Thread by @cardiomet_CE

1) Welcome to Part 1 of a new #accredited #tweetorial in our series of educational programs on #hypertrophic #cardiomyopathy #HCM. Previous programs, still available for 🆓CE/#CME, are at cardiometabolic-ce.com/category/hcm/.
Now you can earn another 1.5hr credit by following ALL of this 🧵!

2) Our expert author is Sergio Kaiser MD PhD FACC FESC 🇧🇷🇮🇱 @pabeda1, cardiologist 🫀, Professor 🎓 of #InternalMedicine, Rio de Janeiro State University. He brings the general cardiologist's perspective to our #HCM discussions. Read and learn!
#FOAMed #CardioTwitter

3) This program is supported by an unrestricted educational grant from Bristol Myers Squibb. Statement of accreditation and faculty disclosures at cardiometabolic-ce.com/disclosures/. Credit for #physicians #nursepractitioners #physicianassociates #nurses #pharmacists from @academiccme.

4a) 1st description of #HCM in modern era was 1958. Dr Donald Teare named its obstructive phenotype “assimetrical septal hypertrophy”.
He discussed 8 young pts; 7 died suddenly. Autopsies showed #septal #hypertrophy, disarray of muscle fibers & clefts between muscle bundles

4b) We now know these to be hallmarks of the more severe forms of obstructive hypertrophic cardiomyopathy #oHCM.
See 🔓ncbi.nlm.nih.gov/pmc/articles/P….

5a) 1964: seminal paper from #EugeneBraunwald et al ➡️ 64 pts w/ "Idiopathic hypertrophic subaortic stenosis" #IHSS, showing the dynamic nature of subaortic obstruction.
Same article documented their initial efforts to perform #septal #myectomy

5b) Their #myectomy ➡️significant symptomatic relief for some patients but by modern standards, the surgical fatality rate was prohibitively high.
See 🔓pubmed.ncbi.nlm.nih.gov/14227306/.

6a) Called #HCM since 1979, then considered a rare inherited 🫀disease w/ almost no tx options & often ☠️⚰️.
Now recognized as a much more common & treatable dz, often compatible with longevity and distributed worldwide.

6b) It affects about one in every 200 or 500 people, although a much smaller proportion ever gets to be clinically diagnosed.
See 🔓pubmed.ncbi.nlm.nih.gov/35086660/

7a) Presently, numerous tx options are available ➡️significant ⤵️in #HCM #morbidity & #mortality. However, as many pts may remain asx for a long time--even a lifetime--a high level of clinical suspicion is required.

7b) Only with accurate dx can appropriate risk strat & ensuing family screening be max'd. #HCM clinical presentation has many nuances & it is paramount to distinguish it from #phenocopies e.g. #Noonan syndrome #Fabry dz #TTR cardiac #amyloidosis & other presentations...

7c) ..assoc'd w/ 🫀 hypertrophy eg arterial #hypertension & characteristic physiologic #hypertrophy of #athlete’s 🫀. Each of these pathologies carries specific tx recs: another imp't reason to pursue correct dx.
See @cardiomet author @IacopoOlivotto et al pubmed.ncbi.nlm.nih.gov/36582184/

8) Before discussing clinical features, dx, & tx, let’s go back to basics: How does 🫀 muscle contract? Let's look specifically at excitation-contraction coupling and how left ventricular #contractile proteins interact in order to generate pumping of 🩸throughout the body.

9) 🫀 muscle work is energy-consuming & is regulated by an active mechanism of Ca ion handling in & out of contractile proteins of the #sarcomere (basic contractile unit of the cadiomyocyte) to cyclically generate force & relaxation. This req's adenosine triphosphate #ATP.

10a) Among ~ 20 #sarcomere proteins, the essentials are the thin filament #actin & the thick filament #myosin. The sarcomere itself consists of roughly 20 proteins. The plasma membrane #sarcolemma bounds each myocyte & invaginates to form a complex tubular network (T tubules)...

10b) ... from where #actionpotential-triggered Ca currents are transmitted to the #sarcoplasmic reticulum & amplified along the myofibrils.

Thin actin filaments are anchored at the Z line & form transient sliding interactions w/ thick myosin filaments.

10c) Actin filaments slide past myosin filaments, so during contraction Z lines & actin filaments converge toward the center of the #sarcomere (M line) and move away from it during relaxation.

Let's look at a microscopic image of the #sarcomere in polarized light:

10d)
👉M Line (center)
👉I Band contains only #actin filaments
👉H zone contains only myosin filaments & is where sliding actin filaments from both sides approach each other
👉A band contains the mass of myosin filaments

10e) #Titin, the largest #protein found in the human body, connects the Z lines & contributes both to the elastic properties of the #sarcomere during relaxation, & to force generation during contraction, when it reexpands like a compressed spring.
From physio-pedia.com/File:Sarcomere…

11a) #Actin filaments are intertwined w/ helical protein #tropomyosin ➡️ major role in coordinating the sliding process. Actin cross-bridging sites to myosin are “hidden” by tropomyosin & can only be exposed when a “gate keeper” – the troponin complex - is activated by Ca ions.

11b) #Myosin heads are projections from the core protein composed of heavy & light chains. The heavy chain has a major domain that interacts with actin and has also a pocket for #ATP binding. Myosin is actually an #ATPase & acts like a propeller.

11c) Energy liberated from ATP hydrolysis ➡️ flexing of the myosin head & the strong binding (power stroke) to the nearest actin site. The power stroke is reversed once the resulting molecule of ADP is released and a new ATP binds to the myosin head pocket, ➡️ relaxation.

12a) Now that we have reviewed some basic features of cardiac muscle contraction, we can discuss more deeply the subject of this #tweetorial. And we begin by asking: What is hypertrophic cardiomyopathy #HCM? Let's make sure you are ready.

12b) What molecule provides fuel to accomplish myocardial contraction?

12c) Mark your best response & tune in here TOMORROW for the next installment of this #tweetorial. You are earning 🆓CE/#CME!
👏 @FudimMarat @BiykemB @AndreasGevaert @SubodhVermaMD @ArgaizR @jpcostabel @NMerke @lynchsantiago @lilianigromaia @alexariasmx20 @luisbeckdasilva

13) Welcome back! We are talking all about #HCM from the general #cardiologyperspective with expert author @pabeda1 🇧🇷🇮🇱 and you are earning LOTS of 🆓CE/#CME by following this 🧵
#CardioTwitter #MedTwitter #MedEd @MedTweetorials @PreMedTweets @4hcm

14) Yesterday's quiz? The correct answer is B: #ATP, which regulates calcium ion handling in & out of contractile proteins of the #sarcomere to cyclically generate force & relaxation.

15a) So, as promised, let's move on to #HCM. What is hypertrophic cardiomyopathy? It is a primary disorder of the #myocardium, mainly characterized by unexplained #LV hypertrophy when no pressure or volume overload or no infiltrative or storage disorders can be deemed causative.

15b) Other features contribute to the phenotypic expression of #HCM
🫀 myocardial fiber disarray
🫀 fibrosis
🫀 apical aneurysm
🫀 microvascular ischemia
🫀 (often) obstruction to LV outflow due to massively hypertrophied LV septum or anterior systolic motion of an elongated MV

15c) Bonus pic: Anterior systolic motion of the mitral valve seen by M-mode echocardiography, leading to left ventricular outflow obstruction. Note the hypertrophied interventricular septum.

16) For a long time #HCM has been seen as #sarcomeric disease caused by an autosomal dominant #mutation of the #myosin filament ➡️hypercontractile state. Below see at least 11 mutations associated with the development of HCM, from pubmed.ncbi.nlm.nih.gov/22874472/:

17a) Alas, the clinical presentation of #HCM does not fit into a simplified vision of a monogenic inheritable disease. There is a wide range of phenotypic expressions w/o detectable mutations & also incomplete penetrance of a pathogenic mutation within the same family cluster.

17b) For example: identical twins with a positive genetic diagnosis of #HCM underwent #echocardiography at the age of 5 years. Septal thickness was normal in both, but five years later, one--& only one--of them developed septal hypertrophy.
See 🔓pubmed.ncbi.nlm.nih.gov/33658374/

17c) Another: Variable phenotypic expression in the offspring of a ♂️w/ #HCM + for #MYBPC3 mutation. 3 of 4 siblings are also carriers. ♂️ B develops massive septal hypertrophy, ♀️ C shows limited hypertrophy, & ♀️ D has normal LV.
🔓 pubmed.ncbi.nlm.nih.gov/31864978/

18a) So #HCM must be dx'd on clinical grounds & imaging, not by genetic tests. Imaging:
👉#echocardiography #CMR or #CT showing max end-diastolic thickness of #LV > 15mm in adults in the absence of an identifiable cause.
👉13-14mm ➡️suspicion for HCM if + FamHx or + genetic tests

18b) In children, the clinical expression of #HCM is much less frequent. Dx requires #LV wall thickness more than two standard deviations greater than the predicted mean (z-score 2, where a z-score is defined as the number of standard deviations from the population mean).

18c) So imaging confirms clinical suspicion. Genetics helpful, but instead of thinking of #HCM purely as a mutation, the interplay among biological, environmental, & social influences will ultimately determine the phenotypic expression of this disease.
🔓 ncbi.nlm.nih.gov/pmc/articles/P…

19) As a general cardiologist, I see #HCM in 3⃣ hemodynamic categories: non-obstructive, obstructive, and latent-obstructive. In latent-obstructive, #LV outflow gradient <30 mmHg at rest but exceeds this threshold on exertion.
🔓 ncbi.nlm.nih.gov/pmc/articles/P…

20a) Clinical evaluation for #HCM may be triggered by ID of + FamHx, symptoms like fatigue, dyspnea on exertion, syncope or pre-syncope, by detecting a murmur, by abnormal #ECG, or w/ #echocardiogram performed for other indications.

20b) Not infrequently, a diagnostic suspicion is raised by the finding, in an otherwise normal person, of deep, inverted symmetrical T waves on the electrocardiogram, mistakenly interpreted as myocardial ischemia
(Figure from ecg-interpretation.blogspot.com/2013/01/ecg-in…)

21a) Once suspicion for #HCM is raised, 2020 @ACCinTouch/ @American_Heart #guidelinesrecommend a comprehensive H&P & complete 3⃣-generation #FamHx. Some clinical features can distinguish #phenocopies from true HCM:
🔓 pubmed.ncbi.nlm.nih.gov/33215931/

21b) Per guidelines, echo at rest & w/ valsalva are usu first imaging. Then Class I recommendation for #CMR if echo is inconclusive, if there is suspicion of alternative dx, or when a decision to proceed to #ICD for sudden death prevention is still uncertain.

21c) A very practical algorithm for assessment & follow-up of patients with suspected #HCM has recently been proposed by Maron et al (🔓 pubmed.ncbi.nlm.nih.gov/35086660/):

22a) It's essential to reassure patients & families that #HCM is treatable & is compatible w/ longevity, but periodic reassessment is req'd ad infinitum. Its evolution is not uniform & there are different pathways it can follow, from no progression at all to significant dis.

22b) Below see guidance for periodic clinical and non-invasive testing in HCM.
Next to that see possible #HCM pathways a pt may follow. Only 10% progress along >1 pathway (🔓 pubmed.ncbi.nlm.nih.gov/25446045/).

22c) #HCM exerts its most significant clinical effect in midlife:
🫀 avg age 1st #ICD to prevent #SCD = 45
🫀 first #mymectomy for #HF = 52
🫀 onset of #AFib = 54,
per 🔓
pubmed.ncbi.nlm.nih.gov/35084989/

22d) Among 1000 consecutive adult pts, mean age 52±17 at dx, followed 9.3±8 y, 4 distinct pathways:
1⃣ ~50% no progression
2⃣ 43% developed #HF from #LVOTO
3⃣ 17% developed atrial fibrillation
4⃣6% experienced sudden death
🔓 pubmed.ncbi.nlm.nih.gov/35084989/

23) Thanks to advances in risk stratification, medical and interventional therapy for #HCM, mortality has sharply ⬇️from 3 – 6% per year in early referral cohorts ➡️ only 0.5% per year in contemporary referral cohorts
🔓pubmed.ncbi.nlm.nih.gov/35084989/

24a) One can never overlook though the possibility of (and pt concern over) sudden cardiac death #SCD with #HCM. We have multiple tools: for example, #CMR w/ late #gadolinium enhancement (#LGE) can predict risk of sudden death (and thus referral to #ICD implant).

24b) When LGE occupies >15% of the LV wall, adverse remodeling ensues and the risk of sudden death increases two-fold. See 🔓pubmed.ncbi.nlm.nih.gov/25092278/

24c) Even w/o #CMR, pts at risk of #SCD can be ID'd w/ clinical & echocardiographic variables. See validated ACC/AHA algorithm at professional.heart.org/en/guidelines-…, with C-statistic 0.81 (95% CI, 0.77-0.85) for discrimination between patients who did or did not experience #SCD.

24d) Here are potential risk factors for sudden death according to ACC/AHA guidelines (🔓 pubmed.ncbi.nlm.nih.gov/33215931/):

25a) So what about tx of #HCM? For many yrs we were limited to very few pharm options for sx control & scant resources to predict/prevent #SCD.
💊Beta-blockers, non-dihydropyridine #CCBs, disopyramide & cautious diuretic use may help sx, but do not modify disease course.

25b) New approaches to tx #LVOTO--surgical #myectomy & alcohol septal #ablation were introduced and addressed many sx, while #SCD episodes were largely ⬇️ after introduction of #ICD’s.

25c) More recently, intro of #myosin inhibitors allows for 1st time a pharmacological approach with disease-modifying potential, though its long term resilience remains to be proven. We will address the data on this in Part 2.

25d) Meanwhile, 2020 ACC/AHA #guidelines for classical pharmacological therapy of patients with #oHCM are summarized here:
🔓 pubmed.ncbi.nlm.nih.gov/33215931/

25e) Regarding those with non-obstructive forms of HCM and preserved ejection fraction, a summary of recommendations for pharmacological therapy is depicted here:
🔓 pubmed.ncbi.nlm.nih.gov/33215931/

25f) Notably, there are no recommendations for pharmacological treatment in asymptomatic patients with proven non-obstructive #HCM.

26a) Re #HeartFailure in #HCM: Data from a large registry of pts #SHARE enrolled 1960-2019 ➡️over 15y, new #LV systolic dysfunction #LVSSD developed 7.5%/y (🔓pubmed.ncbi.nlm.nih.gov/32228044/).

26b) Among those w/ #LVSD, sig predictors of composite all-cause death, cardiac transplantation & #LVAD implantation were
🫀multiple pathogenic/likely pathogenic sarcomeric variants: HR 5.6 [95% CI, 2.3–13.5]
🫀 #Afib: HR 2.6 [1.7–3.5]
🫀 #LVEF < 35% HR 2.0 [1.3–2.8]

26c) Pts w/ pathogenic sarcomeric variants, ⬆️#LV wall thickness, #LV dilation, & borderline low #LVEF (50%–59%) were at higher risk for developing #HCM with #LVSD. Here is the overall incidence of several events reported in the registry:

26d) 1/4 pts dev'd #AFib. Recently, ablation techniques & septal myectomy+/- #Cox_Maze surgery ➡️ 50% ⬇️in recurrent episodes over the short term (pubmed.ncbi.nlm.nih.gov/31727261/).
🫀 BTW, mortality attrib'd to #AF in contemp cohorts of #HCM pts is <1%/y (🔓pubmed.ncbi.nlm.nih.gov/28916640/).

27a) Surgical #myectomy (or alcohol septal ablation in pts at high surg risk) is now assoc'd with high success rates & only 0.5% 30d operative mortality when performed at a center of excellence.
See 🔓pubmed.ncbi.nlm.nih.gov/26361164/.

27b) In such centers, myectomy ➡️survival benefit w/ 99%, 98%, & 95% free from HCM-related mortality at 1, 5, & 10 yrs, respectively. See 🔓pubmed.ncbi.nlm.nih.gov/16053960/. Lower-volume centers don't perform as well: 🔓pubmed.ncbi.nlm.nih.gov/36631204/

28) So what if we could improve #HCM outcomes and treat underlying pathology WITHOUT a need for surgery? That's where the new #myosin inhibitors come in, and that will be the subject of Part 2 of this tweetorial, to follow next week. Meanwhile . . .

29) Which of the following is NOT a #riskfactor for #SCD in a patient with #HCM?
a. unexplained recent syncope
b. recent acute coronary syndrome
c. diffuse and extensive late gadolinium enhancement
d. LV apical aneurysm
Mark your answer!

30) So you don't wish an #ACS on anyone, but in the setting of #HCM, ACS has not been found to ⬆️risk of #SCD. Need a refresher on that? See the table in tweet 24d ⤴️

31) For now, you have earned 0.75h 🆓CE/#CME and you can claim it with a few clicks of the 🖱️at cardiometabolic-ce.com/hcm5a/. I am @pabeda1 and I hope you'll join me next week for Part 2 of this tweetorial!