Biological clock’ is linked to heart attacks


‘Biological clock’ is linked to heart attacks

Abnormal heartbeat occurs most frequently in the morning — and to a lesser degree in the evening hours — and causes a high number of deaths.


clock
BIOLOGICAL CLOCK: The discovery opens up intriguing paths of research, in pinpointing individuals at risk of nocturnal death and devising drugs to shield them. (Photo: Mike Warot/flickr)
Scientists on Wednesday said they had uncovered the first molecular proof that the “biological clock” is linked to a type of sudden, fatal heart attack.
Ventricular arrhythmia, or abnormal heartbeat, occurs most frequently after waking in the morning — and also to a lesser degree in the evening hours — and causes a high number of deaths.
Reporting in the journal Nature, researchers in the United States said they had uncovered the first molecular link between this risk and circadian rhythm, the term by which biological processes vary according to a 24-hour period.
The finger points at levels of a protein called Klf15, they said.

Abnormal heartbeat occurs most frequently in the morning — and to a lesser degree in the evening hours — and causes a high number of deaths.


Previous research has found Klf15 to be a circadian controller — and, startlingly, is also lacking among some patients with heart failure.
The team created mice that had been genetically engineered to either lack Klf15 or make the protein excessively.
In both cases, the rodents had a much higher risk of arrythmias compared to normal counterparts.
“It is the first example of a molecular mechanism for the circadian change in susceptibility to cardiac arrhythmias,” said Xander Wehrens of Baylor College School of Medicine in Houston, Texas.
“If there was too much Klf15 or none, the mice were at risk for developing the arrhythmia.”
Klf15 is only one step in a complex molecular cascade, the researchers believe.
It controls another protein, KChIP2, which affects potassium-generated electrical current that flows though heart muscle cells called cardiac myocytes.
When levels of KChIP2 fluctuate, this causes electrical instability in the myocytes.
As a result, the heart muscle’s action becomes impaired and it takes longer (or conversely, less time) to empty the ventricle — the heart’s pumping chamber. The heart loses the regularity of the beat and labours to pump blood efficiently.
Co-author Mukesh Jain of the Case Western Reserve University School of Medicine in Cleveland,Ohio said that further work could well uncover other circadian-related causes.
The discovery opens up intriguing paths of research, in pinpointing individuals at risk of nocturnal death and devising drugs to shield them, Jain added.
Copyright 2012  AFP Global Edition

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Atlheltes with marked ECG repolarizacion abnormalities


Pelliccia A, Di Paolo FM, Quattrini FM, Basso C, Culasso F, Popoli G et alOutcomes in Athletes with Marked ECG Repolarization Abnormalities. N Engl J Med 2008; 358: 152-161.   TC   PDF

Introducción

Los deportistas presentan alteraciones ECG parecidas a las de la HVI. Estas consisten habitualmente en ondas R o S pronunciadas, pero en ocasiones también presentan T invertidas y profundas. Se desconoce si estas alteraciones de la repolarización son indicativas de alguna cardiomiopatía subyacente.

Objetivo

Evaluar los resultados clínicos asociados a la presencia de trastornos de la repolarización en atletas jóvenes.

Perfil del estudio

Tipo de estudio: Estudio de cohortes
Área del estudio: Pronóstico
Ámbito del estudio: Comunitario

Métodos

En Italia es obligatorio desde hace 25 años que todos los participantes en competiciones oficiales pasen un examen médico y un ECG previo a las mismas. Los deportistas que forman parte de las selecciones nacionales y aquellos a los que se les detectan anomalías electrocardiográficas son atendidos en el Instituto de Ciencia y Medicina de los Deportes, donde se lleva a cabo un estudio que incluye un ECG convencional, una prueba de esfuerzo y un ecocardiograma.
Se revisó la base de datos de los deportistas atendidos en este Instituto entre 1979 y 2001 y se identificaron los que presentaban trastornos de la repolarización importantes (ondas T negativas ≥2 mm en ≥3 derivaciones excepto en DIII y predominantemente en las derivaciones V2-V6). Se excuyó a los que tenían evidencia de lesiones estructurales en el ecocardiograma inicial. Como controles se seleccionaron deportistas entre los 20 siguientes a cada uno de los casos con ECG normal apareados por edad, sexo y duración del seguimiento.

Resultados

Se incluyeron en el grupo de casos 81 deportistas (fig. 1). Para ellos se seleccionaron 229 controles que fueron seguidos durante el mismo periodo de tiempo. En el 67% de los casos se detectaron más alteraciones ECG, entre las que destacaban incrementos de los voltajes de las R o las S (52%) y Q profundas (10%). No se apreciaron diferencias entre los casos y los controles. La edad media de los participantes era de 22 años y el 71% eran varones. Los deportes en los que participaban más frecuentemente eran remo, fútbol y waterpolo. El seguimiento medio fue de 9 años. Al final del periodo de seguimiento, el 78% seguían haciendo deporte regularmente, un 21% habían abandonado la práctica deportiva y 1 de los individuos había muerto.
Durante el seguimiento, las alteraciones de la repolarización se mantuvieron inalteradas en el 67% de los individuos, mejoraron en el 18% (menos derivaciones o menor profundidad de las ondas T) y se normalizaron en el 15% restante. En ninguno de los deportistas se apreciaron cambios en el volumen ventricular.
En 11 deportistas con alteraciones de la repolarización se detectaron cardiopatías en el seguimiento (14%). Uno murió a los 24 años un año después de la valoración inicial por una cardiomiopatía ventricular derecha arritmogénica que no se había detectado. En 3 se detectó una cardiomiopatía hipertrófica y en uno una cardiomiopatía dilatada. Uno de los individuos con cardiomiopatía hipertrófica sufrió un paro cardiorrespiratorio del que se recuperó. Otros 6 pacientes del grupo con alteraciones de la repolarización desarrollaron enfermedades cardiovasculares (3 HTA , 1 cardiopatía isquémica que requirió revascularización, 1 miocarditis y 1 taquicardia supraventricular paroxística que requirió ablación). En todos los deportistas que presentaron cardiomiopatías las anomalías ECG se mantuvieron a lo largo de todo el seguimiento.
Ninguno de los controles desarrolló una cardiomiopatía y sólo 4 desarrollaron algún trastorno cardiovascular: 2 taquicardia supraventricular, 1 miocarditis y 1 pericarditis.

Conclusiones

Los autores concluyen que las alteraciones ECG en deportistas jóvenes y aparentemente sanos pueden ser un indicio de cardiomiopatías subyacentes que pueden no hacerse evidentes hasta años más tarde, por lo que deben ser objeto de vigilancia clínica.

Conflictos de interés

Ninguno declarado. Financiado por el Comité Olímpico Italiano.

Comentario

La práctica habitual de deporte (no deporte de élite) tiene consecuencias cardiovasculares beneficiosas. Sin embargo, no es excepcional que en el deporte de élite se den casos de muerte súbita en el transcurso de una prueba deportiva. Se ha demostrado que un programa de cribado preparticipación disminuye el riesgo de estos accidentes.
En el corazón de las personas entrenadas se desarrollan unos cambios que se conocen como el corazón del deportista. Entre ellos destacan el aumento del tamaño y del volumen de las cavidades cardíacas, en especial del ventrículo izquierdo. Fruto de estos cambios, un 40% de los deportistas presentan alteraciones en el ECG, entre las que las más frecuentes son repolarizaciones precoces, incremento del voltaje del QRS, inversiones más o menos difusas de las ondas T y Q profundas, así como alteraciones de la conducción cardíaca (bradicardias, bloqueos AV tipo Wenkeback y ritmos nodales), así como arritmias ventriculares (extrasístoles e incluso salvas de taquicardia ventricular). Estas alteraciones pueden simular y dificulatar el diagnóstico de determinadas enfermedades cardíacas como las cardiomiopatias hipertrófica, dilatada o la cardioimiopatía ventricular derecha arritmogénica, que es la principal causa de muerte súbita en personas jóvenes.
De los resultados de este estudio se desprende que los deportistas que presentan alteraciones de la repolarización importantes (aproximadamente un 1%) tienen un mayor riesgo de presentar una cardiomiopatía que los que tienen un ECG normal, incluso aunque en la valoración inicial el resto de las exploraciones sean normales (valor predictivo positivo 6%). Estas cardiomiopatías pueden incluso poner en riesgo la vida de la persona (2 sufrieron cuadros de paro cardiorrespiratorio), por lo que parece prudente la recomendación de los autores de hacer un seguimiento clínico.

Bibliografía

  1. Corrado D, Basso C, Pavei A, Michieli P, Schiavon M, Thiene GTrends in Sudden Cardiovascular Death in Young Competitive Athletes After Implementation of a Preparticipation Screening Program. JAMA 2006; 296: 1593-1601.    TC   PDF  RC
  2. Maron BJ, Pelliccia AThe Heart of Trained Athletes: Cardiac Remodeling and the Risks of Sports, Including Sudden Death. Circulation 2006; 114: 1633-1644.   TC (s)   PDF (s)
  3. Pelliccia A, Maron BJ, Culasso F, et alClinical significance of abnormal electrocardiographic patterns in trained athletes. Circulation 2000; 102: 278-284.    TC  PDF

Autor

Manuel Iglesias Rodal. Correo electrónico: mrodal@menta.net.

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Effect of Aspirin on Vascular and Nonvascular Outcomes Meta-analysis of Randomized Controlled Trials


English: Schematic diagram of a plasma CVD (Ch...Image via WikipediaEffect of Aspirin on Vascular and Nonvascular Outcomes

Meta-analysis of Randomized Controlled Trials
Sreenivasa Rao Kondapally Seshasai, MD, MPhil; Shanelle Wijesuriya, MA, MBBChir; Rupa Sivakumaran, MA, MBBChir; Sarah Nethercott, MA, MBBChir;Sebhat Erqou, MD, PhD; Naveed Sattar, MD, PhD; Kausik K. Ray, MD 
Arch Intern Med. Published online January 9, 2012. doi:10.1001/archinternmed.2011.628
Background  The net benefit of aspirin in prevention of CVD and nonvascular events remains unclear. Our objective was to assess the impact (and safety) of aspirin on vascular and nonvascular outcomes in primary prevention.
Data Sources  MEDLINE, Cochrane Library of Clinical Trials (up to June 2011) and unpublished trial data from investigators.
Study Selection  Nine randomized placebo-controlled trials with at least 1000 participants each, reporting on cardiovascular disease (CVD), nonvascular outcomes, or death were included.
Data Extraction  Three authors abstracted data. Study-specific odds ratios (ORs) were combined using random-effects meta-analysis. Risks vs benefits were evaluated by comparing CVD risk reductions with increases in bleeding.
Results  During a mean (SD) follow-up of 6.0 (2.1) years involving over 100 000 participants, aspirin treatment reduced total CVD events by 10% (OR, 0.90; 95% CI, 0.85-0.96; number needed to treat, 120), driven primarily by reduction in nonfatal MI (OR, 0.80; 95% CI, 0.67-0.96; number needed to treat, 162). There was no significant reduction in CVD death (OR, 0.99; 95% CI, 0.85-1.15) or cancer mortality (OR, 0.93; 95% CI, 0.84-1.03), and there was increased risk of nontrivial bleeding events (OR, 1.31; 95% CI, 1.14-1.50; number needed to harm, 73). Significant heterogeneity was observed for coronary heart disease and bleeding outcomes, which could not be accounted for by major demographic or participant characteristics.
Conclusions  Despite important reductions in nonfatal MI, aspirin prophylaxis in people without prior CVD does not lead to reductions in either cardiovascular death or cancer mortality. Because the benefits are further offset by clinically important bleeding events, routine use of aspirin for primary prevention is not warranted and treatment decisions need to be considered on a case-by-case basis.


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Country profiles on noncommunicable disease trends in 193 countries


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WHO maps noncommunicable disease trends in all countries

Country profiles on noncommunicable disease trends in 193 countries

News release
 A new WHO report features information about the noncommunicable diseases (NCDs) situation in 193 countries, as global leaders prepare to meet at the United Nations high-level meeting on noncommunicable diseases in New York, 19-20 September 2011.
“This report indicates where each government needs to focus to prevent and treat the four major killers: cancer, heart disease and stroke, lung disease and diabetes,” says Dr Ala Alwan, Assistant Director-General for Noncommunicable Diseases and Mental Health at WHO.
The report includes details of what proportion of each country’s deaths are due to noncommunicable diseases. Using graphs in a page per country presentation format, the report provides information on prevalence, trends in metabolic risk factors (cholesterol, blood pressure, body mass index and blood sugar) alongside data on the country’s capacity to tackle the diseases.
Noncommunicable diseases are the top cause of death worldwide, killing more than 36 million people in 2008. Cardiovascular diseases were responsible for 48% of these deaths, cancers 21%, chronic respiratory diseases 12%, and diabetes 3%.

“Premature” deaths

In 2008, more than nine million of all deaths attributed to NCDs occurred before the age of 60; 90% of these “premature” deaths occurred in low- and middle-income countries. One of the findings shows that men and women in low-income countries are around three times more likely to die of NCDs before the age of sixty than in high-income countries.
According to these estimates, the proportion of men dying under the age of 60 from NCDs can be as high as 67%. Among women under 60, the highest proportion was 58%.
The lowest rates of mortality from noncommunicable diseases for men under 60 were 8% and for women under 60 it was 6%.

Risk factors

The profiles report on the proportion of people who smoke and are physically inactive. They also indicate trends for four factors that increase people’s risk of developing these diseases, blood pressure, cholesterol, body mass index and blood sugar over the past 30 years.
In the United States of America, for example, 87% of all deaths are due to noncommunicable diseases. 16% of the population smokes and 43% are physically inactive. On average, blood pressure has decreased since 1980; body mass index has increased; and glucose levels have risen.
Overall, the trends indicate that in many high income countries, action to reduce blood pressure and cholesterol is having an impact, but there is a need to do more on body mass index and managing diabetes.

Countries’ capacity to prevent and treat noncommunicable diseases

The profiles show what countries are doing to tackle noncommunicable diseases in terms of institutional capacity, specified funding, and actions to address the four main diseases and their associated risk factors.
The report also highlights what all countries need to do to reduce people’s exposure to risk factors and improve services to prevent and treat noncommunicable diseases.

UN high-level meeting on noncommunicable diseases

The UN meeting will highlight the importance of setting targets for progress. This report provides all countries with a baseline for monitoring epidemiological trends and assessing the progress they are making to address noncommunicable diseases. The WHO plans to issue an updated report in 2013.

For more information, please contact:

Gregory Hartl
Communications Officer
WHO, Geneva
Telephone:             +41 22 791 4458      
E-mail: hartlg@who.int

A cure for the disease of hate


BMJImage via Wikipedia

BMJ 2011; 343:d5715 doi: 10.1136/bmj.d5715 (Published 14 September 2011)

Cite this as: BMJ 2011; 343:d5715
  • Views & Reviews
  • Review of the Week

A cure for the disease of hate

  1. Iain McClure, consultant child and adolescent psychiatrist, Royal Hospital for Sick Children, Edinburgh
  1. imcclure@nhs.net
A Gazan doctor working in Israel describes his life and extraordinary tragedy, with a determination that good must come from bad. Iain McClure recommends his book to all doctors
On 16 January 2009 three Palestinian sisters were killed when an Israeli tank fired two shells into their bedroom. They were the daughters of Dr Izzeldin Abuelaish, a Palestinian gynaecologist, who, uniquely for a Gazan doctor, held a consultant post in an Israeli hospital. Abuelaish’s book, I Shall Not Hate, is an account of his life up to this momentous event and movingly explains his remarkable reaction. In essence, Abuelaish, who likens hate to disease and communication to cure, has drawn on his medical experience to seek a new approach to the resolution of apparently insoluble conflict.
For the three weeks prior to January 2009 the Israeli Defense Forces had been pursuing an incursion into the Gaza Strip to eradicate Quassam rocket attacks into Israel. The Israeli government had prevented Israeli or foreign journalists broadcasting from within Gaza during the operation. However, Abuelaish, a well known public figure in Gaza, had …

Smoked Pfizers Chantix heart problems


Logo of Pfizer Incorporated.Image via Wikipedia

Source: Pharmalot


cigarette-smoke-flickr

Yet another red flag is being raised about the Chantix smoking-cessation drug and the likelihood of cardiovascular problems. A new meta-analysis found that the Pfizer pill was associated with a 72 percent increased risk of serious adverse cardiovascular risks in smokers without a history of heart disease, and two authors suggest the FDA should consider having the drug removed from the market.
Just three weeks ago, the FDA added a warning on the product labeling about an association with a small, but increased risk of cardiovascular adverse events in patients with cardiovascular disease. The agency had reviewed a study in which 700 such patients received either Chantix or placebo, although results showed the pill was effective in helping them quit smoking and remain abstinent for up to year (back story).
In the latest analysis, which was published today in the Canadian Medical Association Journal, the researchers analyzed 14 double-blind, randomized controlled trials that involved 8,216 patients and ranged in duration from 7 to 52 weeks. They found a significantly increased risk of serious cardviovascular adverse events – 1.06 percent in Chantix versus 0.82 percent in placebo – including myocardial infarction, stroke and cardiovascular-related death. Only five trials, though, reported death (read the study here).
The findings are likely to add to the controversy over the drug, which has been associated with suicidal behavior and vivid dreams (see here and here). The government later banned Chantix for pilots and licenses wouldn’t be issued to truck drivers taking the med (see this and this). The FDA subsequently imposed a risk management program and Pfizer added warnings. Last year, a study in The Annals of Pharmacotherapy finds Chantix is not only associated with violent and agressive thoughts and acts (read here). Another in PLoS One found an association with serious acts of violence, such as physical abuse, physical assault and homicide (lookhere).
“Ours is the first study to show that Chantix increases cardiac risk substantially among smokers free of cardiac disease at baseline (13 out of 14 trials did not have heart disease at baseline) – important information that is missing from the Chantix label, despite the recent FDA warning on a small increased risk of cardiac events with Chantix among smokers with heart disease based on a single study of 700 patients (we included this study),” Sonal Singh, one of the authors and an assistant professor at the Johns Hopkins University School of Medicine, writes us.
“Since information that Chantix increases cardiac risks was available and noted by FDA safety reviewers at the time of speedy approval in May 2006 priority review, but never made it to the label, there should be no further delay in disseminating these findings to clinicians and patients. Given that there are other substantial risks with Chantix (neuropsychiatric effects) with only modest benefits compared to other therapies (such as Nicotine replacement therapy), this study shifts the risk-benefit profile of Chantix in an unfavorable direction,” he continues. “The FDA should deliberate, but also act with deliberate speed and consider all regulatory options, including removal from the market or further boxed warnings among smokers without heart disease.”
The lead author on the study, Curt Furberg, a professor of medicine at Wake Forest University, wrote us that the FDA should “clearly add the CV risk to the boxed warning (that already appears in the Chantix labeling) and seriously consider removing the drug from the maket due to the sum of serious adverse effects.”
In a statement, Pfizer says it “disagrees with the interpretation of the data” in the meta-analysis, which the drugmakers notes contains several limitations – notably, a small number of events, “which raises concerns about the reliability of the authors’ conclusions. The authors acknowledge that their risk ‘estimates are imprecise owing to the low event rates.’ The actual difference in cardiovascular event rates seen in the Singh analysis was less than one quarter of one percent – 1.06 percent with varenicline versus 0.82 percent with placebo.
“Pfizer works with regulators, like the FDA, on a continual basis to review and monitor data for Chantix. In particular, we are working with FDA to conduct a combined analysis of clinical trial data (meta-analysis), which will help further evaluate the cardiovascular safety of Chantix.” The drugmaker adds that it believes Chantix remains an important treatment option.
The meta-analysis did note that Chantix increases the chances of successfully quitting smoking by twofold compared with unassisted efforts. And there were limitations: the trials analyzed had enrolled different populations, evaluated different doses and had different lengths of follow-up and proportions lost to follow-up. “Our estimates are imprecise owing to the low event rates. None of the trials was adequately powered to detect individual differences in cardiovascular events,” the authors wrote. Furberg, by the way, is a paid expert for plaintiffs who are suing Pfizer over its Cox-2 painkillers.
“Despite the limitations of our analysis,” the authors wrote, “our findings have potential regulatory and clinical implications. Drugs that receive priority review have limited safety data at the time of approval. The initial safety signal regarding cardiovascular events in people using varenicline was not followed up by an adequately powered safety trial. Until such trials are conducted, clinicians should carefully balance the risk of serious cardiovascular events and serious neuropsychiatric adverse events asociated with varenicline use against the known benefits of the drug on smoking cessation.”
One noted cardiologist had this to say: “I continue to be perplexed by the resistance of companies to putting their subject-level data, published and unpublished, in the public domain and allowing independent investigators to evaluate the safety and efficacy of their products,” Harlan Krunholz, a professor of medicine and epidemiology and public health at Yale University School of Medicine, wrote us. “This article raises concerns but the authors are limited by the summary data that are in the public domain. We need companies to take these concerns seriously enough to support inquires by independent investigators who have unfettered access to all the data.”
In an accompanying editorial, J. Taylor Hays of the Department of Medicine at the Mayo Clinic, who has received grant funding from Pfizer to conduct a Chantix trial, wrote that the adverse events were rare; the rate of participants lost to follow-up was greater in the placebo arm than in the treatment arm in most of the studies included in the analysis, which “introduces bias in determining serious adverse events;” cardiac events were adjudicated in only one study and no significant differences were seen in the number of cardiovascular events or in deaths between those taking Chantix or a placebo.
Finally, he added that the “degree of uncertainty for the number needed to treat for harm is considerably greater than it is for the number needed to treat.” The meta-analysis found that the number needed to treat with Chantix for one additional person to successfully quit smoking was estimated to be 10, while the number needed to cause one additional serious cardiovascular event was estimated to be 28.
“These results represent a significant degree of uncertainty about the relative good or harm from Chantix, leaving the issue unsettled,” writes Hays, who acknowledges the pill is not free of risks. “The best outcome from this analysis would be more rigorous and adequately powered studies evaluating the safety of using (Chantix) among smokers who have known cardiovascular disease. The worst outcome would be for health care providers to abandon (Chantix), which has proven to be among the most efficacious pharmacotherapies used for the treatment of tobacco dependence.”
One of the researchers who explored the association between Chantix and violent behavior responded with this: “The more we learn about the safety profile of Chantix, the more unsuitable it looks as an alternative to low-risk nicotine replacement products. Chantix is linked to acts of serious violence, suicidal behavior, depression, psychosis and now increased cardiovascular risks. Canadian health authorities are examining a link to diabetes, a biologically plausible because of dopamine involvement, but not yet proven. Its effects on vision and motor control have led to it being banned for pilots, air controllers and military missile crews. Chantix is emerging as one of the biggest regulatory breakdowns in recent memory,” says Thomas Moore, a senior scientist with the Institute for Safe Medication Practices and who serves as a consulting expert in the civil litigation regarding Chantix.