluated with multivariate analysis, only PTX-3 (OR, 18.4 [95% CI, 6.2–54.2]; P < 0.001)

    • was found to be an independent predictor for high SYNTAX score (Table 4).

Table 4   http://images.journals.lww.com/jinvestigativemed/Original.00042871-201302000-00007.TT4.jpeg

The ROC curve analysis further revealed that the PTX-3 level was a strong indicator of high SYNTAX score with

  • an area under the curve (AUC) of 0.91 (95% CI, 0.86–0.96) (Fig. 2).

The optimal cutoff of PTX-3 for the high SYNTAX score was 0.75 ng/mL.
Sensitivity, specificity, positive predictive value, and negative predictive value to identify high SYNTAX score for the PTX-3 level

  • were 90%, 84%, 97%, and 60%, respectively.
  • the ROC curve analysis of PTX-3 for intermediate-high SYNTAX score revealed that the AUC value was 0.82 (95% CI, 0.75–0.89).

The optimal threshold of PTX-3 level that

  • maximized the combined specificity and sensitivity to predict
    • intermediate to high SYNTAX score was 0.73 ng/mL.

For the cutoff value of 0.73 ng/mL, sensitivity, specificity, positive predictive value, and negative predictive value

  • to identify intermediate-high SYNTAX score were 56%, 98%, 97%, and 56%, respectively.

Figure 2   http://images.journals.lww.com/jinvestigativemed/Original.00042871-201302000-00007.FF2.jpeg

In the ROC analysis of hs-CRP for high SYNTAX scores, the AUC value was found to be 0.68 (95% CI, 0.59–0.77; P < 0.001).
The optimal threshold of hs-CRP that maximized the combined specificity and sensitivity to predict for high SYNTAX scores was 0.89 mg/dL.
Similarly, the ROC analysis of hs-CRP for the intermediate-high SYNTAX scores revealed an AUC of 0.74 (95% CI, 0.65–0.83; P = 0.001).
The cutoff value of hs-CRP to predict the intermediate-high SYNTAX scores with a maximized sensitivity and specificity was 0.66 mg/dL.
DISCUSSION
In this particular study, we investigated the relationship between the serum PTX-3 level and the severity of CAD

  • assessed by SYNTAX and Gensini scores in patients with SAP.

The PTX-3, was significantly higher than control group in the patients with CAD, and the serum PTX-3 levels

  • were associated with the SYNTAX and Gensini scores.

When compared with the hs-CRP, the PTX-3 was found to be more tightly associated with the complexity and severity of CAD in the patients with SAP.
Pentraxin 3, an acute-phase reactant that is functionally and structurally similar to CRP,1 is produced both by different kinds of cells such as

  • macrophages, dendritic cells, neutrophils, fibroblasts, and vascular endothelial cells.2
  • Pentraxin 3 is released following the inflammatory stimuli19; therefore, it may reflect the local inflammatory status in tissues.20

Serum PTX-3 levels were shown to be elevated in patients with

  • vasculitis,6 acute myocardial infarction,7,8 and systemic inflammation or sepsis,9 psoriasis, unstable angina pectoris, and heart failure.10–13

Higher PTX3 levels were reported to be associated with worse cardiovascular outcomes

  1. after acute coronary syndromes,8,21
  2. in the elderly people without known cardiovascular disease22 and
  3. associated with overall mortality in patients with stable coronary disease,
  4. independent of systemic inflammation.14

There are 2 reports investigating the association of PTX-3 level and the atherosclerotic burden.15,16 In one of these reports,

  • Knoflach et al.15 took B-mode ultrasonography as the atherosclerosis index.

They did not provide any information about coronary anatomy, and in the other report, Soeki et al.16 evaluated 40 patients who

  • underwent coronary angiography and measured their Gensini scores.

However, in none of the studies were the SYNTAX score and Gensini score used together to assess the degree of coronary atherosclerotic burden.
To our knowledge, this is the first report that showed the association of PTX-3 levels with the complexity and severity of CAD assessed by

  • SYNTAX and Gensini scores in patients with stable coronary disease.

Chronic low-grade inflammation has been thought to play a major role in the pathogenesis of atherosclerosis.23,24 Previous studies have reported that

  • levels of inflammatory markers such as hs-CRP, interleukin 6, and so on were increased in atherosclerosis.25

In the present study, both the SYNTAX and the Gensini scores were found to be correlated with serum PTX-3 and hs-CRP levels,

  • which in turn might reflect the degree of inflammation.

The SYNTAX score is an important tool in the classification of complex CAD26 and can give predictive information about short- and long-term outcomes

  • in patients with stable CAD who undergo percutaneous coronary intervention.27–30

Although the SYNTAX score is currently used for assessing the angiographic complexity of CAD rather than the severity of coronary atherosclerotic burden,

  • because more complex lesions tend to have more atherosclerotic burden,
  • the SYNTAX scores may also reflect the severity of coronary atherosclerotic burden.

The Gensini score, a well-known and widely used scoring system to evaluate the severity of CAD,18 was measured and

  • found to be well correlated with the SYNTAX score,
    • which supports the idea that angiographically more complex lesions tend to have more atherosclerotic burden.

When compared with the hs-CRP,

  • the PTX-3 seems to be more tightly associated with coronary disease burden (r = 0.36 vs r = 0.87).

We found out that the serum PTX-3 levels were higher than those in the control group, even in the low SYNTAX group.
On the other side, the serum hs-CRP levels were not different in the control and the low SYNTAX groups.
It was reported that the leukocytes mainly found in the coronary artery lumen are the neutrophils.31
It is also known that PTX-3 is stored in specific granules of neutrophils and released in response to inflammatory signals.32
The reason why serum PTX-3 levels seem more tightly associated with the coronary disease burden

  • when compared with serum hs-CRP levels may be the association of the
  • on-site presence of neutrophils and local inflammatory signal–triggered release of  PTX-3.

On the other hand, some human studies revealed that PTX-3 was produced more in areas of atherosclerosis and may contribute to its pathogenesis.31
Some other studies suggested that PTX-3 may be part of a protective mechanism in

  • vascular repair via inhibiting fibroblast growth factor 2 or some other growth factors responsible for smooth muscle proliferation.33,34

But still, the exact role of PTX-3 in the pathophysiology of atherosclerosis seems to be obscure for the time being. It is well established that atherosclerosis
has an inflammatory background in most of the cases. In addition to that, high blood CRP level is known as an indicator of future cardiovascular disease risk
even in healthy individuals.35 According to the results of univariate and multivariate analyses, for intermediate and high SYNTAX scores,

  1. age, DM, LDL-C, hs-CRP, and PTX-3 were found to be independent predictors, whereas for the presence of
  2. high SYNTAX score, only PTX-3 was found to be an independent predictor.

Because of the tighter association with atherosclerotic burden and the on-site vascular presence,

    • PTX-3 may be a promising candidate marker for vascular inflammation and future cardiovascular events.

LIMITATIONS
The major limitation of the current study is the number of patients included. It would be better to include more patients to increase the statistical power.

Besides, the SYNTAX and Gensini scores give us an idea about the complexity and severity of coronary atherosclerosis; however,
with coronary angiography alone, it is not possible to understand the extent of coronary plaque. In addition to that, the coronary anatomy of the
control group was not known, which was another limitation. Our selected population was free of other confounders of systemic inflammation, and
we did not have data about inflammatory markers other than hs-CRP, such as interleukin 6, tumor necrosis factor α, and so on, which may be accepted
as a limitation. Another limitation of the current study is that because there was no long-term follow-up of the patients, it did not provide any prognostic
data in terms of future cardiovascular events.
CONCLUSIONS
Pentraxin 3, a novel inflammatory marker, is associated with the complexity and severity of the CAD assessed by the SYNTAX and the Gensini scores in patients with SAP and seems to be more tightly associated with coronary atherosclerotic burden than hs-CRP.

REFERENCES

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9. Muller B, Peri G, Doni A, et al.. Circulating levels of the long pentraxin PTX3 correlate with severity of infection in critically ill patients. Crit Care Med. 2001; 29: 1404–1407.
10. Bevelacqua V, Libra M, Mazzarino MC, et al.. Long pentraxin 3: a marker of inflammation in untreated psoriatic patients. Int J Mol Med. 2006; 18: 415–423.
11. Inoue K, Sugiyama A, Reid PC, et al.. Establishment of a high sensitivity plasma assay for human pentraxin3 as a marker for unstable angina pectoris. Arterioscler Thromb Vasc Biol. 2007; 27: 161–167.
12. Suzuki S, Takeishi Y, Niizeki T, et al.. Pentraxin 3, a new marker for vascular inflammation, predicts adverse clinical outcomes in patients with heart failure. Am Heart J. 2008; 155: 75–81.
13. Matsubara J, Sugiyama S, Nozaki T, et al.. Pentraxin 3 is a new inflammatory marker correlated with left ventricular diastolic dysfunction and heart failure with normal ejection fraction. J Am Coll Cardiol. 2011; 57: 861–869.
14. Dubin R, Li Y, Ix JH, et al.. Associations of pentraxin-3 with cardiovascular events, incident heart failure, and mortality among persons with coronary heart disease: data from the Heart and Soul Study. Am Heart J. 2012; 163: 274–279.
16. Soeki T, Niki T, Kusunose K, et al.. Elevated concentrations of pentraxin 3 are associated with coronary plaque vulnerability. J Cardiol. 2011; 58: 151–157.
17. SYNTAX working group. SYNTAX score calculator. Available at http://www.syntaxscore.com. Accessed May 20, 2012.
18. Gensini GG. A more meaningful scoring system for determining the severity of coronary heart disease. Am J Cardiol. 1983; 51: 606.
20. Mantovani A, Garlanda C, Bottazzi B, et al.. The long pentraxin PTX3 in vascular pathology. Vascul Pharmacol. 2006; 45: 326–330.
21. Matsui S, Ishii J, Kitagawa F, et al.. Pentraxin 3 in unstable angina and non-ST-segment elevation myocardial infarction. Atherosclerosis. 2010; 210: 220–225.
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Keywords:  pentraxin 3; coronary artery disease; SYNTAX score; hs-CRP; inflammation

This is not the only recent finding that adds to the ability to evaluate these patients.  An as yet unpublished paper, expected to be published soon reports on

QRS fragmentation as a Prognostic test in Acute Coronary Syndrome,  and this reviewer expects the work to have a high impact.  The authors state that
QRS complex fragmentation is a promising bed-side test for assessment of prognosis in those patients.  Presence of fragmented QRS in surface ECG during ACS

  • represents myocardial scar or fibrosis and reflect severity of coronary lesions and a correlation between fQRS and depression of Lv function is established.

There are still other indicators that need to be considered, such as the mean arterial blood pressure.

There has been review and revisions of the guidelines for treatment of UA/NSTEMI within the last year, with differences being resolved among the Europeans and US.

Guidelines Updated for Unstable Angina/Non-ST Elevation Myocardial Infarction
According to the current study by Jneid and colleagues, new evidence is available on the management of unstable angina. This report replaces the 2007 American College of Cardiology Foundation/American Heart Association (ACC/AHA) Guidelines for the Management of Patients With Unstable Angina/Non–ST-Elevation Myocardial Infarction (UA/NSTEMI) that were updated by the 2011 guidelines.

This guideline was reviewed by

  • 2 official reviewers each nominated by the ACCF and the AHA, as well as
  • 1 or 2 reviewers each from the American College of Emergency Physicians; the Society for Cardiovascular Angiography and Interventions; and the Society of Thoracic Surgeons; and
  • 29 individual content reviewers, including members of the ACCF Interventional Scientific Council.

The recommendations in this focused update are considered current

  • until they are superseded in another focused update or the full-text guideline is revised, and are official policy of both the ACCF and the AHA.

STUDY SYNOPSIS AND PERSPECTIVE
American cardiology societies have caught up with the European Society of Cardiology by

  • issuing their second update to the UA/NSTEMI guidelines in 18 months,
  • with the 2012 focused update replacing the 2011 guidelines [1].

The new recommendations include ticagrelor (Brilinta) as one of the options for antiplatelet therapy alongside prasugrel (Effient) and clopidogrel, bringing them in line with European.
The European guidance, however, gave precedence to the new antiplatelets over clopidogrel, whereas the American update “places ticagrelor on an equal footing with the other two antiplatelets available
this is the main reason for the update,” lead author Dr Hani Jneid (Baylor College of Medicine, Houston, TX), told heartwire . “Doctors now have a choice for second-line therapy after aspirin, depending on

  • the patient’s clinical scenario,
  • physician preference, and cost,”
    • now that clopidogrel is available generically.

The US decision to recommend

  • first prasugrel–in its 2011 update to the UA/NSTEMI guidelines–and
  • now ticagrelor as equivalent antiplatelet therapy choices to clopidogrel after aspirin
    • puts it somewhat at odds with the Europeans,
    • who reserve clopidogrel use for those who cannot take the newer agents.

The reason for the Americans differing stance is that because while they are faster acting and more potent–

  • the cost-effectiveness of the new agents is not known.
  • it isn’t clear how the efficacy observed in pivotal clinical trials of these agents is going to translate into real-world benefit,
  • and issues such as bleeding with prasugrel and compliance with a twice-daily drug such as ticagrelor remain concerns.

Bulk of 2012 Update on How to Use Ticagrelor
The 2012 ACCF/AHA focused update for the management of UA/NSTEMI stresses that

  • all patients at medium/high risk should receive dual antiplatelet therapy on admission,
  • with aspirin being first-line, indefinite therapy.

The bulk of the update centers on how to use ticagrelor which–

  • like prasugrel or clopidogrel–
  • can be added to aspirin for up to 12 months (or longer, at the discretion of the treating clinician).

Jneid notes it’s important to remember that prasugrel can only be used in the cath lab

  • in patients undergoing percutaneous coronary intervention (PCI),
  • whereas ticagrelor, like clopidogrel, can be used in medically managed or PCI patients.

And he emphasizes that, in line with the FDA’s black-box warning on ticagrelor,

The 81-mg aspirin dose is also considered a reasonable option in preference to a higher maintenance dose of 325 mg in

  • any acute coronary syndrome (ACS) patient following PCI, he adds, as
  • this strategy is believed to result in equal efficacy and lower bleeding risk.

With regard to how long antiplatelet therapy should be stopped before planned cardiac surgery, the recommendation is

  • five days for ticagrelor–the same as that advised for clopidogrel.
  • and seven days prior to surgery for prasugrel.

Jneid also highlights other important recommendations from the 2011 focused update carried over to 2012:

It is “reasonable” to proceed with cardiac catheterization and revascularization within

  • 12–24 hours of admission in initially stable, very high-risk patients with ACS.

An invasive strategy is “reasonable” in patients with

  • mild and moderate chronic kidney disease.

In those with diabetes hospitalized with ACS, insulin use should target glucose levels <180 mg/dL,

  • a less-intensive reduction than previously recommended.

Platelet function or genotype testing for clopidogrel resistance are both considered “reasonable”

  • if clinicians think the results will alter management,
  • but Jneid acknowledged that “there is not much evidence to support these assays” .

Committee Encourages Participation in Registries
Jneid observes that unstable angina and NSTEMI are “very common” conditions that carry a high risk of death and recurrent heart attacks,

  • which is why “the AHA and ACCF constantly update their guidelines so that physicians can provide patients with
  • the most appropriate, aggressive therapy with the goal of improving health and survival.”

To this end, he notes that the writing panel encourages

  • clinicians and hospitals to participate in quality-of-care registries designed
  • to track and measure outcomes, complications, and
  • adherence to evidence-based medicines.

Conflicts of interest for the writing committee are listed in the paper.

References

Jneid H, Anderson JL, Wright SR, et al. 2012 ACCF/AHA focused update on the guideline for the management of patients with unstable angina/non-ST elevation myocardial infarction (Updating the 2007 guideline and replacing the 2011 focused update): A report of the ACCF/AHA.
Circulation 2012;      Available at: http://circ.ahajournals.org/  http://dx.doi.org/10.1161/CIR0b013e3182566fleo
source   http://www.medscape.org

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