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
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...
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?
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…)
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/).
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.
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.
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.
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:
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/.
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!
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1a) Welcome to a new #accredited#tweetorial, “MOA and Clinical Trial Data for Novel & Emerging Therapeutic Strategies for #HCM: Can We Target Our Therapy?"
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1a) Welcome to a new #accredited#tweetorial on the management of aFXa-DOAC-associated #hemorrhage and specifically the role of coag laboratory testing in these challenging cases.
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