11/21 HUP Report: Pembrolizumab-Induced Myocarditis

Today we discussed a case that demonstrates an interesting side effect of immunomodulatory chemotherapy. Thank you to Dr. O’Quinn for joining us! The case we discussed today was a young female patient being treated for ovarian cancer with pembrolizumab, who presented with positional chest pain and was found to be in ventricular tachycardia with elevated cardiac enzymes. Her workup included a left heart catheterization that was negative for coronary artery disease, and a CT chest that was negative for pulmonary embolus.

One point that we discussed was the role for contrast to enhance echocardiograms. The use of contrast can be helpful to allow the cardiologists to get a more accurate estimate of LV ejection fraction and assess for presence of regional wall motion abnormalities; in this case the patient had a TTE without contrast that was difficult to interpret, and the addition of contrast provided a study consistent with reduced LV ejection fraction and moderately decreased RV systolic function.

Ultimately this patient’s presentation was thought to be myocarditis secondary to pembrolizumab toxicity. Pembrolizumab is a PD1 inhibitor, and many side effects of this therapy are related to activation of the immune system.

CM1.png

Cardiac side effects of this therapy are relatively rare, but have been reported in case series with presentations similar to our patient. Histologic studies show that pathology involves a lymphocytic infiltrate causing inflammation in cardiac tissue, which can manifest with arrhythmias and heart failure.

The primary treatment for autoimmune side effects of PD1 inhibitors is usually steroids. This patient was treated with corticosteroids and improved initially, but was unable to wean. Next steps in management were discussed with multiple institutions and departments within our own institution, as this is a newly described entity with limited experience. Ultimately, she was given infliximab and did really well!

 

References:

Varracchi et al. Cardiotoxicity of immune checkpoint inhibitors. ESMO Open. 2017 Oct 26;2(4):e000247. doi: 10.1136/esmoopen-2017-000247.

 

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11/15 HUP Report: Infectious Endocarditis

Thank you to Dr. Amorosa for teaching us about advanced management of infectious endocarditis! Today we discussed the case of a young male IV drug user who presented with fever, new cardiac murmur, and evidence of embolic phenomena on his skin exam who was found to have MRSA endocarditis.

When dealing with a case of suspected endocarditis, make sure you get cultures!! This is really important – in the majority of cases cultures will identify an organism and allow for targeted treatment. Ideally, at least two sets of cultures separated in space and time (at least thirty minutes) should be collected. While waiting for this data, if empiric treatment is necessary clinically, consider covering strep, staph (MRSA and MSSA), and enterococcus species.

In cases of MSSA endocarditis, a bacteriocidal agent such as nafcillin or oxacillin is usually recommended; addition of aminoglycoside has not shown clinical benefit and confers the downside of lots of potentially permanent and serious side effects, so their synergistic use has fallen out of favor. In cases of MRSA endocarditis, vancomycin is usually a good first line agent. Coagulase negative staph should be treated like MRSA.

We also discussed surgical interventions in patients with endocarditis. There has been a recent trend toward increased discussion of early surgery (performed before the completion of the initial antibiotic course), especially in cases where the infection has been demonstrated to be causing valvular disease and subsequent heart failure (as in our patient), perivalvular abscess or extension, and other difficult-to-treat situations. Here is some data to support early surgery in cases similar to ours:

  1. This study published in JAMA (full reference below) was a prospective, multicenter study of n= 4166 patients with infective endocarditis. The researchers looked to see which factors were associated with mortality among the patients. Of patients with heart failure symptoms (classified into NYHA classes), those who underwent early surgery had improved in-hospital mortality rates. (Of course, there are confounding factors to consider here).

IE1.png

2. This study from the Journal of Thoracic Cardiovascular Surgery (full reference below) retrospectively reviewed n=212 patients with left-sided native valve infective endocarditis. Early surgery was defined as occurring within 2 weeks of initial diagnosis. They found that in patients who received early surgery, there was statistically significant reduction in IE-related death and major adverse cardiac event (again, there are caveats here too!)

IE2.png

Infectious endocarditis can be difficult to treat. Always get infectious disease colleagues involved! And consider early surgical intervention if clinically indicated. Sadly, this disease is one of the many health hazards that accompanies the opioid epidemic.
References:

Kiefer et al. Association between valvular surgery and mortality among patients with infective endocarditis complicated by heart failure. JAMA 2011; 306(20):2239-2247.

Funakoshi et al. Impact of early surgery in the active phase on long-term outcomes in left-sided native valve endocarditis. J Thorac Cardiovasc Surg 2011;142:836-42.

 

 

11/1 VA Report: SVT and Valsalva – A REVERT Review

At today’s report Dr. Dixit took us through the complicated world of SVT’s and how to better incorporate our understanding of the electrophysiology into the assessment of each patient.

The VA team discussed initial maneuvers to break an SVT including carotid massage and Valsalva which lead us to the REVERT trial summarized below (3).

Major Points:

Valsalva maneuver is a safe first line treatment in ED’s for SVT with roughly the same efficacy between Valsalva and carotid massage (2). Cardioversion is rarely successful in clinical practice (5-20%) (1-2) and patients who remain in an SVT are usually treated with adenosine which is associated with substantial side effects. The REVERT researchers proposed to compare a modified Valsalva (15 second Valsalva + passive leg raise) to a standard Valsalva with a primary outcome of return to sinus rhythm at 1 minute.

Design:

  • Randomized controlled, multicenter parallel group trial
  • N = 433
    • Modified Valsalva (n=216)
    • Standard Valsalva (n=217)
  • Analysis: Intention-to-treat
  • Primary Outcome: Return to sinus rhythm at 1 minute
  • Secondary Outcomes: Use of adenosine, use of any emergency treatment for SVT (including adenosine), the need and reason for admission to the hospital, length of time participants spent in the ED, adverse events.

Population:

  • Inclusion Criteria: >18 yo, presented to ED with SVT (regular, narrow complex tachycardia with QRS duration <0.12s on ECG)
  • Exclusion Criteria: unstable SBP <90mmHg, suspected aflutter requiring adenosine trial, contraindication to Valsalva maneuver (AS, recent MI, glaucoma retinopathy), inability to lay flat or raise legs.

Intervention:

  • Standard Valsalva: pressure of 40 mmHg sustained for 15 seconds by forced expiration measured by manometer while SITTING at 45 degrees + standardized verbal instructions
  • Modified Valsalva: pressure of 40 mmHg sustained for 15 seconds by forced expiration measured by manometer while SITTING at 45 degrees + standardized verbal instructions + THEN laying flat and had their legs lifted by staff member to 45 degrees for 15 seconds

Outcomes:

Screen Shot Valsalva

  • Primary Outcome: 43% of participants in modified Valsalva maneuver group vs. 17% in standard Valsalva group achieved sinus rhythm at 1 minute. The absolute difference was 26.2% therefore 3 patients needed the modified Valsalva maneuver to avoid one case of further treatment.

Bottom Line:

This simple cost-free postural change to a standard Valsalva returns more people to sinus rhythm within 1 minute AND results in a substantial reduction in the number of patients needing other emergency treatments including adenosine.

** To do a Valsalva of about 40 mmHg you can use a 10mL syringe blown to just move the plunger **

References:

  1. Smith G et al. Use of valsalva manoeuvre in the prehospital setting: a review of the literature. Emerg Med J 2009; 26:8-10.
  2. Lim SH et al. Comparison of treatment of supraventricular tachycardia by valsalva manoeuvre and carotid sinus massage. Ann Emerg Med 1998; 31: 30-25.
  3. Appelboam A et al. Postural modification to the standard Valsalva manoeuvre for emergency treatment of supraventricular tachycardias (REVERT): a randomised controlled trial. Lancet 2015; 386: 1747-53.

 

10/30 VA Report: Takotsubo’s vs. ACS

Today we discussed a 78 yo with a history of CAD s/p stenting x4 who presented with dyspnea/SOB in the setting of a recent hospitalization for reported Takotsubo’s Cardiomyopathy at OSH.

From a distance his Takotsubo presentation seemed plausible — he developed sudden onset CP/dyspnea in the setting of his wife’s death on the day of OSH admission. On the deep data dive things got complicated — his LHC at the OSH demonstrated a mid-LAD “thrombus and significant restenosis” and his ventriculogram demonstrated “apical ballooning consistent with stress cardiomyopathy.” They popped in a BMS. Now he’s back in the hospital with worsening SOB/dyspnea and an LVEF still 30% 2 months out from his initial presentation. So what actually qualifies as Takotsubo CM and how can we differentiate it from ACS?

Mayo Clinic diagnostic criteria for Takotsubo Cardiomyopathy:

LV wall motion beyond a single epicardial coronary artery perfusion territory, the absence of obstructive coronary artery disease or angiographic evidence of plaque rupture, the presence of new EKG abnormalities or elevation in troponins in the absence of pheo or myocarditis. (1)

First our team reviewed the data collected and published from the International Takotsubo Registry. The collected data demonstrated that most patients were >50 and about 90% female (1). Even though we THINK about emotional triggers — like in our patient — they actually only make up the trigger for about 1/3 of all Takotsubo patients with physical triggers the most common (36%) and 28.5% without a trigger that is identified! Most patients present with dyspnea (46.9%) and chest pain (75.9%) (1).

Troponin levels were elevated in MOST patients with Takotsubo’s and the mean was about the same as as those with ACS when they were admitted. However, during the course of the admission, Takotsubo’s patient trops only increased 1.8x whereas ACS patients trops increased by a factor of 6! Additionally while ST segment elevation rates were similar in Takotsubo and ACS EKGs, ST segment depression occurred in only 8.3% of Takotsubo patients as compared to 31% of ACS patients (1).

Most patients in the registry had apical ballooning, but as you can see below there are a few varieties of Takotsubo CM and they can look VERY different.

Screen Shot TTE

On reviewing the data for out patient, with a LHC demonstrating thrombus s/p stenting, a troponin peaking at 120, and a persistently reduced EF at 30% — he was recategorized as ICM. So why did it seem like this was a triggered event? Are MI’s triggered by the death of a spouse?

Two recent meta-analyses estimate an increase in the first 6 months after the death of a spouse — some up to a 41% increase (2). With regard to cardiac events, a recent cohort study in JAMA studied approximately 30,000 individuals aged 60-89 who experienced partner death with matched controls who did not experience a death.

Screen Shot Bereaved

Within 30 days of the partner’s death 0.16% of the bereaved group experienced MI or CVA as compared to 0.08% in the control group [IRR 2.20 95% CI 1.52-3.15] (3). This increased risk seemed to attenuate after 30 days (3). Of note, these MI’s did not have to be verified by LHC and so likely a subset of these patients have been lumped in to MI but were really Takotsubo’s CM — this in no way should take away from the fact that acute grief is associated with a short-term increased risk of CV events and may explain why our patient had what seemed to be a “triggered” MI.

References:

  1. Templin C et al. Clinical Features and Outcomes of Takotsubo (Stress) Cardiomyopathy. N Engl J Med 2015;373:929-38. PMID 26332547
  2. Moon JR et al. Widowhood and mortality: a meta-analysis. PLos One. 2011;6(8):e23465. doi: 10.1371
  3. Carey IM et al. Increased Risk of Acute Cardiovascular Events After Partner Bereavement: A Matched Cohort Study. JAMA Intern Med. 2014;174(4):598-605. PMID: 24566983

 

 

9/11 PPMC report: PD-1 inhibitors, myocarditis

Thanks to Kari Torp for presenting a cool case of a middle aged woman with lung cancer who developed ventricular tachycardia after receiving pembrolizumab for NSCLC and was found to have pembrolizumab-mediated myocarditis.

Pearls

PD1 (programmed death-1) and CTLA4 inhibitors are relatively novel drugs used to treat a growing list of cancers (NSCLC, melanoma, Hodgkin’s lymphoma, head/neck cancers and others) under the umbrella of immune therapy.

These drugs basically unleash the immune system to fight cancers by blocking certain costimulatory molecules that would have kept T-cells quiet.

Screen Shot 2017-09-11 at 11.48.17 AM.png

Journal of Clinical Oncology

  • Most common side effects of immune therapy (PD1 or CTLA4)
    • fatigue
    • rash (30-40%), 3-4 weeks into treatment
    • colitis/diarrhea (~5-20%, esp CTLA4 agents), 6 weeks into treatment
    • pneumonitis (~5%), 3-4 months into treatment
    • Other: hepatitis, endocrinopathies, neurotoxicity (rare; transverse myelitis, MG), uveitis, and rarely myocarditis (<0.5%)
  • Myocarditis (and/or myositis) is more common with combined PD1 blockade (ex: nivolumab + ipilimumab)
  • Myocarditis should be treated with high dose steroids (1mg/kg), but may progress despite that even in the absence of underlying cardiac disease

We also touched briefly on the differential for elevated cardiac biomarkers in the absence of ACS and the differences between troponin I and T. See this old blog post for more info!

Finally- see reference #3 below for a review on myocarditis.

References

  1. Fulminant Myocarditis with Combination Immune Checkpoint Blockade. NEJM 2016.

  2. Immune Checkpoint Blockade in Cancer Therapy. Journal of Clinical Oncology 2015.
  3. Myocarditis. Lancet 2011.

 

9/5 HUP intern report: elevated troponins, myopericarditis

Thanks to Rachel Snyder for presenting the case of a young man with chest pain after a recent viral prodrome, who is thought to have a (likely viral) myopericarditis.

We talked about where troponins come from:

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Harrison’s Principles of Internal Medicine: STEMI

We talked about the kinetics of cardiac biomarkers.

Screen Shot 2017-09-07 at 11.56.25 AM.png

Harrison’s Principles of Internal Medicine: STEMI

PEARLS

  • Remember that the diagnosis of ACS depends on the right clinical setting, with appropriate EKG changes, and a rise and fall in troponin with at least one value above the 99th percentile
  • Note that CKMB rises within 4-6h of myocardial necrosis, but is far less sensitive and specific than troponin; it is no longer recommended in most situations, except possibly to diagnose reinfarction. It is released from both myocardial and skeletal muscle
  • Troponin is most sensitive because there’s more of it per gram of myocardium; it also rises within 4-6h and can stay elevated for 7-10 days after injury
  • An increase in troponin of >20% after a recent infarct suggests reinfarction
  • A quick note on Troponin I (TnI) vs T (TnT)
    • At Penn, TnI is used as a point-of-care (POC) test
    • TnT is renally cleared (so is TnI, but less so than TnI), so patients with ESRD may have low grade elevations which may add to the challenge of diagnosing ACS

Remember that many things other than ACS can cause troponin elevation

 

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Daubert et al 2010

Lastly- don’t forget the importance of the physical exam in ruling out tamponade, so make sure you do a pulsus if you’re worried about it! Here’s how to do it.

References

  1. Daubert et al. The utility of troponin measurement to detect myocardial infarction: review of the current findings. Vasc Health Risk Manag 2010.

9/6 (HUP): A Case of Longstanding Refractory Atrial Tachyarrhythmias with New Onset VT

We discussed a case of a middle-aged female with a strong family history of uncertain cardiomyopathy who had a personal history of atrial tachyarrhythmias since teenage years, presenting with monomorphic VT.

We reviewed a differential of arrhythmogenic myocardial diseases:

  • Arrhythmogenic Right Ventricular Cardiomyopathy
    • ventricular arrhythmias predominate
    • pathology involves fibrous/fibro-fatty changes in ventricular tissue
    • workup includes EKG (prolonged S wave upstroke, epsilon wave between QRS and T, inverted T in right precordial leads), TTE (increased RV dimensions, decreased RV systolic function, RV trabecular derangement), ambulatory EKG (PVCs), cardiac MRI (dyssynchronous RV with global dysfunction)
  • Cardiac Sarcoidosis
    • manifestations depend on location of granuloma formation
    • common presentations are conduction abnormalities (AV block, bundle branch blocks), tachyarrhythmias
    • workup includes EKG, TTE (LV base and interventricular septum commonly affected, ventricular aneurysms, LV dilation), cardiac MRI, PET, endomyocardial biopsy
      • cardiac MRI: early gad-enhancement indicates acute inflammation, late gad-enhancement indicates chronic inflammation/scar; high sensitivity and specificity for cardiac sarcoidosis
      • PET: indicates active disease
      • biopsy: low sensitivity, in part due to patchy involvement and difficulty accessing LV/septal base which are commonly involved
  • Amyloidosis
  • Myocarditis
    • infectious: very long list of possible suspects, commonly coxsackie or parvovirus
    • medication-induced: direct cardiotoxicity from meds or hypersensitivity reaction
    • hypereosinophilic syndromes
    • autoimmune: lupus myocarditis can present with symptoms similar to ACS
    • Giant Cell Myocarditis: can cause acute and fulminant disease
    • cardiotoxins: EtOH, cocaine, certain meds

If none of the above fit, as in our patient with a strong family history of cardiomyopathy, both atrial and ventricular tachyarrhythmias, chronic disease and lack of response to steroids…think about glycogen storage diseases! This patient ended up getting diagnosed with Danon Disease, which is an x-linked glycogen storage disease that causes severe cardiomyopathy with milder peripheral myopathy, and sometime ophthalmologic and intellectual deficits. Pathology demonstrates intracellular vacuoles and glycogen deposits.

Reference:

Danon Disease as an Underrecognized Cause of Hypertrophic Cardiomyopathy in Children
Zhao Yang, Colin J. McMahon, Liana R. Smith, Jeathrina Bersola, Adekunle M. Adesina, John P. Breinholt, Debra L. Kearney, William J. Dreyer, Susan W. Denfield, Jack F. Price, Michelle Grenier, Naomi J. Kertesz, Sarah K. Clunie, Susan D. Fernbach, James F. Southern, Stuart Berger, Jeffrey A. Towbin, Karla R. Bowles and Neil E. Bowles