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Archive for November, 2023

Many times , an Innocuous question poses a real challenge, to our life time understanding of circulatory physiology.

This question is very important , if we want to understand the true mechanism of postural hypotension, a commonest autonomic disorder in elderly (& also the newly recognised entity orthostatic hypertension)

Mechanism

Orthostatic hypotension is defined as a sustained drop of at least 20 mm Hg in systolic blood pressure (SBP) or 10 mm Hg in diastolic blood pressure (DBP) within 3-5 minutes of going from a supine to a standing position. In patients with associated supine hypertension, the criteria for orthostatic hypotension allows for a drop of at least 30 mm Hg in SBP or 15 mm Hg in DBP.

Can you discuss the answer to the question please ?

The correct answer is likely to be this. In normal adult, the systolic BP falls and diastolic BP is either static or raises by few mm . DBP is never expected to fall on standing, as the fall in systolic BP is invariable, that trigger a vasoconstriction which will increase the PVR and make sure the DBP doesn’t fall. In the process mean BP is kept near normal and regulated.

However, hemodynamic response to standing has no fixed rules. That’s why we keep definitions, like acceptable fall in systolic and diastolic BP . It depends on , age , central and peripheral neurological nervous system, preconditioning of vascular tone.(Not only arteriolar, even the much neglected venous tone).

For the seekers of evidence, there is one study which was specifically done to find orthostatic BP response .(Smith et al Ref 3) .It highlights the point, the immediate vascular response ie (<30sec) is totally different from prolonged standing, Implying, the response time of even an intact autonomic nervous system can be quiet variable.

Orthostatic hypertension :

It is relatively new entity, and claimed to be equally a problem A proposed consensus definition of “an exaggerated orthostatic pressor response” in subjects in whom systolic blood pressure increases ≥20 mmHg when going from the supine to standing posture. (Jordan J, Consensus statement on the definition of orthostatic hypertension endorsed by the American Autonomic Society and the Japanese Society of Hypertension. Clin Auton Res. 2023 Feb;33(1):69-73. ) Surprisingly, diastolic BP is not included in the defining criteria. There must be valid reason for that I guess.

Secret link between both these entities

Obviously it will add on to the complexity, if we say there are common roots in pathogenesis between the two entities. It is indeed true. Both comes under the basket of dysregulated autonomic nervous system. Please recall , we have a condition called supine hypertension and standing hypotension , POTS syndrome etc that should stimulate us to search for those hidden secrets.

As the name itself suggest, autonomic nervous system has its own control(or no control ) with a complex and poorly understood brainstem and cortical network. This operates through physical wiring directly as cranial nerves or piggy packing along the spinal cord tracts , vascular tree, and somatic nerves. The biochemical orchestra of this system is played by a delicate balance of adrenergic vs cholinergic forces.

Next question

What happens to BP during exercise ?

This again has more dynamic and interesting changes especially in the diastolic BP .Read Guyton’s physiology or the good old Rushmer’s hemodynamics monograph, linked in this site elsewhere.

Reference

1.Wahba A, Shibao CA, Muldowney JAS, Peltier A, Habermann R, Biaggioni I. Management of Orthostatic Hypotension in the Hospitalized Patient: A Narrative Review. Am J Med. 2022 Jan;135(1):24-31. doi: 10.1016/j.amjmed.2021.07.030. Epub 2021 Aug 18. PMID: 34416163; PMCID: PMC8688312.

2.Jordan J, Ricci F, Hoffmann F, Hamrefors V, Fedorowski A. Orthostatic Hypertension: Critical Appraisal of an Overlooked Condition. Hypertension. 2020 May;75(5):1151-1158. doi: 10.1161/HYPERTENSIONAHA.120.14340. Epub 2020 Mar 30. PMID: 32223382.

3.Smith JJ, Porth CM, Erickson M. Hemodynamic response to the upright posture. J Clin Pharmacol. 1994 May;34(5):375-86. doi: 10.1002/j.1552-4604.1994.tb04977.x. PMID: 8089249.

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“Yes, it is true. It is tough to consider oxygen as a “powerful and magical drug”, because it is freely available everywhere.”

Routine nasal Oxygen has little use in the management of STEMI. In fact, it can be harmful as it causes vasoconstriction. Hence current guidelines, has very strict advice about not giving oxygen unless systemic tissue hypoxia is documented.

Now, how about infusing Liquid oxygen right inside the LAD , the target zone , that is hit by hypoxia.?

This is not a new concept. G.W. Stone et al. tried this in 2009 itself.(Ref 1) For some reason, this was not followed up. How did we ignore basic fact myocyte hypoxia require Oxygen at that level. We were concentrating to reperfusing with blood, but what the cell need is not blood b but oxygen. Now,14 years later, some young researchers reaching out to this concept ,via liquid myocardial oxygen . Hope to be a possible breakthrough success .it was presented at the 2023 SCAI meeting in Phoenix. In this study, a 60-minute intracoronary infusion of liquid oxygen after pPCI reduced the infarct size and arrhymic risk .This study was sponsored by ZOLL® TherOx® .

A possible deterrent is the problematic and complex concept of reperfusion Injury. The term Oxygen radicals always sounds sinister .Really I can’t understand how a cell which get injured by the lack of a a particuar gas, get damaged by the same gas .(Oxygen in liquid from might behave differently as in this study ?) I think,its all in timing of delivery of oxygen, and if we start thinking like Einstein, then ,there is nothing called time.

Final message

Innovation and experimentation is must be allowed as liberally as possible. Breakthroughs happen accidentally at any time. Systemic oxygen may be harmful, but localised delivery of O2, might exactly be the thing, the dying tissues are waiting for. Sometimes we Ignore a good concept for no reason. Bias against drug companies also can be counterproductive.

Reference

1.Stone GW, Martin JL, de Boer MJ, Margheri M, Bramucci E, Blankenship JC, Metzger DC, Gibbons RJ, Lindsay BS, Weiner BH, Lansky AJ, Krucoff MW, Fahy M, Boscardin WJ; AMIHOT-II Trial Investigators. Effect of supersaturated oxygen delivery on infarct size after percutaneous coronary intervention in acute myocardial infarction. Circ Cardiovasc Interv. 2009 Oct;2(5):366-75.

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Now, you can view who all are reading this site live on a revolving globe. It makes all the more happier to note that all these grateful and honourable dots (i.e., you) are literally drawing the world map . Six million reads from 190 countries, right from the Solomon Islands in Micronesian Pacific, abutting the International date line, to the extreme west, reaching Chile and Hawaii has happened so far.

Please click here, to see your live location , zoom on the dot and check, it is indeed true.
https://www.revolvermaps.com/livestats/globe/53mvtnd7p2d/

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News: A rare large scale study from ICMR is making news even in the mainstream media. (https://indianexpress.com/article/health-wellness/covid-19-vaccines-sudden-deaths-risk-icmr-study-9036761/)

A casual read of the original paper threw up some thoughts.

India’s apex medical body, ICMR, initiated a study primarily on sudden deaths among young people in covid times . The primary intention of this study was to find what causes sudden unexplained deaths . and also test the hypothesis that the deaths were not probably related to covid vaccination. The study did prove that. (I am not an expert to assess the statistical validity and scrutiny of the study. It is too complex a model. Still, I do have a primitive query as shown in the title )

But, we expected a minimum revelation. What caused these 729 deaths (filtered out of 29000 deaths) I understand physical autopsy could not be done in majority of deaths (Even in witnessed , in hospital deaths). So, the question remains . Is it sudden cardiac death ? Is it sudden “non cardiac ” death ? or can it be a “non sudden” masquerading as sudden in any way.

.A preformed hypothesis

Though this is not a hypothesis-proving study, it is apparent that the intention of the study primarily revolves around removing the stigma and fear associated with vaccination. (The fact that only a fraction of patients, (less than 2%,) were hospitalized for COVID indicates that this study primarily intended to test the risk of COVID vaccination, which was around 85% in both groups.) It makes sense, for the study group , they created a good methodology accordingly and indirectly proved the hypothesis right. As physicians and cardiologists, we wished also look into the data of what caused these deaths by performing autopsies in all possible cases. The results of these autopsies need to be known.

Conclusion is fair

It is traditional (and acceptable ) to blame the heart for all unexplained sudden deaths. The study suggests that heavy drinking, along with with intense physical activity in the background of positive family history, is behind many of the deaths. It is a fair assumption that they are all cardiac. Sudden neurological and pulmonary deaths are under reported. In fact many of the SCD is an arrhythmic event originating from CNS or electro-ionic triggers in blood with the healthy heart

Is this not a major limitation*

When you want to know whether COVID vaccination is related to sudden death in any way ,is not ideal, we need to have a control /cohort arm who have had no vaccination? In this study, both groups had nearly 82-88 % vaccination. In fact, the control group had few percent extra vaccination, and this helped the study, to claim that vaccination prevented some of the sudden deaths. This seems far-fetched with any statistical methodology. This, I feel is a serious limitation. It can even nullify the study conclusion to a large extent. (Experts please clarify , It may be an entirely wrong perception and lack basic knowledge in statistics.)

One more possiblity , can we combine a case-control study with add on accessory cohort and follow up as a dual mode study ?

Final message

It is a landmark attempt to study the mysterious deaths among young Indians in covid & post covid times. Two things .This study can talk about only vaccinated population. Does this study prove, people who have not vaccinated had more or less sudden deaths ? No. this study has no scientific grounds to talk about either positive or negative status of unvaccinated population , because there is no, unvaccinated cohort and follow-up.

At the end of the day, an unexplained death remains unexplained because we couldn’t do autopsy (Of course we have found the same known risk factors responsible , except probably new one vigorous physical activity , )

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ASDs are classically oval, but devices are typically circular.(Exact Incidence of ovoid ASD is not known. but it easily exceed 50 % .(Recall, the embryologically ill-fated hole expands around the fossa ovalis not circularis )

Do we have Oval devices ?

I think, we don’t have one . Please check from this list , a good document on ASD device implantation from Poland

Source : Grygier M, S. Percutaneous closure of atrial septal defect: a consensus document of the joint group of experts from the Association of Cardiovascular Interventions and the Grown-Up Congenital Heart Disease Section of the Polish Cardiac Society. Kardiol Pol. 2020 Oct 23;78(10):1066-1083.

Why do we accept this shape mismatch ? What are the potential issues because of that ?

When closing non-circular ASD, the size of device should be considered according to the multiple diameters of the defect. One diameter of the circular device could be too large for the shortest diameter causing a deformity in residual rims. The cardiac erosion after successful implantation as one of the most important complications due to a larger device in the oval defect compared to the circular defect (This text was taken from (Ref 1)

Why the idea ovoid device was never popular ?

Technical issues in sizing the exact oval defects ,device company’s lack of interest. However, designer devices with perfect fit with the help of 3D printing is very much possible.

Is it true ,an Oval device might hold good even in the setting of deficient IVC or posterior rim ?

May be. Some truth in it. I am not an expert to comment.

Do we really require a perfect fit devices ?

When I discussed with an expert , he said there is no need for oval device . A large circular device 2mm larger than the long axis diameter of the oval orifice is not an issue at all . Some how, find it difficult to accept that. What about you readers ? Please respond if you have any comments.

Any study on this issue ?

Yes. one study specifically looked into this. It compared the effect of circular device on oval defects. It concluded there no difference in any adverse outcome , but oversizing is unavoidable with oval defect.. This study , though addressed a vital query ,is never meant to find the truth we want, as it has no oval vs circular device to compare the outcome.

Final message

It is strange ,cardiologists look for perfection and precision in every cardiac intervention,while in case of ASD device closure, size is sacrosanct, but shapes, we are allowed to shrug off. May be things will change.

Reference

1.Song J, Lee SY, Baek JS, Shim WS, Choi EY. Outcome of transcatheter closure of oval shaped atrial septal defect with amplatzer septal occluder. Yonsei Med J. 2013 Sep;54(5):1104-9.

2.Roberson DA, Cui W, Patel D, Tsang W, Sugeng L, Weinert L, et al. Three-dimensional transesophageal echocardiography of atrial septal defect: a qualitative and quantitative anatomic study. J Am Soc Echocardiogr. 2011;24:600–610. [PubMed] [Google Scholar

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Forget NEJM, Circulation, JACC, for some time. Hope & wish every one of us is aware of a journal called Blood, bringing stunning and dramatic discoveries week after week ,about the most crucial fluid that sustains our life. The journal Blood is published by the American Society of Hematology since 1949. Its impact factor is currently 20.8, celebrating its 75th year of existence .

We know, heart disease consistently tops the global mortality and morbidity charts . Without blood, heart is just a purposeless organ with four empty chambers. More than ninety percent of the cardiac mortality happens due to freezing and interruption of blood flow to the vital organs. Can any one dispute, heart is an Innocent bystander, when ACS happens due to an unscheduled pitched battle between blood and the coronary arterial wall ?

It is no surprise ,cardiologists spend most of their practicing time, fighting blood from freezing and trying to restore the flow. It is hard to believe there is absolutely little interaction between Hematologists and cardiologists dealing with the same organ.

Meanwhile, the drugs we use , pose a constant threat of bleeding elsewhere.As a clinician and cardiologist, anxious queries from our fellows such as this one are not infrequent. Sir, that lady with a prosthetic valve in room 306, is bleeding in gums . Should I stop the OAC ? She is also getting clopidogrel for the recent PCI. What shall we do?

Want answers to such questions ? Need to spend time guys. In an excellent review article, the prestigious journal talks about tackling bleeding patients and how to counter various drugs that can cause bleeding.

Reversal strategies in a bleeding patient

This table is just a sample from the paper. Thankfully full text is free in its site.

Final message

It seems , there are about 30,000 medical journals listed in Pubmed . Cross-specialty reading for relevant, up-to-date knowledge is always welcome. This will help us come out of the undesirable tag of super specialist or individual organ specialist.

Looking forward to the days when hematologists and cardiologists sit together frequently to discuss the strategies in unexplained ACSs, DVTs, other procoagulant (as well as pro-bleeding conditions)

With more and more metallic foreign bodies ,making heart as their residence, this type of Interactions will become all the more important.

Reference

Piran S, Schulman S. Treatment of bleeding complications in patients on anticoagulant therapy. Blood. 2019 Jan 31;133(5):425-435. doi: 10.1182/blood-2018-06-820746.

Next thought

Trying to go deep into this journal, and find the truth behind Red and white clot , which I never understood right from the medical school days.

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It is still a huge mystery, why the father of medicine stressed more about “not doing bad” than “doing good” .What made him to hold on to, such pessimistic thoughts , 2500 years ago . I am unable to think how he would react to this “tampered version” if he is alive ! My gut feeling is, he will find it hard to object .

Further reading (There is some debate , about the origin of this quote attributable to Hippocrates)

1.Origin and Uses of Primum Non Nocere—Above All, Do No Harm! by Cedric M. Smith

2.Relevance of the Hippocratic Oath in the 21st Century

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Festive Greetings from India

Diwali is celebrated today November 12 th, as “Festival of lights” an Important spiritual event in India, On this day, we pray God, knowledge, goodness, and peace replace Ignorance, evil and turbulence in this world.

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Statins belong to a group of drugs, stolen and reengineered from the blueprint of natural Chinese red yeast rice (Monocoline K) in the late 1980s. The rest is the remarkable history in the pharma industry.

Statins directly interrupt the cholesterol synthesis by blocking HMG-CoA within the hepatocytes. It significantly lowers the LDL, fights human vascular atherosclerosis. It makes the plaque either regress, prevent progress, make it harder and in the process make them less vulnerable . There are innumerable studies that document the evidence. Statin has become a must-prescribe drug in any one with clinically established CAD or even in concealed CAD. Guidelines are available to prescribe statins various intensity, depending on the risk profile.

Which statin ?

There has been a long list of statins. Many of them have retired from the ring .Currently, the fight is between Atorvastatin, a Rosuvastatin. Like Pepsi vs. Coke.

Note the graphic ,A meteoric rise of one drug since 2005 . (Can you guess the reason ?)

ATRORVA or ROSUVA Which one should I choose ?

There is very little “one to one” comparison study between Rosuvastatin and Atorvastatin .The gap in the pros and cons are narrow. Following points are observed, without much dispute.

1.Rosuvaststin is more powerful.

2.Plaque stabilisation effect is not different((Satrun, study NEJM 2011 based on IVUS)

3.New onset diabetic risk is more likely with Rosuvastatin

4.Worsening of cataract is also more with Rosuvastatin

5.Atrovastatin has some additional benefits in lowering triglycerides. (Bakker-Arkema RG, JAMA. 1996)

No one is dare enough to give strong verdict . Surprised to find one this month. BMJ has come out with a possible answer. It is called LODESTAR trial (Ref 1)

Mechanism of new onset diabetes with statins (REF 3)

It can be 7% with Rosuvastatin (less with Atorvastatin). We think, statins act primarily within the hepatocytes where cholesterol synthesis takes place, but they also have an eye on the pancreatic β-cells as well. It down-regulates GLUT-4 in adipocytes, and results in compromised insulin signalling. Furthermore, statins’ impact on epigenetics may also contribute to statin-induced T2DM via differential expression of microRNAs.

Mechanism of cataract with statins (Ref 2)

The cells lining that line the lens are dynamic and require cholesterol on a day-to-day basis. Statins inhibit proper epithelial cell development within the crystalline lens, where cholesterol biosynthesis is critical to maintain transparency and structure of the lens.

Final message

So, is it Atorvastatin or Rosuvastatin? It is left to you.

Mind you, “no statin at all” is the best option if circumstances and risk profile allows. Statins are never considered life-saving staple drugs in our fight with CAD and atherosclerosis. We, along with our scientists might may make you feel like that. Lipids can be controlled within desirable means exclusively with diet and exercise in most of the population* .

(*Forget about statins in the last 5000 years of known human existence, so many great people have lived a long and successful life in this world, without even knowing there is an organ called the heart that is responsible for the circulatory system)

Reference

1.Lee YJ, Hong SJ, Kang WC, Hong BK, Lee JY, Lee JB, Cho HJ, Yoon J, Lee SJ, Ahn CM, Kim JS, Kim BK, Ko YG, Choi D, Jang Y, Hong MK; LODESTAR investigators. Rosuvastatin versus atorvastatin treatment in adults with coronary artery disease: secondary analysis of the randomised LODESTAR trial. BMJ. 2023 Oct 18;383:e075837. doi: 10.1136/bmj-2023-075837. PMID: 37852649; PMCID: PMC10583134.

2.Leuschen J, et al Association of statin use with cataracts: a propensity score-matched analysis. JAMA Ophthalmol. 2013 Nov;131(11):1427-34.)

3.Carmena R, Betteridge DJ. Diabetogenic Action of Statins: Mechanisms. Curr Atheroscler Rep. 2019 Apr 30;21(6):23. doi: 10.1007/s11883-019-0780-z. PMID: 31037345.

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This a story from a middle aged IT professional who had recently suffered from a cardiac event. His concern is, he has an ejection fraction (EF) of 45%, finds difficult to walk to the nearby mall ,while his neighbour, also a heart patient, has only 32% EF , but goes for cycling and hiking ! He finds this very odd and totally unacceptable. .He desperately needed an answer from his cardiologist.


How is this possible, doctor? I am sort of depressed for two reasons. You are saying, I had only a mild heart attack and recovered well with no significant blocks in the angiogram, but, I still find it difficult to do routine activities. The latest EF is recorded as 45%. I am taking all your medications sincerely.

“Doctor, I feel awkward, but I can’t stop asking this question to you. More than my heart condition, it is my neighbour’s one that is bothering me. He was critically ill sometime back. Has undergone a bypass, after two early stent failures, I am seeing him daily now. So active he is, able to hike even the hill in our county. He told me his EF is just 32%. It sounds atrocious. What is the use of having more EF than him, doctor ? Do you think I need to be referred to any specialized cardiac centre ?”

“My dear patient, relax. If you want a straight-forward answer, “you are suffering from EF neurosis” Exercise capacity and overall well-being of an individual have little to do with the Ejection Fraction (EF) of the heart. Forget that number”.

“Sorry doctor, I am not clear , do you mean to say I have a mental health issue? ”

Ok , let me go little more deeper for the sake of your understanding. Hope you don’t mind. EF% can be sort of the daily weather report. It can change even beat to beat depending upon the loading conditions of the heart. We, the cardiologists are partly responsible for creating this anxiety at your level with this number .The prevailing literature and the confused google , has misled you guys, to believe that EF% is akin to “bank balance” of available heart function. Let me apologize on behalf of all of us.

There are many cardiac and non-cardiac parameters that determine one’s exercise capacity. Lung function is vital. Systemic factors like quality of your Hb%, renal function, lastly, the most important factor, the status of your skeletal muscle structure and function. If I can go technical, the degree of LV size, associated MR, the stress of LV filling, pulmonary vein compliance, the way your lung vasculature reacts, RV function, degree of PH, all that matters.

In your case, each of these parameters is good. So, I can reiterate that your heart is in fairly good condition. It is most likely that your skeletal muscles are hibernating and taking too much rest, and their mitochondria are suffering from disuse. Further, your thinking pattern also makes you easily fatigued. You must also understand dyspnoea is a cortical sensory perception defect. It depends upon the behaviour of your cerebral centres that are localized in the amygdala nuclei.

“Please doctor, I expected a practical solution from you”

“Ok, let me tell you a positive proposal which will definitely help. Trust your heart and believe in my words and the drugs you take. Ignore this EF stuff. Send a friend’s request immediately to your neighbour and join him on his daily hiking. If he can do it, you can also do it. I expect ,both the issues that is causing you depression will vanish soon. One caution, don’t overexert. Stop 10 to 20% short of your maximum possible capacity.”

Thank you doctor , I think you’re right I am not taking enough efforts and lack confidence .Will meet you again with good news “

Final message

Unless, it is extremely low contractile function, EF% has no linear correlation with functional capacity. This is the message to all those heart failure patients. Don’t feel bad if you are labelled as LV dysfunction or ‘Heart failure’. You can steal a success story from with the help of skeletal muscle training and dyspnea sensitization program (This is not a great new discovery, it’s all there in the ancient Indian medicine, it was called pranayama, a controlled regular breathing exercise)

Reference

1.Lv J, Li Y, Shi S, Xu X, Wu H, Zhang B, Song Q. Skeletal muscle mitochondrial remodeling in heart failure: An update on mechanisms and therapeutic opportunities. Biomed Pharmacother. 2022 Nov;155:113833. doi: 10.1016/j.biopha.2022.113833. Epub 2022 Oct 7. PMID: 36271583.

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