Congestive Heart Failure

     Congestive heart failure is a condition in which the heart can no longer pump blood efficiently throughout the body. Due to the inability of the heart to adequately pump blood, blood backs-up into the venous system (the veins of the body where blood is returning from the body to the heart). The blood which backs-up causes "congestion" in these organs.

    This congestion is manifest by peripheral edema (limb swelling, usually in the legs), pulmonary edema (fluid in the lungs, causes coughing, difficulty breathing, shortness of breath), congestive hepatomegaly (liver damage due to backed-up blood in the liver), and jugular venous distention (swelling of the neck veins due to excess blood).

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Immune Surveillance: A Balance Between Pro- and Anti-tumor Immunity

Immune Surveillance: A Balance Between Pro- and Anti-tumor
Immunity

Suzanne Ostrand-Rosenberg
University of Maryland, Department of Biological Sciences, 1000 Hilltop Circle, Baltimore, MD
21250, 410 455-2237 (voice), 410 455-3875 (FAX), < srosenbe@umbc.edu>

Summary
Pre-cancerous and malignant cells can induce an immune response which results in destruction of
transformed and/or malignant cells, a process known as immune surveillance. However, immune
surveillance is not always successful, resulting in “edited” tumors that have escaped immune surveillance. Immunoediting is not simply the absence of anti-tumor immunity, but is due to protumor immunity that blocks anti-tumor adaptive and innate responses, and promotes conditions that favor tumor progression. Several immune pro-tumor effector mechanisms are up-regulated by chronic inflammation, leading to the hypothesis that inflammation promotes carcinogenesis and tumor growth by altering the balance between pro-and anti-tumor immunity, thereby preventing the immune system from rejecting malignant cells, and providing a tumor-friendly environment for progressive disease.

Introduction
The concept that the immune system can be harnessed as a therapeutic agent to treat established tumors (immunotherapy) was first proposed in the early 1900’s by Paul Ehrlich. He suggested that molecules that we now know as antibodies, could deliver toxins directly to cancer cells. Ehrlich’s “magic bullet” strategy was expanded upon in the 1950’s by Burnet and Thomas. They hypothesized that the immune system may also protect against nascent cancers by destroying malignant cells before they developed into detectable tumors, a concept that has become the immune surveillance hypothesis [1,2]. Although enthusiasm for the validity of immunotherapy and immune surveillance waned in the 1970’s, subsequent studies demonstrated that the immune system can protect against tumor onset and be manipulated to reject established tumors. Revival of the immune surveillance hypothesis led to a re-working of the initial concept, to include the concept of “immunoediting.” During immunoediting, the immune system destroys many pre-cancerous and malignant cells; however, some cells escape the immune response and give rise to progressively growing tumors. Immunoediting is thought to continue throughout the life of the tumor so that the phenotype of an established tumor has been directed by the host’s immune response. It has also become apparent that both innate and adaptive immunity have a “dark” side and can promote tumor progression as well as mediate tumor destruction. Not surprisingly, chronic inflammation, which has long been associated with increased tumor risk, is involved in polarizing immunity towards those effectors that facilitate tumor growth. As a result, the immune system has the potential to either promote or  delay tumor onset and progression, and the effectiveness of immune surveillance and the efficacy of immunotherapy depend on the balance between these diametric opposites (Figure 1). After a brief over-view of the observations supporting the concept of immune surveillance, this article will review the cells that mediate pro-and anti-tumor immunity including a discussion of how inflammation polarizes innate and adaptive immunity towards either a protumor or anti-tumor phenotype.

Immune surveillance and immunoediting
Rejuvenation of the concept that the immune system protects against nascent malignant cells
occurred with the demonstration that mice deficient for various components of the adaptive or innate immune systems were more likely to develop some types of tumors, specifically sarcomas as opposed to carcinomas, as compared to immune competent mice, when exposed to carcinogens or transplanted with syngeneic tumor cells. Immune deficiencies included the absence of B cells and αβ or γδ T cells due to deletion of the recombination-activating gene-2 (RAG2) required for immunoglobulin and T cell receptor gene rearrangements, and the absence of interferonγ (IFNγ) or the ability to respond to IFNγ, a key mediator of cellular immunity. Similarly, mice that were knocked-out for perforin, an essential molecule for cell-mediated cytotoxicity used by most effector cells of the innate and adaptive immune systems, or mice deficient for natural killer (NK) or NKT cells, effector cells of the innate immune system, were also more susceptible to spontaneous tumors or had more rapid growth rates of transplanted tumors as compared to wild type or immune competent mice [3,4]. Circumstantial evidence suggests that immune surveillance and immunoediting also occurs in cancer patients. Individuals with hereditary or acquired immunodeficiencies have higher incidences of some types of viral- and carcinogen-associated cancers. Organ transplant patients maintained on immune suppressive drugs are 3–8 fold more likely to develop cancer than
normal controls, although tumors are not randomly distributed in all anatomical locations [1, 2]. In contrast, ovarian, colorectal [5], and melanoma patients whose tumors have high levels of tumor-infiltrating lymphocytes have a better prognosis [1,2]. Collectively, experimental
studies and the clinical observations in patients indicate that the immune system can foil carcinogenesis and mediate regression of established tumor.

CD4+ and CD8+ T lymphocytes               CD4+ and CD8+ T cells are the principal helper and effector cells, respectively, of adaptive cellular immunity, and many immunotherapy strategies are aimed at activating these cells to promote tumor cell destruction and long-term immune memory against recurrence of primary disease or outgrowth of metastases. Type 1 CD4+ T cells (Th1) facilitate tissue destruction and tumor rejection by providing help to cytotoxic CD8+ T cells, while Type 2 CD4+ T cells T (Th2) facilitate antibody production by B cells and polarize immunity away from a beneficial cell-mediated anti-tumor response (Figure 2). CD4+ T regulatory cells (T regs), which are naturally occurring or antigen-induced, promote tumor immunity by blocking the activation of CD8+ cytotoxic T cells. Although additional studies are needed to fully characterize the mechanism(s) by which CD4+ T regs block CD8+ T cell activation, T reg expression of cytotoxic T lymphocyte antigen 4 (CTLA4), an inhibitory signal for T cells, may be involved [6]. As for many pro-tumor mediators, inflammation enhances T reg function since prostaglandin E2 (PGE2) causes differentiation of T regs and increases their immune suppressive activity [7,8]. In addition to their inhibiting CD8+ T cell activation, CD4+ T regs block killing by natural killer cells [9], and thereby down-regulate both adaptive and innate anti-tumor immunity. Although most T regs are CD4+, CD8+ T regs induced by plasmacytoid DC have been identified in ovarian cancer patients [10].  Recently identified CD4+ Th17 cells [11,12], may also promote tumor progression. Th17 cells are induced by IL-23, a cytokine closely related to IL-12 and whose receptor shares the IL-12Rβ1 with IL-12 [13]. Upon activation by IL-23, Th17 cells produce IL-17 which exacerbates inflammation by inducing IL-6, TNFα, G-CSF, and other acute phase proteins [14]. IL-23 itself, has been shown to reduce CD8+ T cell infiltration into tumors, thereby promoting tumor growth [13,15] (Figure 2). Earlier experiments using IL-17-transfected tumor cells were inconclusive as to whether IL-17 promoted tumor growth or tumor rejection [16, 17]. This ambiguity may be explained by a recent study showing that Th17-induced IL-6 blocks CD4+ T regs [18]. Additional experiments are clearly necessary to clarify the roles of IL-23, Th17 cells, IL-17, and regulatory T cells in tumor progression.

B lymphocytes
Tumor-reactive monoclonal antibodies can have significant anti-tumor efficacy when passively administered to cancer patients. In contrast, most cancer vaccines or other therapies that are aimed at inducing tumor-reactive antibodies are largely ineffective in promoting tumor rejection, although there are exceptions [19]. More recent experiments indicate that activated B cells and their soluble products, presumably antibodies, can also facilitate carcinogenesis. Using a transgenic mouse model in which the human keratin 14 promoter drives expression of early region genes of human papilomavirus 16, B cells were shown to promote a chronic inflammatory microenvironment that recruits innate immune cells and factors to the tumor site, thus establishing a stromal environment that supports de novo carcinogenesis. Thus, humoral immunity can enhance malignant transformation by activating the innate immune system [20,21].

Macrophages
Macrophages are part of the innate immune system and play important roles in all aspects of
immunity. They are an exceptionally heterogeneous population of cells. Similar to CD4+ T cells, macrophages can contribute to tumor destruction or facilitate tumor growth and
metastasis, depending on their phenotype (Figure 3).

Macrophages that are “classically activated” by IFNγ and bacterial lipopolysaccharides destroy tumor cells through their production of nitric oxide and type 1 cytokines and chemokines. These macrophages also function as antigen presenting cells to activate cytotoxic CD8+ T [22]. In contrast, macrophages activated through the “alternative” pathway with IL-4, IL-13 and/or TGFβ promote tumor progression by enhancing angiogenesis and producing type 2 cytokines and chemokines [23]). Because of the similarities in cytokine profiles, Mills coined the terminology “M1/M2” after the Th1/Th2 paradigm for classically-activated and alternatively activated macrophages, respectively [24]. This jargon was further developed by Mantovani and colleagues, although they are careful to point out that macrophages are a continuum of phenotypes with M1 and M2 being the polarized extremes [25,26].

Most progressively growing tumors are infiltrated by large numbers of macrophages. These tumor-associated macrophages (TAMS) are a key component of the tumor stroma and are essential for the angiogenesis and matrix remodeling that supports progressively growing
neoplasms. Using a spontaneous mouse mammary tumor model, the transition from premalignant to malignant phenotype was associated with increased blood vessel formation, and that the elimination of TAMS blocked the neoangiogenesis, while early infiltration of TAMS
enhanced angiogenesis [27]. Metastasis is also enhanced by TAMS when they promote the intravasation of tumor cells into local blood vessels, as graphically shown by intravital multiphoton imaging of live mammary tumors in situ [28]. As shown in human ovarian cancer, TAMS also promote tumor progression by blocking the activation of tumor-specific T cells by their expression of B7-H4, a negative regulator of T cell activation [29] Since TAMS promote tumor progression, they are often called M2 macrophages. Gene profiling of TAMS and alternatively-activated peritoneal macrophages (M2) has confirmed that TAMS and M2 macrophages express many of the same molecules; however, TAMS also express some IFN-inducible genes that are characteristic of M1 macrophages, indicating that they are intermediate in the continuum of macrophage phenotypes [30,31].

Natural killer (NK) cells
NK cells are components of the innate immune system that interact with adaptive immunity through their production of cytokines that modulate dendritic cell (DC) and cytotoxic T cell
maturation. They are well recognized for their ability to directly lyse MHC class I-deficient tumor cells through the engagement of their activating receptors and lack of engagement of
their inhibitory receptors. However, a subset of NK cells are also cytotoxic for activated CD8+ T cells [32] and DC [33], and thereby can reduce CD8-mediated anti-tumor immunity. In addition, NK cells have been shown to inhibit DC-mediated antigen presentation through a non-cytotoxic mechanism [34], and elimination of NK cells increases activation of tumor specific CD8+ T cells following immunization [35].

NKT cells
NKT cells, which express both NK and TCR, bridge the innate and adaptive immune systems.
They are usually CD4+ and respond to lipid and glycolipid antigens as presented by nonclassical
MHC class I CD1d molecules. Until recently there was confusion as to whether NKT cells promote tumor rejection or enhance immune surveillance. NKT cells prevent the spread of B16 melanoma metastases and promote immune surveillance in mice treated with the carcinogen 3-methyl-cholanthrene. However, CD1d knockout mice, which lack CD1drestricted NKT cells, reject recurrent fibrosarcomas and are resistant to the 4T1 mammary carcinoma. These apparently conflicting findings were resolved when it was found that type I NKT cells, which express the invariant Vα14Jα18 TCR Vβ chain, mediate tumor rejection, while type II NKT cells, which express a non-Vα14Jα18 TCR Vβ chain, promote tumor growth [36].

Myeloid-derived suppressor cells (MDSC)
MDSC are a morphologically and functionally heterogenous population of cells of myeloid origin that are elevated in almost all patients and experimental mice with cancer [37]. They suppress both innate and adaptive anti-tumor immunity by inhibiting CD8+ and CD4+ T cells,
K and NKT cells, and by blocking DC maturation [38–41]. MDSC suppress T cells through their production of arginase and/or reactive oxygen species (ROS); however, there is variability in which mediator(s) is used depending on the tumor model [38,42,43]. MDSC heterogeneity
is further demonstrated by the requirement for CD80 expression for suppression by some MDSC [44] and the absence of CD80 on other MDSC [45,46]. Likewise, the IL-4Rα is required for the IL-13-induced activation of some MDSC [47]; however, equally suppressive MDSC have been isolated from IL-4R-deficient and wild type mice [40]. Suppression requires MDSC to T cell contact, and for suppression of CD8+ T cells, MDSC nitrate tyrosines of the CD8+ T cells’ TCRs, thereby rendering the T cells incapable of activation by peptide-MHC I complexes of antigen presenting cells [48].

In addition to inhibiting anti-tumor immunity by blocking T cell activation, MDSC also induce CD4+ T regs through an IL-10 and IFNγ-dependent process that is ROS-independent [49]. They also polarize immunity towards a tumor-promoting type 2 phenotype by secreting high levels of IL-10 and shutting down macrophage production of the Type 1 cytokine, IL-12. Macrophages in turn, up-regulate MDSC production of IL-10 further favoring tumor progression [50].

MDSC are similar to other immune system cells in that chronic inflammation heightens their pro-tumor activity. IL-1β and IL-6 increase the accumulation and suppressive activity of MDSC [46,51,52], while reductions in these cytokines reduce MDSC levels [52]. PGE2 is one of the inflammatory inducers of MDSC, since co-cultures of c-kit+ mouse bone marrow stem cells with PGE2 produce immune suppressive Gr1+CD11b+ MDSC [53], and cyclooxygenase-2 (COX-2) produced by human lung cancer cells up-regulates arginase expression in human MDSC [54].

Conclusions
The immune system has the capacity to either block tumor development and deter established
tumors, or to promote carcinogenesis, tumor progression, and metastasis. Which of these
conditions prevails depends on the balance between the pro- and anti-tumor mediators of both innate and adaptive immunity. Presumably, there are unifying mechanisms that orchestrate
immunity towards tumor promotion vs. tumor destruction. Since many of the tumor-promoting
elements of the immune system are induced by, or themselves cause, inflammation, chronic inflammation may be a key process that polarizes immunity towards a tumor-promoting phenotype [55]. Accordingly, chronic inflammation would produce an immune suppressive, tumor-friendly environment that would negate immune surveillance and be permissive for carcinogenesis. As tumor growth progressed and tumors themselves produced proinflammatory molecules, innate and adaptive immunity would be further polarized towards a tumor-promoting phenotype, creating an ideal environment for further tumor growth and metastasis (Figure 4). Chronic inflammation has long been associated with increased risk of tumor onset and progression, and is known to enhance angiogenesis and tissue remodeling, and promote protein and DNA damage through oxidative stress, processes that are integral to tumor progression [55–57]. By polarizing immunity towards a tumor-promoting phenotype, inflammation not only promotes the genetic and histological changes that facilitate carcinogenesis, but it also deters immune surveillance, thereby functioning as both an initiator and a protector for neoplastic cells.

Acknowledgments
The author’s laboratory is supported by National Institute of Health grants R01CA118550 and R01CA84232, and Susan G. Komen Foundation for the Cure BCTR0503885.

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53•. Sinha P, Clements VK, Fulton AM, Ostrand-Rosenberg S. Prostaglandin E2 promotes tumor
progression by inducing myeloid-derived suppressor cells. Cancer Res 2007;67:4507–4513. [PubMed: 17483367]Using a mouse mammary tumor, this paper from the author’s laboratory demonstrated that the inflammatory agent PGE2 induces the differentiation of myeloid-derived suppressor cells from bone marrow stem cells and that tumor progression is delayed in mice that are deficient for the E-prostanoid receptor 2 for PGE2. This paper, together with ref. #54, provide direct evidence that induction of this important population of suppressor cells that is found in most cancer patients and experimental animals with tumors, is directly regulated by inflammation.
54•. Rodriguez PC, Hernandez CP, Quiceno D, Dubinett SM, Zabaleta J, Ochoa JB, Gilbert J, Ochoa AC. Arginase I in myeloid suppressor cells is induced by COX-2 in lung carcinoma. J Exp Med 2005;202:931–939. [PubMed: 16186186]This paper demonstrated that a mouse lung tumor produces COX-2 which up-regulates the immunosuppressive enzyme arginase I in myeloid-derived suppressor cells via the E-prostanoid receptor 4, thereby promoting immune suppression.                                            55•. Karin M, Greten FR. NF-kappaB: linking inflammation and immunity to cancer development and progression. Nat Rev Immunol 2005;5:749–759. [PubMed: 16175180]This comprehensive review article describes the studies demonstrating a linkage between infection, inflammation, and cancer, and proposed that NF-κB is a key regulatory molecule in inflammation-induced tumor progression.
It also reviews the various immune mediators that are activated by inflammation.
56. Balkwill F, Charles KA, Mantovani A. Smoldering and polarized inflammation in the initiation and promotion of malignant disease. Cancer Cell 2005;7:211–217. [PubMed: 15766659]
57. de Visser KE, Eichten A, Coussens LM. Paradoxical roles of the immune system during cancer
development. Nat Rev Cancer 2006;6:24–37. [PubMed: 16397525]

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Guidelines for Chronic Kidney Disease

KDOQI Clinical Practice Guidelines for Chronic Kidney Disease: Evaluation, Classification, and Stratification Figures Tables Acronyms and abbreviations KDOQI advisory board members Work group and evidence review team membership and support group Foreword Part 1. Executive Summary Part 2. Background Part 3. Chronic kidney disease as a public health problem Part 4. Definition and classification of stages of chronic kidney disease * Guideline 1. Definition and Stages of Chronic Kidney Disease * Guideline 2. Evaluation and Treatment * Guideline 3. Individuals at Increased Risk of Chronic Kidney Disease

Part 5. Evaluation of laboratory measurements for clinical assessment of kidney disease * Guideline 4. Estimation of GFR * Guideline 5. Assessment of Proteinuria * Guideline 6. Markers of Chronic Kidney Disease Other Than Proteinuria Part 6. Association of level of GFR with complications in adults * Guideline 7. Association of Level of GFR With Hypertension * Guideline 8. Association of Level of GFR With Anemia * Guideline 9. Association of Level of GFR With Nutritional Status * Guideline 10. Association of Level of GFR With Bone Disease and Disorders of Calcium and Phosphorus Metabolism * Guideline 11. Association of Level of GFR With Neuropathy * Guideline 12. Association of Level of GFR With Indices of Functioning and Well-Being Part 7. Stratification of risk for progression of kidney disease and development of cardiovascular disease * Guideline 13. Factors Associated With Loss of Kidney Function in Chronic Kidney Disease * Guideline 14. Association of Chronic Kidney Disease With Diabetic Complications * Guideline 15. Association of Chronic Kidney Disease With Cardiovascular Disease Part 8. Recommendations for clinical performance measures Part 9. Approach to chronic kidney disease using these guidelines Part 10. Appendices * Appendix 1. Methods for Review of Articles * Appendix 2. Kidney Function and Associated Conditions in the United States: Methods and Findings From the Third National Health and Nutrition Examination Survey (1988 to 1994) * Appendix 3. Methodological Aspects of Evaluating Equations to Predict GFR and Calculations Using 24-Hour Urine Samples Part 11. Work group members Part 12. Acknowledgements Bibliography Disclaimer

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cause of hyponatremia

Major causes of hyponatremia

Disorders in which ADH levels are elevated
• Effective circulating volume depletion
• True volume depletion—vomiting, diarrhea, bleeding, urinary loss
• Congestive heart failure and cirrhosis
• Thiazide diuretics
• Syndrome of inappropriate ADH secretion
• Hormonal changes: adrenal insufficiency, hypothyroidism, and pregnancy

Disorders in which ADH may be appropriately suppressed
• Advanced renal failure
• Primary polydipsia
• Beer drinkers’ potomania

Pseudohyponatremia
• High plasma osmolality: hyperglycemia or mannitol
• Normal plasma osmolality: hyperlipidemia, glycine solutions, and hyperproteinemia

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dengue fever

Dengue Fever

Author: Daniel D Price, MD, Director of Ultrasound Fellowship, Department of Emergency Medicine, Highland General Hospital, Alameda County Medical Center
Coauthor(s): Sharon R Wilson, MD, Assistant Professor of Emergency Medicine, Department of Emergency Medicine, University of California at Davis Medical Center
Contributor Information and Disclosures
Updated: Jan 31, 2008

Introduction

Background
Dengue has been called the most important mosquito-transmitted viral disease in terms of morbidity and mortality. Dengue fever is a benign acute febrile syndrome occurring in tropical regions. In a small proportion of cases, the virus causes increased vascular permeability that leads to a bleeding diathesis or disseminated intravascular coagulation (DIC) known as dengue hemorrhagic fever (DHF). Secondary infection by a different dengue virus serotype has been confirmed as an important risk factor for the development of DHF. In 20-30% of DHF cases, the patient develops shock, known as the dengue shock syndrome (DSS). Worldwide, children younger than 15 years comprise 90% of DHF subjects; however, in the Americas, DHF occurs in both adults and children.
Dengue is a homonym for the African ki denga pepo, which appeared in English literature during an 1827-28 Caribbean outbreak. The first definite clinical report of dengue is attributed to Benjamin Rush in 1789, but the viral etiology and its mode of transmission via mosquitos were not established until the early 20th century.


Pathophysiology
Dengue viral infections frequently are not apparent. Classic dengue primarily occurs in nonimmune, nonindigenous adults and children. Symptoms begin after a 5- to 10-day incubation period. DHF/DSS usually occurs during a second dengue infection in persons with preexisting actively or passively (maternally) acquired immunity to a heterologous dengue virus serotype. Illness begins abruptly with a minor stage of 2-4 days' duration followed by rapid deterioration. Increased vascular permeability, bleeding, and possible DIC may be mediated by circulating dengue antigen-antibody complexes, activation of complement, and release of vasoactive amines. In the process of immune elimination of infected cells, proteases and lymphokines may be released and activate complement coagulation cascades and vascular permeability factors.
Frequency
United States
Between 1990 and 1992, reports of 10 imported cases of dengue fever were published. While still rare, this is a dramatic increase from 1 case reported during the period from 1987 to 1989; this probably results from increases in air travel and an exotic vector that has adapted to cold climates. Cases along the Texas-Mexico border have been cited recently.
International
Dengue virus causes about 100 million cases of acute febrile disease annually, including more than 500,000 reported cases of DHF/DSS. Currently, dengue is endemic in 112 countries. The world's largest known epidemic of DHF/DSS occurred in Cuba in 1981, with more than 116,000 persons hospitalized and as many as 11,000 cases reported in a single day. Current outbreaks can be monitored via the ProMed listserve by contacting owner-promed@promedmail.org.
Mortality/Morbidity
• Treated DHF/DSS is associated with a 3% mortality rate.
• Untreated DHF/DSS is associated with a 50% mortality rate.
Race
Ethnicity is nonspecific, but the disease's distribution is geographically determined. Fewer cases have been reported in the black population than in other races.
Sex
No predilection is known; however, fewer cases of DHF/DSS have been reported in men than in women.
Age
All ages are susceptible. In endemic areas, a high prevalence of immunity in adults may limit outbreaks to children.
Clinical
History
• Fever
o Abrupt onset, rising to 39.5-41.4°C
o Accompanied by frontal or retro-orbital headache
o Lasts 1-7 days, then defervesces for 1-2 days
o Biphasic, recurring with second rash but not as high
• Rash
o Initial rash transient, generalized, macular, and blanching; occurs in first 1-2 days of fever
o Second rash occurring within 1-2 days of defervescence, lasting 1-5 days
o Second rash morbilliform, maculopapular, sparing palms and soles
o Occasionally desquamates
• Bone pain
o Absent in dengue hemorrhagic fever (DHF)/dengue shock syndrome (DSS)
o After onset of fever
o Increases in severity
o Not associated with fractures
o May last several weeks
o Most common in legs, joints, and lumbar spine
• Miscellaneous symptoms
o Nausea and vomiting
o Cutaneous hyperesthesia
o Taste aberrations
o Anorexia
o Abdominal pain (severe in DHF/DSS)
Physical
• Fever
• Signs of intravascular volume depletion
o Hypotension with narrowed pulse pressure
• Hemorrhagic manifestations
o Positive tourniquet test
o Petechiae, purpura, epistaxis, gum bleeding, GI bleeding, menorrhagia
• Rash
• Hepatomegaly (inconsistent)
• Generalized lymphadenopathy
Causes
• Dengue virus types 1-4
o Aedes aegypti mosquito vector
o Human-mosquito-human cycle
o Found in tropical regions, especially Southeast Asia
Differential Diagnoses
Hepatitis
Tick-Borne Diseases, Rocky Mountain Spotted Fever

Malaria
Yellow Fever

Meningitis

Pediatrics, Bacteremia and Sepsis

Pediatrics, Meningitis and Encephalitis

Other Problems to Be Considered
Leptospirosis
Rickettsioses
River viruses
Scrub typhus
Typhoid
Viral infections (eg, influenza, chikungunya, Mayaro fever, Rift Valley fever, West Nile, Sindbis, and Ross River)
Workup
Laboratory Studies
• Isolation of virus in serum and detection of immunoglobulins (IgM and IgG) by enzyme-linked immunosorbent assay (ELISA) antibody capture, monoclonal antibody, or hemagglutination
• Complete blood count
o Hemoconcentration (hematocrit increased 20%)
o Thrombocytopenia (platelet count <100 x 109/L)
o Leukopenia
• Chemistry panel
o Electrolyte imbalances
o Acidemia
o Elevated BUN
• Liver function tests
o Elevated transaminases
o Hypoproteinemia
• Guaiac test for occult blood in stool
• DIC panel, as indicated
Imaging Studies
• Chest radiography
o Bronchopneumonia
o Pleural effusion
• Head CT scan without contrast
o For altered level of consciousness
o Intracranial bleeding
o Cerebral edema
Other Tests
• Electrocardiography
o Nonspecific changes may be effects of fever, electrolyte disturbances, tachycardia, or medications.
o Usefulness of these changes as a marker of cardiac involvement is unclear.
Treatment
Prehospital Care
• Initiate supportive therapy
o Intravenous (IV) crystalloids, as needed to keep systolic blood pressure above 90 mm Hg
o O2, empirically
Emergency Department Care
• Supportive therapy
o IV access, O2, and monitoring are helpful.
o IV crystalloids may be necessary for hypotension; central line may be needed.
o Correct electrolyte abnormalities and acidemia.
• Implement therapy for DIC if indicated.
• Corticosteroids are not helpful.
• No antiviral therapy is available.
Consultations
• Infectious disease
• Travel clinic, if available
Medication
No specific medications are indicated for direct treatment of the dengue virus infection.
Follow-up
Further Inpatient Care
• Admit to ICU if hypotensive or in DIC, otherwise admit to medicine ward.
o Patient may require a central line.
o Patient may require an arterial line.
o Patient may require blood components.
Deterrence/Prevention
• Reduce A aegypti vector populations.
• Reduce exposure to A aegypti.
o Use insect repellent.
o Sleep under a mosquito net in affected areas.
o Wear protective clothing.
• Vaccines against all 4 serotypes are currently under development. While this is challenging due to the complex immune response, vaccines may ultimately be the most effective control strategy, since vector control programs have been largely unsuccessful and of only short-term local benefit.
Complications
• Complications are rare but may include the following:
o Brain damage from prolonged shock or intracranial hemorrhage
o Myocarditis
o Encephalopathy
o Liver failure
Prognosis
• Morens states that the rapid clinical response to aggressive fluids and electrolytes in even moribund children with DHF/DSS "is among the most dramatic events in clinical medicine." Treated promptly, children in shock and coma can wake up and return to near normalcy within hours.
• Convalescence may be prolonged, with weakness and mental depression.
• Continued bone pain, bradycardia, and premature ventricular contractions (PVCs) are common.
• Survival is related directly to early hospitalization and aggressive supportive care.
• Dengue fever is not contagious through person-to-person contact.
Patient Education
• See Deterrence/Prevention section.
Miscellaneous
Medicolegal Pitfalls
• Failure to admit patients for aggressive supportive therapy
• Failure to rule out other possible illnesses and specific therapies
Special Concerns
• Pediatric deaths associated with dengue viral infection most commonly occur in infants younger than 1 year.

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Systemic lupus erythematosus

Systemic lupus erythematosus
Jessica J Manson* and Anisur Rahman
Address: Centre for Rheumatology Research, Windeyer Building, University College London,46 Cleveland Street, London W1T 4JF, UK
Email: Jessica J Manson* - j.manson@ucl.ac.uk; Anisur Rahman - anisur.rahman@ucl.ac.uk

Abstract
Systemic lupus erythematosus (SLE) is a clinically heterogeneous disease, which is autoimmune in origin and is characterized by the presence of autoantibodies directed against nuclear antigens. It is a multi-system disease, and patients can present in vastly different ways. Prevalence varies with ethnicity, but is estimated to be about 1 per 1000 overall with a female to male ratio of 10:1. The clinical heterogeneity of this disease mirrors its complex aetiopathogenesis, which highlights the importance of genetic factors and individual susceptibility to environmental factors. SLE can affect every organ in the body. The most common manifestations include rash, arthritis and fatigue. At the more severe end of the spectrum, SLE can cause nephritis, neurological problems, anaemia and
thrombocytopaenia. Over 90% of patients with SLE have positive anti-nuclear antibodies (ANA). Significant titres are accepted to be of 1:80 or greater. SLE is a relapsing and remitting disease, and treatment aims are threefold: managing acute periods of potentially life-threatening ill health, minimizing the risk of flares during periods of relative stability, and controlling the less lifethreatening, but often incapacitating day to day symptoms. Hydroxychloroquine and non-steroidal anti-inflammatory drugs are used for milder disease; corticosteroids and immunosuppressive therapies are generally reserved for major organ involvement; anti-CD20 monoclonal antibody is now used in patients with severe disease who has not responded to conventional treatments. Despite enormous improvements in prognosis since the introduction of corticosteroids and immunosuppressive drugs, SLE continues to have a significant impact on the mortality and morbidity of those affected.
Disease name and synonyms

Systemic lupus erythematosus Lupus
Definition/Diagnostic criteria
Systemic lupus erythematosus (SLE) is a clinically heterogeneous disease which is autoimmune in origin, and characterized by the presence of autoantibodies directed against nuclear antigens. It is, by definition, a multi-system disease, and patients can present in vastly different ways. Classification criteria have been developed, in part in an attempt to keep the patient group as homogeneous as possible for research purposes. These criteria (Table 1), which are published by the American College of Rheumatology (ACR), were revised in 1982 [1] and combine clinical signs and symptoms with abnormalities detected in blood tests such as a positive anti-nuclear antibody or thrombocytopaenia. They were further updated in 1997 [2] to reflect a greater under- standing of the role of antiphospholipid antibodies in patients with SLE.
Epidemiology
SLE is up to 10 times more common in women than men, and typically has a predilection for women in their childbearing years [3]. Reliable data about the prevalence of SLE are difficult to come by. Variable methods for data collection and inconsistency regarding case definition contribute to this problem, but it is clear that the statistics vary with ethnicity. The overall prevalence is estimated to be about 1 per 1000. A study from Birmingham, UK, found the prevalence to be 27.7/100,000 in the general population, but nearly 9 times higher in Afro-Caribbean females [4]. Data from a national health survey in the USA found the self-reported prevalence of SLE (defined as having been given a diagnosis of SLE by a physician) to be 241/100,000 [5]. Recognizing that this may well be an over-estimate, combining self-reporting with evidence of a current prescription for anti-malarials, corticosteroids, or other immunosuppressive medications reduced this figure to 53.6/100,000 [5].
Aetiology/Pathogenesis
The clinical heterogeneity of this disease is mirrored by its complex aetiopathogenesis (reviewed in [6]). Twin studies initially indicated the importance of genetic factors, and genome screening has highlighted a number of potential loci of interest [7]. In the susceptible individual, disease may result from a variety of environmental triggers including exposure to sunlight, drugs and infections, particularly with Epstein-Barr virus. Even within one patient, lupus flares can result from different precipitants at different times. Despite extensive work, the precise pathological mechanisms of SLE are still not fully understood. The majority of patients have elevated levels of autoantibodies, directed
in particular against nuclear components such as nucleosomes, DNA and histones, and it is generally accepted that at least some of these have a directly pathogenic role, either by precipitating as immune complexes in target organs or by cross-reacting with other functionally relevant antigens. The presence and persistence of these autoantibodies indicate an abnormality in tolerance, which results from a combination of abnormal handling of autoantigens following apoptosis, and deranged function of T and B lymphocytes.
Differential diagnosis
The list of possible differential diagnoses is broad, and will vary with the presentation of each case. The non-specific clinical features of widespread pain and fatigue mean that in some cases fibromyalgia and other chronic pain syndromes may be appropriate differentials. Indeed, it is important to note that fibromyalgia and SLE can co-exist in the same patient. A number of patients will present with a cluster of features suggestive of an autoimmune rheumatic disease, though at initial presentation the final diagnosis appears unclear. A proportion of these "undifferentiated" patients will go on to develop full blown SLE, or other diseases such as systemic sclerosis. Some malignancies, particularly lymphoma and leukaemia, which are relevant to this age-group, can present with a similar clinical picture. Similarly, there is significant overlap with the presentation of some infections, notably,
Table 1: Diagnostic criteria of SLE. Adapted from Tan et al, 1982 [1]. A person is said to have SLE if he/she meets any 4 of these 11
criteria simultaneously or in succession
Criterion Definition/examples
1. Malar rash Fixed erythema over the malar eminences, tending to spare the
nasolabial folds
2. Discoid rash Erythematosus raised patches, may scar
3. Photosensitivity Skin rash as a result of unusual reaction to sunlight
4. Oral ulcers Usually painless
5. Arthritis Non-erosive: Jaccoud's arthropathy
6. Serositis a) Pleuritis – pleuritic pain, pleural rub, pleural effusion b) Pericarditis –
ECG changes, rub, pericardial effusion
7. Renal disorder a) Proteinuria (> 3+ or 0.5 g/day) b) Cellular casts in urine
8. Neurological disorder a) Seizures b) Psychosis
9. Haematological disorder a) Haemolytic anaemia b) Leukopaenia c) Lymphopaenia d)
Thrombocytopaenia
10. Immunological disorder a) Anti-DNA antibodies b) Anti-Sm antibodies c) Anti-phospholipid antibodies
11. Anti-nuclear antibody Exclude drug causes tuberculosis, HIV/AIDS and bacterial endocarditis. In view of the immunosuppressive nature of the required drugs, it is clearly crucial to exclude underlying infection before starting treatment for SLE.
The acutely ill patient
Even when the diagnosis of SLE has been established, the acutely ill patient must be thoroughly assessed before the illness is presumed to be due to a flare of their lupus. Since both SLE itself and the drugs used to treat it can cause immunosuppression, sepsis is common and may present in atypical ways. Thus, the physician must remain vigilant in looking for infection. In addition, the possibility of catastrophic antiphospholipid syndrome should be considered. We are becoming increasingly aware of this rare, but devastating association. A recent paper [8] describes a series of 80 such patients. The occlusion of multiple small vessels results in multi-organ failure, and mortality was reported to be 48% in this group.
Clinical manifestations
The clinical features of SLE are diverse and will be discussed by system as much as possible, and where appropriate, each section will refer to a review for more information. Quoted frequencies of each disease manifestation come from a prospective European study which followed 1000 patients with SLE over 10 years [3].
Constitutional symptoms such as fatigue, weight loss and fever are not life threatening, but have a significant impact on quality of life. Patients with SLE describe overwhelming
fatigue and unsatisfying sleep, though the extent to which this tiredness relates directly to lupus disease activity remains controversial [9].
Renal disease affects about 30% of patients with SLE, and remains the most dangerous, life-threatening complication. Patients who will develop lupus nephritis most commonly
do so within the first few years of their disease. As renal involvement is often asymptomatic, particularly initially, regular urinalysis and blood pressure monitoring is
crucial. Renal involvement is characterized by proteinuria (> 0.5 g/24 hours), and/or red cell casts, and early referral for renal biopsy is generally advocated. The histological classification of lupus nephritis has recently been updated [10]. Table 3 shows the revised classification criteria, developed under the auspices of the International Society of Nephrology and the Renal Pathology Society. Lupus nephritis classes I-V describe mesangial (I, II), proliferative (III, IV) or membranous (V) lesions, and each biopsy may have features of more than one class of disease. Classes III and IV are subdivided further depending on the activity or chronicity of the abnormalities seen. Class VI is reserved for widespread sclerotic disease. The renal biopsy findings are used to assess prognosis and guide management. Response to treatment can be assessed using serial urine protein/creatinine ratios, in addition to other more general measures of disease activity (see below).
Neuropsychiatric lupus (NPSLE) is seen in about 20% of cases. NPSLE is often a difficult diagnosis to make. Not only are there 19 different clinical manifestations as described by the American College of Rheumatology [11] (Table 3), but there is also no single, simple diagnostic test. In many cases, a brain biopsy would be the only definitive test, and this is rarely performed. The clinical features vary from central nervous system disease causing headache and seizures, or psychiatric diagnoses including
Table 2: The revised classification of glomerulonephritis in SLE [10]
Class I Minimal mesangial lupus nephritis Normal on light microscopy. Mesangial immune deposits on immunofluorescence
Class II Mesangial proliferative lupus nephritis Mesangial hypercellularity or matrix expansion, with mesangial immune deposits on
immunofluorescence
Class III Focal lupus nephritis Glomerulonephritis involving < 50% of glomeruli, typically with sub-endothelial immune deposits.
Class IV Diffuse lupus nephritis Glomerulonephritis involving > 50% of glomeruli, typically with sub-endothelial immune deposits. Can be
segmental or global.
Class V Membranous lupus nephritis Global or segmental sub-epithelial immune deposits
Class VI Advanced sclerotic lupus nephritis > 90% of glomeruli globally sclerosed without residual activity
Table 3: Neuropsychiatric syndromes seen in systemic lupus
erythematosus [11]
Central nervous system Peripheral nervous system
Aseptic meningitis Acute inflammatory polyneuropathy
Cerebrovascular disease Autonomic disorder
Demyelinating syndrome Mononeuropathy (single or multiplex)
Headache Myasthenia gravis
Movement disorder Cranial neuropathy
Myelopathy Plexopathy
Seizure disorders Polyneuropathy
Acute confusional state
Anxiety disorder
Cognitive dysfunction
Mood disorder
Psychosis
depression and psychosis, to peripheral nervous system involvement causing neuropathy.
The investigations of choice will vary with the presentation. Central nervous system disease usually warrants magnetic resonance imaging (MRI) of brain or spinal cord, and examination of the cerebrospinal fluid where appropriate. It must be remembered, however, that normal investigations, and lack of evidence of disease activity in another system, do not rule out the diagnosis of NPSLE – in a recent study of MRI in patients with NPSLE, 34% had normal brain scans [12]. This included patients with focal disease clinically. Interestingly, only one of the 85 patients included in this study proceeded to brain biopsy, which is probably indicative of generally accepted practice. The frequency of musculoskeletal disease in SLE means that rheumatologists often make the initial diagnosis. Arthralgia and myalgia occur in most patients. The classical "Jaccoud's arthropathy" although not causing a destructive arthritis, can result in significant deformity and functional impairment. A rheumatoid-like arthritis is seen more rarely, sometimes associated with a positive rheumatoid factor. Similarly, an overlap with myositis also occurs.
Skin involvement in lupus is also very common. In addition to the classic malar and discoid rashes, more generalized photosensitivity is often present, and furthermore sun exposure is known to trigger systemic disease flares. Alopecia can be scarring when associated with discoid lesions, or more diffuse, often fluctuating with disease activity. Recurrent crops of mouth ulcers are also a feature of active disease. Other oral manifestations include dryness as a result of secondary Sjogren's syndrome, and these patients also experience dryness of the eyes and vagina.
Haematological features include normocytic normochromic anaemia, thrombocytopaenia (sometimes, but not always associated with antiphospholipid antibodies) and leukopaenia. Severe haematological disease can occur, but this is relatively rare [13].
Pleuritis , causing chest pain, cough and breathlessness, is the most common pulmonary manifestation of SLE [14]. Although pleuritic symptoms may relate directly to active lupus, pulmonary embolism must always be considered, particularly in those who have antiphospholipid antibodies. Pleural effusions are usually exudates, have low levels of complement, and test positive for anti-nuclear antibodies (ANA). Infections are common, and any parenchymal lesion must be treated as infectious until proven otherwise. Rarer complications include interstitial lung disease and pulmonary hypertension (both more common in systemic sclerosis) and pulmonary haemorrhage.
Gastrointestinal involvement [15] most commonly results in non-specific abdominal pain and dyspepsia though it can be unclear whether such pain results from the illness itself or from drug side-effects. Hepatosplenomegaly can come and go with disease activity. Mesenteric vasculitis is very rare, but can be life-threatening, especially if it leads to perforation, and may only be diagnosed at laparotomy. SLE is associated with a variety of vascular manifestations. Raynaud's phenomenon, causing the classical triphasic colour change, was seen in 16% of patients in the European study[3]. Abnormalities in the micro vasculature are also thought to account for the association with livedo reticularis. Arterial and venous thrombosis affected up to 10% of the cohort, particularly in association with the secondary antiphospholipid syndrome. In the last decade, it has become clear that patients with SLE are at increased risk of atherosclerosis. Chronic inflammation and the use of corticosteroids contribute to this risk, and have led rheumatologists to treat SLE as an independent risk factor for stroke and myocardial infarction, much as an endocrinologist might regard the risk associated with diabetes. Ward [16] showed that in women between 18 and 44 years of age, those with SLE were twice as likely to develop a myocardial infarction or stroke, and nearly 4 times as likely to present with heart failure. Screening for cardiac disease with echocardiography (ECHO) has established that asymptomatic valvular lesions are common. In addition, pericarditis and pericardial effusions are common though myocardial disease is relatively rare.
Laboratory findings
Over 90% of patients with SLE have positive anti-nuclear antibodies (ANA). Significant titres are accepted to be of 1:80 or greater. ANA although sensitive, is far from specific for SLE. A positive ANA is also seen in many other illnesses including systemic sclerosis and polymyositis, as well as some chronic infections. All patients should be screened for extractable nuclear antigens (ENA). Different ENAs are associated with different disease manifestations – for instance, anti-Sm is associated with renal involvement, and anti-Ro with secondary Sjogren's syndrome. Antibodies to double-stranded DNA (dsDNA), and more recently to nucleosomes (though this test is not commonly available in most routine labs) are more specific for SLE, and anti-dsDNA titres are also predictive of renal involvement. Typically, a disease flare is accompanied by a rising titre of dsDNA antibodies and erythrocyte sedimentation rate (ESR), and falling complement and lymphocyte count. The C-reactive protein (CRP), unlike the ESR, does not usually rise with disease activity unless there is arthritis or serositis, and a raised CRP in a patient with SLE must always make you consider infection.
Treatment
SLE is a relapsing and remitting disease, and treatment aims are threefold: managing acute periods of potentially life-threatening ill health, minimizing the risk of flares during periods of relative stability, and controlling the less life-threatening, but often incapacitating day to day symptoms. Our limited understanding of the precise pathogenesis of SLE means that the majority of treatments are still broadly immunosuppressive in action, and hence carry asignificant risk of adverse effects. At the milder end of the spectrum, hydroxychloroquine is commonly used. This is effective for skin disease, joint pain and fatigue. Non-steroidal anti-inflammatory drugs are also useful for arthralgia and arthritis, though more aggressive treatment with methotrexate may be required. Low dose oral steroids or intramuscular injections of depot steroid preparations are sometimes used for mild disease, but immunosuppressive therapies and high dose steroids are generally reserved for major organ involvement. Lupus nephritis remains the complication which carries with it the biggest risk of death or long-term morbidity. Treatment of renal disease (Cochrane review [17]) was standardized by the National Institute of Health guidelines [18] published in 1992. Combining high dose corticosteroids with cyclophosphamide was the gold standard in the management of proliferative lupus nephritis for many years. Although efficacious, this regimen is limited
by significant toxicity. Both agents are immunosuppressive. In addition, corticosteroids are associated with a whole host of adverse effects including osteoporosis and weight gain, and cyclophosphamide can cause haemorrhagic cystitis and infertility. More recently, the classic regimen of monthly boluses of 1g cyclophosphamide for 6 months, followed by once every three months for the next 2 years, has been modified by some groups, who instead advocate the use of "low-dose" cyclophosphamide (6 fortnightly pulses of 500 mg). The so-called Euro-lupus trial, published in 2002, showed that the use of this lower dose regimen has better outcomes in terms of infertility risk, with no deleterious impact on renal disease [19]. Following remission induction, azathioprine is commonly used for maintenance therapy. Mycophenolate mofetil [20] has been added to the repertoire of drugs used for the treatment of lupus nephritis. This is now used commonly as maintenance therapy following cyclophosphamide, and its use in the induction phase has been adopted in some centres. Similarly, immunosuppressive treatments, such as cyclophosphamide and azathioprine, are also used for central nervous system involvement and rarely, serositis and haematological disease. Furthermore, persistent autoimmune thrombocytopenia sometimes requires immunoglobulin. In an attempt to improve management, biological therapies are being developed, which target specific cells or molecules within the abnormally functioning immune system. For example, the depletion of B cells using rituximab, an anti-CD20 monoclonal antibody previously used in the treatment of B cell lymphomas, is now being used in patients with severe disease which has not responded to conventional treatments [21].
Prognosis
Despite significant advances in treatment over the last decade, SLE still caries a significant risk of mortality and long term morbidity. A European study of 1000 patients with SLE, demonstrated a 10 year survival probability of 92% overall, reduced to 88% in those who presented with nephropathy [3]. Mean age at death was 44, but varied widely from 18–81 years. Cause of death varies with disease duration. In one cohort [22]), renal lupus accounted for the biggest number of deaths in those with less than 5 years of disease, whereas vascular disease was the most important factor in the group who died later in the disease course.As mentioned previously, we are becoming increasingly aware of the impact that premature atherosclerosis is having on the long term prognosis of lupus patients who survive the early years of illness. As we develop better immune targeted therapies, optimizing the management of these longer term complications will become increasingly important.
References
1. Tan EM, Cohen AS, Fries JF, Masi AT, McShane DJ, Rothfield NF, Schaller JG, Talal N, Winchester RJ: The 1982 revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum 1982, 25:1271-1277.
2. Hochberg MC: Updating the American College of Rheumatology revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum 1997, 40:1725.
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Heart Attack

What is a heart attack?

A heart attack (also known as a myocardial infarction) is the death of heart muscle from the sudden blockage of a coronary artery by a blood clot. Coronary arteries are blood vessels that supply the heart muscle with blood and oxygen. Blockage of a coronary artery deprives the heart muscle of blood and oxygen, causing injury to the heart muscle. Injury to the heart muscle causes chest pain and chest pressure sensation. If blood flow is not restored to the heart muscle within 20 to 40 minutes, irreversible death of the heart muscle will begin to occur. Muscle continues to die for six to eight hours at which time the heart attack usually is "complete." The dead heart muscle is eventually replaced by scar tissue.

Approximately one million Americans suffer a heart attack each year. Four hundred thousand of them die as a result of their heart attack.

What causes a heart attack?


Atherosclerosis

Atherosclerosis is a gradual process by which plaques (collections) of cholesterol are deposited in the walls of arteries. Cholesterol plaques cause hardening of the arterial walls and narrowing of the inner channel (lumen) of the artery. Arteries that are narrowed by atherosclerosis cannot deliver enough blood to maintain normal function of the parts of the body they supply. For example, atherosclerosis of the arteries in the legs causes reduced blood flow to the legs. Reduced blood flow to the legs can lead to pain in the legs while walking or exercising, leg ulcers, or a delay in the healing of wounds to the legs. Atherosclerosis of the arteries that furnish blood to the brain can lead to vascular dementia (mental deterioration due to gradual death of brain tissue over many years) or stroke (sudden death of brain tissue).

In many people, atherosclerosis can remain silent (causing no symptoms or health problems) for years or decades. Atherosclerosis can begin as early as the teenage years, but symptoms or health problems usually do not arise until later in adulthood when the arterial narrowing becomes severe. Smoking cigarettes, high blood pressure, elevated cholesterol, and diabetes mellitus can accelerate atherosclerosis and lead to the earlier onset of symptoms and complications, particularly in those people who have a family history of early atherosclerosis.

Coronary atherosclerosis (or coronary artery disease) refers to the atherosclerosis that causes hardening and narrowing of the coronary arteries. Diseases caused by the reduced blood supply to the heart muscle from coronary atherosclerosis are called coronary heart diseases (CHD). Coronary heart diseases include heart attacks, sudden unexpected death, chest pain (angina), abnormal heart rhythms, and heart failure due to weakening of the heart muscle.

Atherosclerosis and angina pectoris

Angina pectoris (also referred to as angina) is chest pain or pressure that occurs when the blood and oxygen supply to the heart muscle cannot keep up with the needs of the muscle. When coronary arteries are narrowed by more than 50 to 70 percent, the arteries may not be able to increase the supply of blood to the heart muscle during exercise or other periods of high demand for oxygen. An insufficient supply of oxygen to the heart muscle causes angina. Angina that occurs with exercise or exertion is called exertional angina. In some patients, especially diabetics, the progressive decrease in blood flow to the heart may occur without any pain or with just shortness of breath or unusually early fatigue.

Exertional angina usually feels like a pressure, heaviness, squeezing, or aching across the chest. This pain may travel to the neck, jaw, arms, back, or even the teeth, and may be accompanied by shortness of breath, nausea, or a cold sweat. Exertional angina typically lasts from one to 15 minutes and is relieved by rest or by taking nitroglycerin by placing a tablet under the tongue. Both resting and nitroglycerin decrease the heart muscle's demand for oxygen, thus relieving angina. Exertional angina may be the first warning sign of advanced coronary artery disease. Chest pains that just last a few seconds rarely are due to coronary artery disease.

Angina also can occur at rest. Angina at rest more commonly indicates that a coronary artery has narrowed to such a critical degree that the heart is not receiving enough oxygen even at rest. Angina at rest infrequently may be due to spasm of a coronary artery (a condition called Prinzmetal's or variant angina). Unlike a heart attack, there is no permanent muscle damage with either exertional or rest angina.

Atherosclerosis and heart attack

Occasionally the surface of a cholesterol plaque in a coronary artery may rupture, and a blood clot forms on the surface of the plaque. The clot blocks the flow of blood through the artery and results in a heart attack (see picture below). The cause of rupture that leads to the formation of a clot is largely unknown, but contributing factors may include cigarette smoking or other nicotine exposure, elevated LDL cholesterol, elevated levels of blood catecholamines (adrenaline), high blood pressure, and other mechanical and biochemical forces.

Unlike exertional or rest angina, heart muscle dies during a heart attack and loss of the muscle is permanent, unless blood flow can be promptly restored, usually within one to six hours.

Heart Attack illustration - Myocardial Infarction

While heart attacks can occur at any time, more heart attacks occur between 4:00 A.M. and 10:00 A.M. because of the higher blood levels of adrenaline released from the adrenal glands during the morning hours. Increased adrenaline, as previously discussed, may contribute to rupture of cholesterol plaques.

Approximately 50% of patients who develop heart attacks have warning symptoms such as exertional angina or rest angina prior to their heart attacks, but these symptoms may be mild and discounted.

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