The Da Vinci crock

[paracelsus]

Absolutely.. hmmm, it's true it's counterindicated, though... for instance, if you'd ask any cardiologist before 1990s about β-blockers being used in heart failure, they'd tell you they're counterindicated as they have the potential to worsen the condition. Yet, studies in the late 1990s showed their positive effects on morbidity and mortality in congestive heart failure patients. It may seem counterintuitive to administer drugs with negative inotropic activity to a patient with HF, but several clinical studies have clearly demonstrated improved systolic functioning and reverse remodeling in patients receiving β-blockers. These benefits arise in spite of occasional initial exacerbation of symptoms. The benefit of β-blockers is attributed, in part, to their ability to prevent the changes that occur because of the chronic activation of the sympathetic nervous system, including decreasing the heart rate and inhibiting the release of the renin.

Sorry! The precise mechanism by which β-adrenoceptor blockers exert their beneficial actions in patients with heart failure remains unclear. Several possibilities have been proposed, including heart rate reduction, β2-adrenoceptor–mediated modulation of catecholamine release, antagonism of the receptor-mediated toxic actions of norepinephrine on the myocardium, and favorable effects on myocardial energetics. Although carvedilol treatment was associated with a significant improvement in left ventricular ejection fraction and left ventricular stroke work, this effect was unrelated to changes in total systemic or cardiac norepinephrine spillover. The rise in left ventricular stroke work is accompanied by a modest rise in myocardial oxygen consumption per beat, although contractile efficiency was unchanged. The favorable effects of carvedilol on ventricular function in the failing heart are not explained by alterations in norepinephrine release or by changes in myocardial contractile efficiency.

[fortified bread]

Sorry! The precise mechanism by which β-adrenoceptor blockers exert their beneficial actions in patients with heart failure remains unclear. Several possibilities have been proposed, including heart rate reduction, β2-adrenoceptor–mediated modulation of catecholamine release, antagonism of the receptor-mediated toxic actions of norepinephrine on the myocardium, and favorable effects on myocardial energetics. Although carvedilol treatment was associated with a significant improvement in left ventricular ejection fraction and left ventricular stroke work, this effect was unrelated to changes in total systemic or cardiac norepinephrine spillover. The rise in left ventricular stroke work is accompanied by a modest rise in myocardial oxygen consumption per beat, although contractile efficiency was unchanged. The favorable effects of carvedilol on ventricular function in the failing heart are not explained by alterations in norepinephrine release or by changes in myocardial contractile efficiency.

To date, it has been proposed that the superior cardiac protection provided by carvedilol is not a consequence of hemodynamic variances but rather is due to its additional antioxidant effects. Studies in animals suggest that antioxidant effects may be protective in myocardial ischemia and may help retard the progression of atherosclerosis. Carvedilol decreases nitric oxide, the chemical that causes endothelial dysfunction and apoptosis (programmed cell death). In addition, carvedilol decreases the expression of structural extracellular proteins, an effect that reverses cardiac remodeling.

[Henning]

To date, it has been proposed that the superior cardiac protection provided by carvedilol is not a consequence of hemodynamic variances but rather is due to its additional antioxidant effects. Studies in animals suggest that antioxidant effects may be protective in myocardial ischemia and may help retard the progression of atherosclerosis. Carvedilol decreases nitric oxide, the chemical that causes endothelial dysfunction and apoptosis (programmed cell death). In addition, carvedilol decreases the expression of structural extracellular proteins, an effect that reverses cardiac remodeling.

fortified, winbow has already mentioned what you say, albeit tangentially.. now, maybe she's saying too many things (perhaps to make sure she's being all things to all people as it is the case when you can be nothing to everyone but she does mention the "remodeling" thing you explain in a little bit of more detail...

[byraze]

Thanks for the explanation, Henning - it was very clear and helpful

[tbreckenridge]

Thanks for the explanation, Henning - it was very clear and helpful

Are you being sarcastic, byraze? I can not really tell if you're serious or not..

[like]

So what is it - are we beginning to explore the amazing world of cardiology here?

[inner]

[...] It may seem counterintuitive to administer drugs with negative inotropic activity to a patient with HF [...]

winbow, doesn't "counterintuitive" mean that smth does not seem likely to be true when assessed using intuition or gut feelings? Are you not using it more in the sense of "logically" here?

[gent]

To date, it has been proposed that the superior cardiac protection provided by carvedilol is not a consequence of hemodynamic variances but rather is due to its additional antioxidant effects. Studies in animals suggest that antioxidant effects may be protective in myocardial ischemia and may help retard the progression of atherosclerosis. Carvedilol decreases nitric oxide, the chemical that causes endothelial dysfunction and apoptosis (programmed cell death). In addition, carvedilol decreases the expression of structural extracellular proteins, an effect that reverses cardiac remodeling.

Is there some kind of cohort or case-control study confirming this?

[e v e r]

To date, it has been proposed that the superior cardiac protection provided by carvedilol is not a consequence of hemodynamic variances but rather is due to its additional antioxidant effects. Studies in animals suggest that antioxidant effects may be protective in myocardial ischemia and may help retard the progression of atherosclerosis. Carvedilol decreases nitric oxide, the chemical that causes endothelial dysfunction and apoptosis (programmed cell death). In addition, carvedilol decreases the expression of structural extracellular proteins, an effect that reverses cardiac remodeling.

Is there some kind of cohort or case-control study confirming this?

Well, gent, it is true that cohort and case-control methodologies are the main tools for analytical epidemiological research. This is not to say, though, that findings from both cohort and case-control studies always reflect true associations which can be universally generalized. Epidemiological research is, to a large extent, of an observational character as opposed to experimental research. One should not forget that observational epidemiological studies are subject to the influence of factors over which the investigators most often do not have full control, and that findings from these studies are less reliable than those of studies with an experimental research design. It is therefore imperative that findings from analytical epidemiological studies are critically scrutinized before any judgement of causality is made. Furthermore, findings from one single epidemiological study only exceptionally provide conclusive evidence of a causal relationship between exposure and disease.

Experimental research provides data from which firmer conclusions can be made as compared with epidemiological studies. In experimental research, investigators can manipulate one factor while controlling others, and the main research question can be broken down into subquestions with comparatively simple causal assumptions. Through repeated manipulation of one or more factors in a series of experiments concerned with subquestions, the main research question can be resolved. The experimental approach allows control of the effect of extraneous factors that may have an effect on the outcome under study, but are not under investigation. Such extraneous factors may, if not under control, distort the results of the research and lead to false conclusions about cause and effect. In biomedical research on human beings the randomized clinical trial is the closest option to experimental research methodology. Observational epidemiological research has the disadvantage that extraneous factors cannot be manipulated by the investigators. Although information of such extraneous factors is collected and quantitatively adjusted for when they are known to be present, findings from observational epidemiological studies are generally less conclusive than those from experimental studies because of the less strict control of extraneous factors.

Bradford Hill has listed nine aspects concerned with the association between exposure and disease which need to be considered. The first of these is the strength of the association. A strongly elevated relative risk is more likely to reflect a causal association than is a slightly or moderately increased risk. Consistency of findings across studies conducted with different methodologies and in different settings, is another aspect. A third characteristic is specificity, that the exposure causes a particular disease, e.g. the observation that cigarette smoking is associated with squamous cell carcinoma of the respiratory tract. An important condition is the Sequence of events: the potentially causative factor must precede the effect, which in this context is disease. The dose-response relationship, or biological gradient, is another aspect. For example, massive exposure to sunlight is more likely to cause melanoma in susceptible individuals than is little or moderate sunlight. Biological plausibility is an aspect which is important, but depends on the biological knowledge of the day. The association should be consistent with what is generally known about the occurrence of the disease, its natural history and pathophysiology, and should not conflict with this knowledge. The causal interpretation of an association is furthered if there is experimental evidence in support of it, for example if elimination of exposure reduces the incidence of the disease. The ninth aspect is analogy. For example, if a virus is shown to be oncogenic in animal studies, we are more prone to accept that the human papilloma virus may be the cause of cervical cancer in humans. In his essay on association and causation, Bradford Hill notes that " none of my nine viewpoints can bring indisputable evidence for or against the cause-and-effect hypothesis and none can be required as a sine qua non ". The challenge of assessing causation is one of many fascinating aspects of epidemiological research.

[e v e r]

Now as to the specific advantages and disadvantages of cohort and case-control studies you mention:

Cohort studies

Advantages

- Allow complete information on the subject’s exposure, including quality control of data, and experience thereafter.
- Provide a clear temporal sequence of exposure and disease.
- Give an opportunity to study multiple outcomes related to a specific exposure.
- Permit calculation of incidence rates (absolute risk) as well as relative risk.
- Methodology and results are easily understood by non-epidemiologists.
- Enable the study of relatively rare exposures.
 
Disadvantages

- Not suited for the study of rare diseases because a large number of subjects is required.
- Not suited when the time between exposure and disease manifestation is very long, although this can be overcome in historical cohort studies.
- Exposure patterns, for example the composition of oral contraceptives, may change during the course of the study and make the results irrelevant.
- Maintaining high rates of follow-up can be difficult.
- Expensive to carry out because a large number of subjects is usually required.
- Baseline data may be sparse because the large number of subjects does not allow for long interviews.

Case-control studies

Advantages

- Permit the study of rare diseases.
- Permit the study of diseases with long latency between exposure and manifestation.
- Can be launched and conducted over relatively short time periods.
- Relatively inexpensive as compared to cohort studies.
- Can study multiple potential causes of disease.

Disadvantages

- Information on exposure and past history is primarily based on interview and may be subject to recall bias.
- Validation of information on exposure is difficult, or incomplete, or even impossible.
- By definition, concerned with one disease only.
- Cannot usually provide information on incidence rates of disease.
- Generally incomplete control of extraneous variables.
- Choice of appropriate control group may be difficult.
- Methodology may be hard to comprehend for non-epidemiologists and correct interpretation of results may be difficult.

http://www.fda.gov/OHRMS/DOCKETS/ac/02/briefing/3839s1_12_alter/sld006.htm