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The CardioNerds Cardiology Case Reports series shines light on the hidden curriculum of medical storytelling. We learn together while discussing fascinating cases in this fun, engaging, and educational format. Each episode ends with an “Expert CardioNerd Perspectives & Review” (E-CPR) for a nuanced teaching from a content expert. We truly believe that hearing about a patient is the singular theme that unifies everyone at every level, from the student to the professor emeritus.

We are teaming up with the ACC FIT Section to use the #CNCR episodes to showcase CV education across the country in the era of virtual recruitment. As part of the recruitment series, each episode features fellows from a given program discussing and teaching about an interesting case as well as sharing what makes their hearts flutter about their fellowship training. The case discussion is followed by both an E-CPR segment and a message from the program director.

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Patient Summary

A man in his early 40s, with a history of type 1 diabetes and prior failed renal and pancreatic transplants currently on iHD, was referred to Johns Hopkins Hospital for dialysis access. A left groin AV loop graft was pursued due to multiple access point failures in the past secondary to severe peripheral artery disease. Pre-op evaluation included risk stratification with RHC which was consistent with WHO Group 2 pulmonary HTN and diffuse atherosclerosis in the RCA on LHC. Intra-op, patient had an episode of significant hypotension after administration of protamine that required phenylephrine and ephedrine. In the PACU, his BPs continued to be low (70s/40s mmHg), requiring admission to the SICU where cardiology was consulted. 

In the SICU, patient had ongoing hypotension despite pressors and fluids. Exam demonstrated a systolic murmur consistent with TR and elevated JVP. Labs were notable for a mild elevation in liver enzymes, elevated troponin, high NT-proBNP and elevated lactate. TTE demonstrated a moderately dilated and hypokinetic RV, elevated RVSP and evidence of pressure/volume overload. CTA abdomen/pelvis demonstrated extensive mesenteric atherosclerosis and signs of gastric ischemia. Patient was treated for RV failure with norepinephrine, inhaled epoprostenol, and CVVHD for volume removal. He became febrile and was treated empirically with broad spectrum antibiotics. Due to concern for the new loop graft causing high output heart failure vs RV failure, it was temporarily occluded for testing and then permanently ligated by vascular surgery with significant improvement in his BPs and RV function on repeat TTE. 

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Case Media

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Episode Schematics & Teaching

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The CardioNerds 5! – 5 major takeaways from the #CNCR case

1. In this case the patient became hypotensive shortly after administration of protamine. What are the risk factors for a protamine reaction and the proposed mechanisms? 

• Protamine is a protein commonly used in cardiovascular procedures to reverse the effects of heparin. Although rare, it can cause severe reactions that have multiple different proposed mechanisms. They include hypotension mediated by histamine release from mast cells and IgE-mediated anaphylaxis. Other proposed mechanisms include acute severe pulmonary hypertension with or without RV failure mediated by complement and thromboxane A₂ and fulminant noncardiogenic pulmonary edema likely through a thromboxane-mediated process. 
• Risk factors for protamine reactions have been difficult to rigorously prove, but might include patients with a true fish allergy (Protamine is produced from the sperm of salmon or similar species), men s/p vasectomy (disruption of blood-testes barrier and sensitization against sperm), insulin dependent diabetic patients taking NPH insulin (protamine is used in NPH), and previous exposure to protamine 

2. Our patient had signs of RV failure clinically and on TTE following AV graft creation. How common is this, what is the mechanism, and when might one consider avoiding fistula or graft creation in a patient with CHF?  

• AV fistulas (AVF) are the preferred chronic iHD access due to reductions in infections, morbidity, and mortality compared to central venous access. However, this data is based on observational studies.  
• Remember, changes in hemodynamics occur in phases following creation of AV hemodialysis access. Acutely, an AVF or prosthetic graft (AVG) decreases systemic vascular resistance (SVR) through a surgical arterial to venous shunt. This acute decrease in SVR leads to increased stroke volume and a decrease in blood pressure. The decrease in SVR activates the sympathetic nervous system and leads to increased HR and combined with the increased SV, an increase in cardiac output. 
• The increased cardiac output leads to increased right sided venous return and sub-acutely can lead to progressively increasing left and right sided filling pressures. Eventually, there can be worsening RV dilation and systolic dysfunction, elevated pulmonary artery pressures, and myocardial remodeling. 
• Retrospective analyses have shown that creation of an AVF/AVG can increase the prevalence of RV dilation and dysfunction by 2-3 fold in patients with ESRD.  The risk of worsening heart failure in patients with pre-existing cardiac disease is generally related to the flow in the AV access. Some small studies have suggested there is increased risk of developing heart failure in patients with an upper-arm AV fistula compared with a forearm fistula 
• Although there are not clear guidelines that dictate when a patient should not receive an AVF/AVG, a permanent dialysis catheter should be considered as an alternative option in patients with pre-existing heart failure or pulmonary hypertension due to increased risk of right heart failure. 

3.  AV vascular access can lead to high output heart failure. What is high output heart failure and what are the major mechanisms?  

• Most CHF occurs in the setting normal or low CO. However, certain conditions can precipitate high output heart failure (HoHF). The underlying pathophysiologic change in HoHF seems to be disproportionately low SVR +/- increased oxygen consumption. The low SVR leads to decreased afterload, increased LV emptying and thus increased stroke volume and cardiac output. Furthermore, this leads to increased cardiac preload. Increased oxygen demand also requires increased cardiac output. 
• The persistently low SVR causes low renal perfusion pressure (renal hypoperfusion) which leads to RAAS activation and volume expansion. Combined with the increased preload, this can lead to heart failure in susceptible individuals. 
• Obesity (the most common etiology), AV fistulas (congenital or acquired), cirrhosis, and Paget’s disease lead to HoHF predominantly due to systemic vasodilation. Lung disease, myeloproliferative disorders, and hyperthyroidism can cause HoHF and have a proportionally larger contribution from increased metabolic demand and therefore increased oxygen consumption. Lower SVR has been associated with higher mortality. 

4. How might someone differentiate high output heart failure from low output heart failure or RV failure?  

• RHC is the gold standard to diagnose high output heart failure. Characteristic features include an elevated CO or CI (CI ≥4 L/min/m²) and a low SVR in the setting of clinical signs of heart failure. In a Mayo Clinic study of patients with CI > 4 L/min/m² with or without signs of heart failure, a CI ≥3.54 L/min/m² estimated by TTE identified HoHF patients with 62% sensitivity and 96% specificity. Furthermore, patients with HoHF frequently demonstrated doppler-estimated RV systolic pressure ≥ 42 mmHg (92% sensitivity and 100% specificity). 

5. After temporary occlusion of his loop graft, our patient had improvement of his blood pressure and a decrease in his HR. What does this indicate and how is it mediated?   

• A rapid rise in BP and decrease in HR after occlusion of an AVF/AVG is called the Nicoladoni-Branham sign and indicates a hemodynamically significant AV fistula that could benefit from ligation in the right clinical context. Similar to the Bezold-Jarisch reflex, this is thought to be mediated by mechano-, baro-, and chemoreceptors in the LV and vasculature. The high output state leads to increased shear stress and elevated nitric oxide (NO) production. When the shunt is occluded, there is a rapid increase in afterload. Consequently, there is a decrease in cardiac output and preload. The rapid increase in afterload is thought to trigger high-pressure baroreceptors causing bradycardia, while the reduction in preload triggers low-pressure baroreceptors causing vasoconstriction. Additionally, rapid reduction in CO could also lead to vigorous contraction of the LV stimulating mechanoreceptors (leading to further reflex bradycardia) and reduction in NO production, leading to less vasodilation. Thus the net result is bradycardia and relative hypertension. 

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References

1. Alkhouli, M., Sandhu, P., Boobes, K., Hatahet, K., Raza, F., & Boobes, Y. (2015). Cardiac complications of arteriovenous fistulas in patients with end-stage renal disease. Nefrología (English Edition), 35(3), 234–245. 
2. Clinical Practice Guidelines for Vascular Access. (2006). American Journal of Kidney Diseases, 48, S176–S247. 
3. Park, K. W. (2004). Protamine and Protamine Reactions. International Anesthesiology Clinics, 42(3), 135–145. 
4. Protamine. (1998). Journal of Allergy and Clinical Immunology, 101(6), S507–S509. 
5. Reddy, Y. N. V., Melenovsky, V., Redfield, M. M., Nishimura, R. A., & Borlaug, B. A. (2016). High-Output Heart Failure: A 15-Year Experience. Journal of the American College of Cardiology, 68(5), 473–482. 
6. Reddy, Y. N. V., Obokata, M., Dean, P. G., Melenovsky, V., Nath, K. A., & Borlaug, B. A. (2017). Long-term cardiovascular changes following creation of arteriovenous fistula in patients with end stage renal disease. European Heart Journal, 38(24), 1913–1923. 
7. Schmidli, J., Widmer, M. K., Basile, C., de Donato, G., Gallieni, M., Gibbons, C. P., Haage, P., Hamilton, G., Hedin, U., Kamper, L., Lazarides, M. K., Lindsey, B., Mestres, G., Pegoraro, M., Roy, J., Setacci, C., Shemesh, D., Tordoir, J. H. M., van Loon, M., … Roca-Tey, R. (2018). Editor’s Choice – Vascular Access: 2018 Clinical Practice Guidelines of the European Society for Vascular Surgery (ESVS). European Journal of Vascular and Endovascular Surgery, 55(6), 757–818. 
8. Velez-Roa, S., Neubauer, J., Wissing, M., Porta, A., Somers, V. K., Unger, P., & van de Borne, P. (2004). Acute arterio-venous fistula occlusion decreases sympathetic activity and improves baroreflex control in kidney transplanted patients. Nephrology Dialysis Transplantation, 19(6), 1606–1612. 
9. Wattanasirichaigoon, S., & Pomposelli, F. B. (1997). Branham’s sign is an exaggerated Bezold-Jarisch reflex of arteriovenous fistula. Journal of Vascular Surgery, 26(1), 171–172. 

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CardioNerds Case Reports: Recruitment Edition Series Production Team

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