Ivabradine And Diastolic Dysfunction

[firewatcher]

A Heart-Rate-Reducing Medication Reduces the Risk of Heart Failure and Cardiac Fibrosis

ScienceDaily (July 28, 2011) — The findings of a Montreal Heart Institute (MHI) study published in the scientific journal Cardiology suggest that ivabradine, a heart rate reduction medication, is also effective in reducing the risk of diastolic heart failure (left ventricular insufficiency) and cardiac fibrosis.

The benefits of slower heart rate on mortality and morbidity associated with cardiovascular disease no longer need to be demonstrated. In this study, titled "Heart Rate Reduction by Ivabradine Reduces Diastolic Dysfunction and Cardiac Fibrosis," researchers sought to determine the effectiveness of ivabradine in treating diastolic dysfunction of the left ventricle, a condition affecting 40% of people with heart failure.

The study was conducted on rabbits given a standard diet, a cholesterol-enriched diet or a cholesterol-enriched diet with ivabradine. It revealed that as well as improving the myocardial performance index, ivabradine greatly improved left ventricular diastolic dysfunction in animals receiving a cholesterol-enriched diet. Ivabradine also reduced fibrosis of the heart chambers.

According to Dr. Jean-Claude Tardif, Director of the MHI Research Centre and professor of medicine at the Université de Montréal, the results are both interesting and encouraging. "The effectiveness of ivabradine in treating angina pectoris is now well known. However, few treatments are available to patients with diastolic heart failure. The beneficial effects of ivabradine demonstrated in laboratory suggest that this course of treatment should be further investigated." Clinical studies with subjects are expected to follow.

Edited July 30, 2011 by firewatcher

[firewatcher]

Heart rate: a forgotten link in coronary artery disease?

Fox KM, Ferrari R.

Nat Rev Cardiol. 2011 Apr 26;8(7):369-79. doi: 10.1038/nrcardio.2011.58.

Royal Brompton Hospital, Sydney Street, London SW3 6NP, UK.

Abstract

A considerable body of evidence indicates that elevated resting heart rate is an independent, modifiable risk factor for cardiovascular events and mortality in patients with coronary artery disease. Elevated heart rate can produce adverse effects in several ways. Firstly, myocardial oxygen consumption is increased at high heart rates, but the time available for myocardial perfusion is reduced, increasing the likelihood of myocardial ischemia. Secondly, exposure of the large elastic arteries to cyclical stretch is increased at high heart rates. This effect can increase the rate at which components of the arterial wall deteriorate. Elastin fibers, which have an extremely slow rate of turnover in adult life, might be particularly vulnerable. Thirdly, elevated heart rate can predispose the myocardium to arrhythmias, and favor the development and progression of coronary atherosclerosis, by adversely affecting the balance between systolic and diastolic flow. Comparisons of the effects of the specific heart-rate-lowering drug ivabradine with those of β-blockers could help clarify the pathophysiological effects of elevated heart rate. Effective heart rate control among patients with coronary artery disease is uncommon in clinical practice, representing a missed therapeutic opportunity.

PMID: 21519356

It would appear that a chronic, high heart rate DOES have lasting physical harm, despite what we may have been told. I think that many of us whom have had untreated POTS for long periods may also show later renal and cardiovascular abnormalities. The good news is that treatment slows the decline.

Edited July 30, 2011 by firewatcher

[MomtoGiuliana]

It seems like the article is saying it is a risk factor for patients with coronary artery disease. What about patients without CAD? I don't think that research has been done??

I know my dr used to say that unless I have sustained hr at 120 or above tachycardia is not causing damage. I don't know what that statement is based on...if anything.

[firewatcher]

Tachycardia-induced diastolic dysfunction and resting tone in myocardium from patients with a normal ejection fraction.

Selby DE, Palmer BM, Lewinter MM, Meyer M.

J Am Coll Cardiol. 2011 Jul 5;58(2):147-54.Source

Cardiology Division and Department of Physiology, University of Vermont College of Medicine, Burlington, Vermont.

Abstract

OBJECTIVES:

The purpose of this study is to evaluate tachycardia-induced relaxation abnormalities in myocardium from patients with a normal ejection fraction.

BACKGROUND:

Diastolic dysfunction and left ventricular (LV) hypertrophy are closely linked. Tachycardia can induce heart failure symptoms in otherwise asymptomatic patients. To study the effects of tachycardia on myocardial contractility and relaxation, we evaluated the effects of increasing pacing rates in myocardial biopsy samples obtained from patients with a normal ejection fraction.

METHODS:

LV biopsy samples were obtained during coronary bypass surgery. Myocardial strip preparations were electrically paced at rates from 60 to 180 beats/min. Diastolic resting tone was assessed by cross-bridge deactivation. Calcium transporting systems were functionally examined, and myofilament calcium sensitivity was studied.

RESULTS:

Incomplete relaxation developed in 7 preparations, with increased diastolic tension development at increasing pacing rates. This was absent in the remaining 7 preparations. Incomplete relaxation was found to be associated with increased LV mass and left atrial volume. Cross-bridge deactivation showed that these preparations also had a significant resting tone. Additional functional analyses suggest that incomplete relaxation is associated with disproportionately elevated cellular calcium loads due to a reduced sarcolemmal calcium extrusion reserve.

CONCLUSIONS:

Tachycardia-induced incomplete relaxation was associated with increased LV mass and left atrial volumes. We also found a disproportionately increased calcium load at high rates and a substantial resting tone due to diastolic cross-bridge cycling. These observations may play a role in reduced exercise tolerance and tachycardia-induced diastolic dysfunction.

Copyright © 2011 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

PMID: 21718911

My Cardiologist told me the same thing, but there are many studies on Ivabradine coming out that suggest otherwise. Whether the conclusion that sustained, chronic tachycardia induces heart failure is simply a "given" used by pharmaceutical companies or something that is just not known yet is another question.

Edited July 30, 2011 by firewatcher

[MomtoGiuliana]

Heart failure SYMPTOMS--is that the same as heart failure?

[firewatcher]

Heart rate and heart failure. Not a simple relationship.

Heusch G.

Circ J. 2011 Feb;75(2):229-36. Epub 2010 Oct 28.

Source

Institut für Pathophysiologie, Universitätsklinikum Essen, Essen, Germany. gerd.heusch@uk-essen.de

Abstract

Resting heart rate (HR) is increased in patients with heart failure (HF). Sustained tachycardia can cause HF. The magnitude of HR reduction in treatment trials of patients with HF is associated with a reduction in mortality. Yet, the mechanistic and causal role of HR in HF is unclear, and recent trials with selective HR reduction have not consistently achieved benefit: the BEAUTIFUL trial in patients with coronary artery disease and left ventricular dysfunction did not achieve a significant benefit in the primary endpoint, and only the coronary outcome, not the HF outcome, was improved; in the SHIFT trial, however, patients with symptomatic heart failure had a significant benefit in the primary endpoint of cardiovascular mortality and hospitalization for worsening HF. The present review addresses the pathophysiology of tachycardia-induced HF, the force-frequency relationship, and the clinical potential of HR reduction in HF.

PMID: 21041970

Again, I don't know that this statement is true. The current pharmaceutical chatter states that it is. I question both this assumption AND what my cardiologist has told me, that POTS has no adverse effects. Anecdotal evidence from other forum members with longstanding POTS and/or untreated tachycardia suggests that POTS may have a long-term health risk. I will not be surprised if we see Ivabradine prescribed more for POTS.

Edited July 30, 2011 by firewatcher

[issie]

I do remember a post from a girl a while back who did have a heart attack and it was felt that POTS played a key role in her heart attack. I never heard what her outcome was. That told me that doctors saying that you have a strong heart, don't worry about the tachy. wasn't what I should believe. We are over working our heart and high heart beats and high blood pressures (for us that are hyperPOTS) can't be a good thing. My doctor at Mayo is insistant that my blood pressure be brought down. This is going to be hard, because I have liable blood pressure - which means that a good part of the time it is normal or even low. So, how do you treat the high - when there are low pressures also. Going to try a new drug - haven't started yet - will post the results if they are good.

[janiedelite]

Once I was admitted to the hospital because of an episode of high BP and chest pain. My CK was normal, but my troponin was elevated at 0.35. My BP was sustained at 180's/110's and I couldn't get it to come down for over an hour. I ended up responding well to nitroglycerin. It ended up that I was having odd sympathetic surges as a result of being on mestinon.

My cardiologist (who is a POTS expert) said that anytime our hearts are stressed it can lead to elevated cardiac enzymes. It doesn't have to be from a blockage or arterial spasm that would cause a heart attack (which happens when part of the heart muscle is deprived of blood flow and can die). The heart is a muscle, and whenever it works too hard it releases those enzymes.

What my doc also told me is that it's not momentary swings in heart rate or BP that can stress the heart enough to cause permanent heart muscle damage. One has to have quite a sustained event in order for that to happen.

My cardiologist wants me to have yearly echos done as well as EKG's. My heart is still working just fine in spite of my hyperadrenergic POTS issues, but I take comfort in knowing that I have a knowledgeable doc to help if I start to have distressing symptoms and who can monitor my heart in the meantime.

[lieze]

My feeling right away when seeing the high heart rates was that it was not something I was comfortable ignoring and just pushing on if I was able especially to work a full time job. I feared some type of issue like congestive heart failure due to overworking the heart. If I could control the heart rate by sitting or lying down I thought that was safer long term especially when this started my impression was my case was postviral and had the potential of resolving or improving. If it was a temporary state why damage my heart while my body was going through that stage of the excessive tachycardia. I do think that a couple hours or less a day of the high heart rates might not be as concerning similar to an aerobic workout but maintaining that for long lengths of time didn't sound like something I wanted to

try to do.

Since that time my heart rates have come down for the most part but I have altered my lifestyle dramatically.

This was just my feeling and fear related to the issue and it's hard to say what the real

results would have been.

I questioned if a person was just to push on if the body would adjust and heart rates would come down a bit.

The feelings I had in my chest and the anxiety that accompanied it were too intense for me to handle and I made my decision accordingly.

I'm glad to hear they do have a drug they have found to effectively bring heart rates down and that it is helping people-yeah!

[firewatcher]

I think that this would only be an issue for those of us who have had POTS for a long time. I went 30+ years with no diagnosis and much of that time, I know I had orthostatic tachycardia. The longer my HR has stayed down (thanks to proper meds) the more my labs have normalized, and the better I've felt.

[ramakentesh]

There isnt any evidence that the tachycardia in POTS and in inappropriate sinus tachycardia leads to heart failure. Not all studies suggest that POTS patients have an elevated resting heart rate. Tachycardia and reduced endothelial nitric oxide occur in heart failure and they are believed to worsen prognosis in this condition but that doesnt mean that all people with elevated heart rates experience eventual heart failure.

Id be more concerned about the effects of chronic reductions in stroke volume and perpetually increased sympathetic drive to the cardiovascular system as concerns for long term cardiac health.

[Annaliese]

On a slightly different topic, I saw in some medical lectures that chronic elevation of the renin angiotensin system leads to cardiac fibrosis and hypertrophy and that this is why patients with congestive heart failure are given ACE inhibitors. I was starting to get scared because i have had low flow pots with all the hallmarks of chronically elevated renin-angiotensin. But then i found this : https://iris.Raised blood pressure, not renin-angiotensin systems, causes cardiac fibrosis in TGR m(Ren2)27 rats

Abstract

OBJECTIVES: Elevated systemic arterial blood pressure is associated with left ventricular hypertrophy and fibrosis. It has been suggested that both circulating and local myocardial renin-angiotensin systems play a role in mediating these responses. Here we describe the natural history of ventricular hypertrophy and fibrosis in the transgenic (mRen2)27 rat--a monogenetic model--which has a high tissue expression of the murine renin transgene, and suffers severe hypertension. We further explored the relative contribution of both hypertensive burden and circulating and tissue renin-angiotensin systems to the fibrotic process. METHODS: The transgenic rats were treated from 28 days old with (1) a hypotensive dose of the ACE inhibitor ramipril which inhibited both tissue and circulating ACE activity, (2) the calcium antagonist amlodipine, or (3) a non-hypotensive dose of ramipril which inhibited about 60% of tissue ACE activity with little effect on circulating ACE. Normotensive Sprague-Dawley rats were used as controls. RESULTS: The transgenics developed left ventricular hypertrophy along with perivascular and interstitial fibrosis which became progressively worse up to 24 weeks of age. Both the high dose of ramipril and amlodipine prevented the hypertrophy and fibrosis, whereas tissue ACE inhibition without lowering blood pressure had no effect, and actually led to a worsening of the fibrosis by 24 weeks. CONCLUSIONS: These results suggest that the development of left ventricular hypertrophy and fibrosis in the transgenic (mRen2)27 rat are regulated by blood pressure and not activity of the renin- angiotensin systems and that progression of fibrosis at 24 weeks involves a mechanism unrelated to local renin-angiotensin activity

[issie]

Most of us with Low Flow POTS/HyperPOTS - have high blood pressures and low renin/aldesterone levels. I'm trying to get my doc to test my angiotension II levels to see if it is elevated like the study participants has been. I've taken allot of studies and liturature in to my doc supporting my thinking on this issue. Some of us may be deficient in potassium and that has to do with the function of this system along with low nitric oxide levels (as Rama has pointed out to us in numerous threads). I'm waiting for my doc to read the info - this was something new to him and he wouldn't consider it earlier. But, when I took the info from scientific studies - he is willing to consider the possibility.

I personally do believe that the high blood pressures and the constant tachy has to affect the heart - even though they tell us that there is nothing wrong with our hearts. They keep trying to assure me that my heart won't wear out. But, I'm not convinced of that. Part of my issue is possibly with MCAD issues - there is a good chance that this is affecting my heart with Konius Syndrome. The docs are looking into this also. Got two doc's doing research on these things. I'll post if there is some new info or thoughts that come from my efforts in these areas.

Issie

[Annaliese]

Hi Issie, the reason i think ive had chronic elevation of the renin angiotensin pathway is because ive experienced thirst and anxiety for over a year. When i started florinef the thirst went away. I basically think ive had low blood volume and that my high standing bp has been an overreaction to the low vol issue. I also seem to have histamine issues causing polyurea which i think has perpetuated the low blood vol. Im pretty sure im low flow POTS.

[issie]

I understand why you may think this. From reading how things are supposed to work - you might come to that conclusion. But, for some reason us HyperPOTS people have a paradox (opposite) response in our aldesterone/renin systems and it seems that somehow ours is low. And the angiotension II levels are elevated. Most docs say this is impossible because that's not how the chain of events take place in the conversion process - but ---somewhere along the line something goes out of order and the angiotension II levels elevate - despite the renin and aldesterone levels being low. I know for a fact mine are low - just don't know the levels of the angiotension II levels because I haven't had them checked - YET. I too have low volume and seem to be dehydrated all the time - despite adequate drinking. I'm not able to take the florinef and wonder if that is the best thing since it will lower your bodies aldesterone levels even more and then your body become dependant on the florinef (syntehtic aldesterone) to work. Now if you elevate your aldesterone levels and the angiotension II levels are already too high - would this elevate the angiotension II levels even more - since this is supposed to be the way it happens??????? I don't know - but, it makes you wonder. Maybe our body is lowering these levels for a reason. If you already have high blood pressures and you increase your salt levels and aldesterone levels the blood pressure goes even higher. Could it be our bodies are trying to compensate for an out of balance system?????

Having an emergency room visit - due to what I think was an allergic reaction and my blood pressures going really, really high - the thing that was done for me was nitroglycerin - NO (nitric oxide). My blood pressure came down and the tachy got better - and although I had a killer headache - I got over this really bad spell. So, thinking that NO being too low could be a major factor. Also, having the veins too constricted causing blood pooling because it's not flowing properly and the NO opening the veins up and allowing blood flow. I think that is why Tramadol and Bentyl help me too - it has those same type of properties.

[Annaliese]

Issie, Im glad youve posted if ive got this mixed up! i havent been reading that many articles because i find my eyes cant cope with it. Instead ive been listening to med lectures on youtube and thought i had the renin ang system understood. So with regard to the paradox you are talking about, have they actually measured the renin and aldosterone in hyper pots people and found them to be low and measured the angiotensin II and found it to be high? I started taking florinef because over the last year my standing bp has lowered to the point now that its now too low (could this be due to adrenal burnout? ). The biggest worry for me though is my lying bp. It gets very low and it triggers histamine flushing and then tachy. Im worried im going to have a hypoxic stroke. I see what you mean about taking florinef and then my body learning not to make aldosterone. I have been wondering about that myself. I really want to be on no drugs at all to allow my body to try to sort itself out but at the moment i think its dangerous because of the potential stroke issue but alo because im starting to get neuropathy in my legs. I wonder if i would be better off on midodrine. During the day i dont care so much about the low blood pressure because at least i can monitor it, its the nights that are the problem. My legs are always freezing and i dont think much blood is getting down there. How are you at the moment?

[Annaliese]

I should also say ive actually been avoiding reading too many POTS papers because they keep repeating that quote someone said once about people getting POTS through pregnancy having the condition for life. Whenever i read that it makes me cry! I should quit being such a baby.

[Annaliese]

Issie, ignore my last Q, i looked it up. Is it possible the low renin and high angiotensin could be an estrogen dominance problem? See below....

Effects of Estrogen Replacement Therapy on the Renin-Angiotensin System in Postmenopausal Women

Abstract

Background Oral estrogen replacement therapy (ERT) is known to stimulate the synthesis of angiotensinogen. The effects of such therapy on renin, ACE, and aldosterone are less clear. This seems noteworthy, however, since further activation of the system could be disadvantageous to postmenopausal women who replace estrogen in the context of heart failure, coronary artery disease, or hypertension.

F

Methods and Results Estrogen status and components of the renin-angiotensin system were examined in a population-based sample of postmenopausal women and age-matched men. Renin was quantified immunoradiometrically, ie, independent of substrate abundance; aldosterone, angiotensinogen, and ACE activity were determined by standard methods. Renin levels were lower in women with ERT (n=107; 12.0±0.7 mU/L) compared with women without ERT (n=223; 16.6±0.9 mU/L; P=.001) or men (n=342, 20.5±1.5 mU/L, P<.0001). In contrast, angiotensinogen was higher in women with ERT (1.36±0.08 mg/L) compared with women without ERT (1.03±0.02 mg/L; P<.0001) or compared with men (0.97±0.01 mg/L; P<.0001). Renin suppression was seen with either oral or transdermal estrogen replacement (-30% and -31%, respectively; both P<.001). In contrast, the increase of angiotensinogen was limited to women taking oral estrogens (+58%, P<.001). Multivariate analysis revealed that these estrogen effects were independent of age, body mass index, blood pressure, and/or antihypertensive medication. Finally, only marginal differences between groups were observed for serum ACE activity and aldosterone.

Conclusions Aside from a well-documented induction of angiotensinogen, ERT is related to a substantial suppression of renin, a phenomenon that might have received little attention because of widely used indirect measurements of the hormone.

[Annaliese]

I just looked up estrogen dominance and i have all those symptoms!

[potsgirl]

What about those with low BP? I was diagnosed with CHF, AF, and cardiomyopathy along with bradycardia about 6 years ago at Mayo Scottsdale. It was about 2 years later, when my heart symptoms were under control that I was diagnosed with dysautonomia. My low BP, which has now gotten lower, is not only causing fainting spells, but violent seizures as well. Mayo says that it is because of the extremely low BP, and I just finished more autonomic testing three days ago. I'll get the results on Monday, along with a new med to try to raise my BP. It's a new one, not Florinef or Midodrine, which I couldn't tolerate. I'll let you know about it when I've tried it (sorry, Issie, I stole your line there.)

[issie]

Annaliese,

That's interesting about the estrogen dominace possiblity. I have/had that - I had a complete hysterectomy due to, amongest other things, endometrosis. This is, they think, caused by an estrogen dominance issue. Since I don't use oral estrogen, but only transdermal estriol - not sure if that could still be one of my issues. But, I suppose it's a possiblity. Progesterone is supposed to help with estrogen dominance - but that increases my POTS issues.

One other thing, wondering about is estrogen is supposed to help increase NO (Nitric oxide) which in a hyperPOTS person could possibly be low. But, I do know that I do better not using even the transdermal form more than once or twice a week. It seems my liver doesn't throw it off properly and it builds up in my body. Doctors from Mayo had wanted me to quite using hormone replacements because of a lesion on my liver that they felt was due to hormone issues. But, at the time, I was hardly ever using estrodiol/estriol. So, I was switched to just the estriol.

If there is an estrogen dominance issue - this could also be the case for males too. The balance could be off for them also. Is our bodies over producing estrogen to up our nitric oxide levels? Maybe, just using the l-arginine would help to balance out that issues too. If our nitric oxide levels come up - would our estrogen levels go down??????? Is there an imbalance in testerone and progesterone or is the imbalance in NO (nitric oxide)?

Issie

[Annaliese]

Thanks for posting Issie- i like the way your brain works. Yes, i googled estrogen and NO and was disappointed to find a postive rather than negative correlation between the two. The reason im thinkng estrogen is because of the autoimmne issues that seem to crop up a lot and also because dys is primarily a girl thing. Loads of dys women i know have had cystic boobs, ovaries and fibroids and have had hysterectomies. My psych also tld me that the breast cancer drug tamoxifen (an anti estrogen compound) has been used or trialed (cant remember what she said) to treat autoimmune disease. I think its tricky to work out if progesterone or estrogen improves or worsen pots. Estrogen we know helps us retain water so it apppears like it helps but perhaps only on that level. Short term Improvement in ortho tolerance with estrogen annoyingling doesnt exclude estrogen excess being the cause of pots in the first place. Why did pregnancy set off autoimmune processes in me? What happens in pregnancy- massive hormonal changes. Ive noticed that EDS woman with the worst symptoms of dys also have the worst cystic boobs and uterine problems. Perhaps EDS is linked to a supersenitivity to a particular hormone or something.... Who knows....my brain hurts! All i know is that the hormone link is very suspicious! Oh, btw, i saw an artcle on progesterone and pots, l will try and ind it again.

[RichGotsPots]

My 2 bits: High HR does not = Heart attack, but it is a form of heart disease just like BP. BP= heart pressure. The heart triggers the pressure that circulates the blood in our bodies. So HR is not a good thing.

On the other hand we all have HR maxs that most of us with POTS have exceeded by just walking. Our maxs are (Males: 214-(0.8*age). Females: 209-(0.7*age). So I'm 33 and my max is 188 (214-(33x.8=26)=188 HR. Most of the time I don't go higher than 160.

If we go above our HR maxs and very often then that could be trouble. High heart rate even above our maxs does not mean automatic heart attack, but its dangerous. Especially for 70+ age group who have tons of heart disease and erosion and are just weaker in general.

Anyway I think this a good medicine because it is very selective to the sinus node that controls pulse and it doesnt affect BP. But you do need to be careful with some of the side-effect, start slow..

[L4UR3N]

Well..... I just had an echo (last one was 2 years ago) and I now have diastolic dysfunction stage II as well as regurgitation of ALL of my valves. Thank you for these articles. I'm only 29! Something has to give....