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Is the new professionalism and ACP's new ethics really just about following guidelines?

The Charter ( Medical Professionalism in the New Millennium.A Physician's Charter) did not deal with just the important relationship of ...

Monday, November 19, 2018

20 years from demonstration of AF origin in pulmonary veins to a clincal trial with controversial results

 In 1998, Haissaguerre et al (1) described atrial ectopy or premature atrial beats within the pulmonary veins as the trigger for atrial fibrillation.It seemed to be a particularly attractive theory for the origin of paroxysmal AF (PAF) and has also been proposed as a facilitator of continuation of AF to persistent AF.

This lead to the idea that electrical isolation of the pulmonary veins by burning atrial tissue would keep the ectopy from reaching the rest of the atrium .

And so Pulmonary vein isolation (PVI) really caught on being used for not only PAF but for persistent AF as well  and ever since  the electrophysiology world has awaited a randomized clinical trial answering the question does PVI decrease mortality in atrial fibrillation (AF). It is accepted dogma,backed by considerable experience that PVI is superior to medication treatment in suppressing AF and there is general agreement that restoration of sinus rhythm improves quality of life .A  unanswered question was does PVI decrease risk of death associated with AF.

The Long-awaited CABANA trial was supposed t  or at least hoped would  provide an "Answer" to that question.

When the results of this large (2204 subjects) multi-center,multi national (https://www.acc.org/latest-in-cardiology/clinical-trials/2018/05/10/15/57/cabana) were announced there was no widespread celebration in the EP community. When the data were analyzed according to the standard statistical method used in randomized superiority clinical trials ( namely the "intention to treat" (ITT)) method), there was no difference in the primary outcome which was the combined end points of death,disabling stroke,serious bleeding or cardiac arrest  between the ablation group and the treated with drugs group.Further using ITT analysis there was no significant difference between the two treatment arms for each of the components of the combined end point .

For ablation versus drug therapy :8% vrs. 9.2%  with a hazard ratio of 0.86 (0.65-1.15, ) p=0.3 in regard to the primary endpoint.

There was no difference in death nor in serious stroke between the two arms of the study.

However looking at secondary outcomes-The category of death or cardiovascular hospitalization  there was a significant difference.

 There is more than one way to analyze data and results of the "per protocol " analysis gave  consolation to the EP cardiologists.

The per protocol analysis showed: a significant decrease in the composite primary end point with ablation  -ablation 7% versus  drug10.9 %  ( HR 057 , 0.50 -0.89) and decrease in all cause mortality in the ablation group , 7.5 % for drugs versus 4.4 % for ablation.

So intention to treat analysis indicated that ablation was not superior while per protocol analysis indicated that ablation was superior.Something for everyone.

Though heralded by some as a "game changer", I see nothing in the results changing any game. EP cardiologists are not likely to change their practice in any meaningful way  Just look at the final sentence in the Conclusion slide presented at the American College of Cardiology meeting in August 2018:

"Ablation is an accepted treatment strategy for treating AF with low adverse event rates even in higher risk patients."

 Since the study confirms what other data have shown namely that ablation converts AF to sinus rhythm more often than drugs and the results are more durable why would EP docs  change the way they are practicing ?

 1)Haissaguerre M, Jais P, Shah DC, Takahashi A, Hocini M, Quiniou G, Garrigue S, Mouroux AL, Metayer PL, Clementy J. Spontaneous initiation of atrial fibrillation by ectopic beats originating in the pulmonary veins. N Engl J Med.1998;339:659

Wednesday, November 14, 2018

Is aerobic endurance training even better for the muscles than the heart?

Aerobic exercise capacity is strongly linked to 02 max which is the product of the cardiac output ( stroke volume X heart rate) multiplied by the A-v 02 difference.

Five middle aged men who underwent aerobic training at age 20 in 1966 participated in a 6 month endurance training program in 1996.Their average 02 max increased 14% but there was no change in their maximal cardiac outputs. Their A-V 02 difference did increase by 10% accounting for the  entire improvement in their aerobic power.

The increase in mitochondrial function brought about by aerobic exercise is well documented and the more mitochondrial the higher the 02 uptake by the exercising muscles.

1)McGuuire, DK et al A 30 year followup of the Dallas Bedrest and training Study11Effect of age on cardiovascular adaptation to exercise training. Circulation2001 Sept 18 104 (12) 1358-66

Friday, November 09, 2018

Endurance exercise,aortic stiffness,Windkessel effect

The beneficial effect of prolonged endurance aerobic exercise on the aortic and great vessels may be as  important or more important that its effects on diastolic function and favorable remodeling. 

First the aorta is not  a stiff pipe. One  model used to explain aortic function and the shape of  the aortic pressure waves is the Windkessel effect model which considers the aortic and large elastic arteries as if it were an elastic buffering chamber which provides a cushioning or reservoir effect providing blood flow during diastole and damping the pulsatile flow. This reservoir effect flow is said to be as much as 40% of the stroke volume. The large elastic arteries act as capacitors , storing energy during systolic while bulging  a bit and then pushing back  or recoiling during diastole maintaining  a more or less steady flow of blood and offering protection to the vulnerable arterial vessels of the brain and kidney to which excessive pulsatile flow may be harmful. The capacitance effect does not eliminate pulsatilty,of course ,the textbook normal diastolic blood pressure is 80 and  not zero which is what it would be if  the aorta were a lead pipe. 

With aging,and arguably more so with sedentary aging,the elastic vessels become less elastic, stiffer and provide less of the Windkessel effect reflected in higher systolic blood pressure, lower diastolic blood pressure (increased pulse pressure) and more rapid blood flow. This   can measured  by noninvasive measurement of pulse wave velocity with an higher velocity indicating stiffer arteries.Loss of the reservoir  function. i.e.. a stiffer aorta and other great vessels  increase the left ventricular afterload predisposing to left ventricular wall thickening. 

It is easy to find data supporting the claim that exercise will improve aortic compliance.As early as 1973 a report from the Baltimore  Longitudinal Study on Aging (BLSA) (ref 1) indicated improved pulse wave velocity ,augmentation index and systolic blood pressure in older endurance athletes as compared with sedentary controls.

Other more recent detailed physiologic studies have confirmed that finding. Gates et al(2) studied men with varying exercise histories in three different age groups and reported that the regular endurance trained subjects has lower large artery stiffness as measured by a reduced aortic pulse wave velocity.

An excellent, detailed exposition of the physiology of the adaptation of the aorta to endurance exercise can be found in full free text in reference 3.

1)Vaitkevicius, PV et al Effect of age and aerobic capacity or arterial stiffness in healthy adults.Exp Physiology 2005:90.645-651

2)Gates PE,Left ventricular structure and diastolic function in human aging. Europen Heart Journal 2003,24, 2213-2220

3) Montero, FJC Adaptation of the aorta to training.Physiological perspective.
Apunts,Medicena de L'esport. 2017:52 (193): 3-9

Thursday, November 08, 2018

Football lineman may be damaging hearts as well as brains

Dr. J Kin along with Dr. Aaron Baggish, who directs the Cardiovascular Performance Program at MGH, studied a group of NCAA Div.1 college football lineman and compared results with non-lineman over the course of a single season. (1)

They reported that the lineman were all normotensive preseason while post season , 30% had developed Stage one hypertension and 60% developed pre-hypertension. The non-lineman improved their Global Longitudinal Strain measurement (as determined by speckle echocardiography)while the lineman worsened theirs.Concentric hypertrophy was noted in the lineman while the non-linemen displaced eccentric hypertrophy.

This was after a single season.Consider that many high school player play for four years and a number then have a college career.

The authors concluded:
... participation at a lineman field position may lead to a form of sport-related myocardial remodeling that is pathologic rather than adaptive. Future study will be required to determine if targeted efforts to control blood pressure, minimize weight gain, and to include an element of aerobic conditioning in this subset of athletes may attenuate this process and translate into tangible downstream health benefits."
I have blogged before about the occurrence of CTE in collegiate football players quoting a study from the Boston University CTE center. The authors reported 48 cases who only played high school and college ball.

There have also been several articles reporting imaging abnormalities in young players with both concussive and subconcussive head trauma.Now we seem to have evidence of subclinical heart damage  that like subconcussive blows might lead to downstream health problems.

1)Lin, J Blood pressure and left ventricular remodeling among American style football players.
JACC,vol 9, number 12 dec. 2016.

Friday, October 26, 2018

Cleveland Clinic article says the more fit live longer

Dr. Kyle Mandsager and colleagues at the Cleveland Clinic reported on the long term mortality  ( median followup of 8.4 years)  on 122,007 patients who were referred for symptom limited exercise treadmill testing.They were stratified by age and sex  into five cardiorespiratory  performance groups .(low,below average,above average,high and elite expressed as metabolic equivalent units (METs) which is 3.5 ml 02 uptake/kilogram/minute) which was estimated by treadmill incline and speed.

The 25th, 50th,75th and 97.7 percentiles were tabulated for age and sex .Low is defined as less than 25 th percentile and elite as greater than 97.7 th percentile.

They found that cardiorespiratory fitness (CRF) was "inversely associated with long term mortality with no observed upper limit of benefit. Cardiorespiratory  fitness is a modifiable indicator of long term mortality …"

We have another coarse grain study that could be used to support  the thesis that exercise is good and lots of exercise is better and you will live longer. I don't believe it is that simple.

 This study does not correlate exercise history with longevity as it correlates exercise performance with longevity. Admittedly exercise performance or capability does correlate with exercise history but they are not exactly the same thing.  Further, while it may well be the case that CRF is modifiable and  that one can actually improve mortality by improving one's CRF their data does not direct address those point although I like to believe that proposition is true.

What is shown impressively in their Figure 1, is  the 10 survival probability for the above average or the high group is about 95% ( just by my eyeballing the chart) versus the low group where the survival probability is slightly less than 80%

So how low is the low group in terms of exercise capability.For example in the 70-79 year age group the low group had a MET of less than 6. Some one in that category could likely walk a mile in 15 minutes or complete Stage 1 of the Bruce treadmill protocol. 

A 70-79 year old in the high group could likely complete stage 3 on the Bruce protocol and run a 12 minute mile. METs from the high group had METs in the 8.5 to 11.4 range and about 9 METS is needed to complete Stage 3.

What about a 40 year old? Subjects in the 40-49 year old group had a MET levels of less than 9.8. This corresponds to being able to finish Stage 2 and a bit into Stage 3 and be able to run a 12 minute mile.
Someone in the high category would have a MET value of 12.5 to 14.6 which corresponds to being able to reach Stage 5 on the Bruce  protocol and run a mile in 9 minutes.

The authors made comments that are headline attractors.  "The increase in all cause mortality associated with reduced CFR (low versus elite:adjusted HR,5.04:95% CI, 4.10--6.20;p<.002) was comparable to or greater than traditional risk factors." See figure 2 in their artcle for details of that comparison.<0 .001...was="" 2="" comparable="" compared="" diabetes="" esrd.="" factors.="" factors="" figure="" greater="" hypertension="" nbsp="" or="" p="" risk="" see="" smoking="" than="" the="" their="" to="" traditional="">

Skeptics of the thesis that there is a "U -shaped"curve relating risk of death to exercise level will perhaps find some comfort in their finding : "There was also no evidence to suggest relative harm associated with extreme levels of fitness in these subgroups of patients"In fairness I should add that no one has claimed that excessive fitness is deleterious but rather the claim has been that excessive exercise may be harmful, again realizing that fitness levels and exercise levels are highly correlated. 

Nitpicking aside, their data provide more fuel to the argument that exercise ( or at least CRF) is good and apparently the more the better.

1)Mandsager,k et al "Association of cardiorespiraory fitness with long-term mortality among adults undergoing exercise treadmill testing" JAMA Network open, 2018 1 (6)Oct 19


Friday, October 19, 2018

Changing status for use of aspirin in primary prevention of heart disease

In the not too distant past based in part  on the results of the Physicians Health Study (1989) and the Women's Health Study (2005) it seemed reasonable to recommend aspirin for cardiovascular disease prevention. Recommendations were typically based on various guidelines that were estimates of a person's risk based on various risk factors such as cholesterol level,Blood pressure, smoking status, family history, etc. Since age is a major risk factor many of elderly are taking low dose aspirin with or without a physicians's advice.Is that still a good idea?

Dr. Paul Ridker in a editorial in the NEJM (1) questions whether the old advice is still justified in light of more recent clinical trial data  and perhaps a changing risk baseline for the population in general. More people now are on medication for blood pressure,fewer smoke and many more now are taking statin drugs than they were at the times of the PHS and WHS.

In the same issue of NEJM 3 primary prevention trials were published. Only the trial in diabetic patients (the ASCEND trial) was there shown to be a statistically signficiant reduction in vascular events. A 12% reduction is vascular events was countered by a 29% increase in major bleeding and the all-cause mortality was the same in the control and the treatment groups.

The ARRIVE trial was  a primary prevention trial in"high risk " subjects The intention-to-treat analysis showed that the primary outcome was the same in the control and aspirin groups. The primary outcome was a composite of stroke,heart attack,unstable angina,TIAs and death from CV causes.Gi bleeding was twice as common in the aspirin group.

The ASPREE trial was a primary prevention trial in subjects 70 years of age and older who were free of CV disease ,dementia or disability on entry into the study. After five years of 100 mg aspirin a day versus placebo there was no CV benefit .There was more GI bleeding with aspirin ( Hazard ratio of 1.39).

So unlike aspirin's well established  role in secondary CV disease prevention the benefit-risk ratio in primary prevention is ( in Ridker's words) "exceptionally small" . Dr. Ridker has been an advocate of statin use and it is not surprising  that he end his commentary with: "Thus beyond diet maintenance,exercise, and smoking cessation,the best strategy for the use of aspirin in the primary prevention of cardiovascular disease my simply be to prescribe a statin instead."

1) Ridker, PM Should Aspirin be used for primary prevention in the post-statin era? NEJM 379;16 oct 18 2018. 1572

Saturday, October 13, 2018

More physical activity may be needed to prevent HF than some other CVD events

 The title is a reworded version of the title of the article which is designated as reference 2 in the footnotes.

There are  2 (at least 2) epidemiologic studies that indicate a linear dose-response relationship between physical activity (PA) and the risk of heart failure. While one study ( Pandy et al see below) does demonstrate a "modest" reduction in HF risk at a lower levels of PA, both studies how a more robust reduction in HF at higher exercise levels.

Pandy et al (Circulation 2015,, see ref 1 below) did a meta-analysis involving about 370  thousand subjects , 20 thousand of which developed HF over a 13 years period.They compared the HF risk in 3 categories based on level of exercise, namely 500 MET-min per week ,1000 MET-min per week and 2000 MET-min per week.

500 MET-min per week is equivalent to 2.5 hours of "moderate" exercise per week or 1.25 hours of "vigorous" exercise per week.Moderate is defined a exercise requiring 3-5.9 MET and vigorous as about 7 METS. (It requires about7 METS to run a 15 minute mile or to finish Stage 2 on the Bruce protocol treadmill exercise tests. One should be able to walk a fifteen minute with a 02 consumption of 5 METS.)

1000 MET-hrs per week is 5 hours of moderate or 2.5 hours of vigorous exercise per week and 2000 as twice that or 10 hours of moderate exercise per week. Yes, that does seem like a lot,

Both the 2008 US exercise  guidelines and the 2018 guidelines recommend at least 500 but state that more benefits accrue with higher levels .

Pandy reported a linear,dose response with a "marked reduction in risk at very high doses of PA ( about 35%) at 2000 MET-min per week".

Their data:
exercise level                                HF RF

500 MET hrs per week                  0.9 (0.87-0.92)
1000 "  " " " " " " " "                       0.81(0.77-0.80
2000 "  "   "   "" """""                     0.65 (0.58-0.73)

Quoting the authors; "Only a moderate reduction ( about 10%) risk in HF noted at the minimal ( US guidelines) recommended level,"

The authors offer a mechanistic explanation namely that CAD event risk occurs at a lower level of exercise by reducing the usual suspect Risk factors (BP,Lipids,blood sugar control) while HF risk reduction occurs at a higher levels of exercise perhaps  by altering cardiac function and structure, i.e beneficial remodeling.

An earlier article Patel K, (Int J Cardiol 2013 see ref 2) had reached generally similar conclusions regarding the levels of exercise needed to decrease HR risk versus the amount adequate to  reduce general  CV risk, e m.gyocardial infarction.

Patel et al studied 5503 patients age 65 and older
During the 13 years of follow up incident HF developed in:
26% of those with little or no regular exercise
23% of those with "low"level of exercise
20% of those with "moderate"
19 % of those with high .

Low was defined a 1-499 Met-min per week
medium as 500-99
high as greater than 1000

The HRs for incident HF were:
low level exercise     0.87 (0.71-1.06)
medium                     0.68 (0.54-0.85) stat sig 
high                            0.60 (0.49-0.74) stat sig 

All exercise level groups had reduced HR for incident MI, stroke, and cardiovascular mortality but the lowest level group did not have a statistically significant  decrease in HR risk.

These 2 studies indicate that more exercise is associated with greater reduction in HF risk, although some HR HF decrease was noted in the lowest exercise group in the Pandy study.

Now for something completely different. A different type of study published by CR de Fillippi from the Cardiovascular Health study ( reference 3) provides an interesting  insight regarding possible mechanism(s) by which more exercise is better in terms of HF risk reduction. 

They studied 2, 9333 subject free of HF at the onset and  who had normal values for two biomarkers, NT-Pro BNP and cTnT (troponin).They then measured these markers every 2 to 3 years and compared incident increase in those markers in groups divided by their exercise levels.(They quantitatedle exercise using  a particular system and used numerical scores to define groups and I was not a to translate those values in to MET hrs to compare with the other 2 articles)

 They found compared with the participants with the lowest PA activity scores those with the highest (i.e. more exercise) had an low odds ratio of 0.50 (0.33-0.77) for a significant increase in NT proBNP and an OR of 0.3 for and increase in troponin.  Quoting  the authors "increased levels of NTProBNP and cTnT may reflect pathological precursors of hemodynamic stress and injury that are prevented by PA at some as yet more precisely defined level.

So how to put all this together.

An  appealing ( at least to me) mechanistic explanation is that an overall decrease in CV mortally and arguably a slight reduction in HF risk  can be brought about by modest exercise and even  perhaps slightly less  than modest levels  by reducing the usual suspect,traditional CVD risk factors.Modest here refers to about 500 MET hrs per week. but some studies have shown a decreased heart attack risk at even lower exercise levels.

A more robust risk reduction in HF risk (perhaps 20-35%) seems  to require higher levels of exercise  ( in the 1000 Met-hrs per week range and higher) by perhaps bringing about an advantageous remodeling of the heart or at least a mitigation of the deleterious remodeling of the heart than occurs with sedentary aging which in turn may predispose to the development of heart failure with preserved ejection fraction (HFpEF).

To the extent that CVD risk factor reduction can decrease heart attacks and the  accompanying reduction in   heart function some reduction in HF risk would be likely, i.e.some reduction in heart failure with reduced ejection fraction ( HFpEF). But at least half of cases of HF are not associated with decreased systolic function ( at least as measured by the ejection fraction  (EJ) but by the echocardiographic finding of decreased left ventricular compliance and distensibility which according to the work of Dr. Ben Levine and others at SW  Medical School in Dallas predispose to diastolic heart failure  (HFpEF) .That group suggests that at least 30 minutes of exercise 4 to five times a week might be sufficient to prevent that age related loss of cardiac compliance. ( see ref 4 below for more on this argument) and perhaps prevent at least some cases of HFpEF.

1)Pandy,A "Linear,dose dependent inverse association between PA(physical activity) and heart failure risk Circ. 115.132 p 1786-1794

2.Patel K. "Prevention of heart failure in older adults may require higher levels of physical activity than needed for other cardiovascular events." Int J Cardiol. 2013, Oct 168 (3) 1905-1909)

3)de Fillippi, CR "Physical activity, change in biomarkers of myocardial stress and injury, and subsequent heart failure risk in older adults. JAm Coll Cardiol.. 2012 Dec. 18;60 (24), 2539-47

4) Bhella, PS  "Impact of lifelong exercise "dose" on left ventricular compliance and distensibility"J Amer coll cardiology. 2014 , 64, no 12,p 1267