Advanced systolic heart failure in undiagnosed cardiac amyloidosis

Introduction: Transthyretin (TTR) amyloidosis is a life-threatening disease characterized by extracellular deposition of hepatocyte derived TTR with hereditary and acquired variants. Although there are over 120 genetic mutations in the (TTR) gene, only a few are responsible for hereditary TTR amyloidosis. The most common mutation in African-Americans is Val142Ile substitution, occurring with a frequency of 3.5%. Accumulation of misfolded TTR within the myocardium results in cardiac restriction and dysfunction, most commonly presenting as heart failure with preserved ejection fraction. Delay of diagnosis is associated with elevated cardiac biomarkers, worsening patient outcomes, and an unfavorable prognosis in a potentially treatable and reversible disease. Tafamidis was approved by the FDA in 2019 and prevents progression of disease by stabilizing misfolded protein fibrils. Liver transplant is the definitive therapy in patients diagnosed at a young age. Our case describes a patient who presented with advanced nonischemic systolic heart failure with subsequent diagnosis of hereditary TTR amyloidosis. Case: A 72 year old African-American male with a past medical history of worsening nonischemic heart failure diagnosed 20 years ago status post AICD placement in 2016 presented as a transfer with NYHA III systolic heart failure symptoms. His family reported he was experiencing worsening fatigue, generalized weakness, and exertional dyspnea limiting ambulation without assistance for two weeks prior to presentation. Significant bilateral lower extremity edema was also noted. Family history revealed his father and uncle died of heart failure. At the outside hospital, he required dobutamine for persistent hypotension with systolic blood pressure 70-80s. BNP was 2,443 pg/mL, EKG demonstrated low-voltage tracings and echocardiogram showed decreased right ventricular function with pulmonary artery pressure of 46 mmHg, ventricular wall hypertrophy with biatrial enlargement and an ejection fraction of 25%. Dobutamine was weaned after a normal right heart catheterization with recurrence of hypotension to 60/40s with mean arterial pressures in the 40s and norepinephrine infusion was started and subsequently changed to midodrine 5mg three times daily after achieving hemodynamic stability. Genetic testing was obtained, identifying a valine to isoleucine substitution at position 142 (Val142Ile) in the TTR protein. Goals of care were discussed with family who decided to pursue comfort measures, thus the patient was discharged home. Discussion: TTR cardiac amyloidosis is the hereditary or acquired extracellular deposition of misfolded TTR proteins in the myocardium resulting in restriction and dysfunction, most commonly presenting as heart failure with preserved ejection fraction. The Val142Ile mutation has a frequency of approximately 3.5% in African-Americans and is likely to be underdiagnosed, resulting in an unfavorable prognosis and poor patient outcomes. Subtle clinical and imaging signs include a constellation of ventricular hypertrophy with a low amplitude voltage EKG, biatrial enlargement, heart failure with preserved ejection fraction, and arrhythmias. The most sensitive and specific test for cardiac amyloidosis is 99Tc-pyrophosphate scintigraphy. With advances in genetic testing, it is possible to diagnose hereditary disease early with the potential of reversal with medical therapy and definitive treatment with transplantation. Delay in diagnosis is associated with elevated BNP, troponins, development of systolic heart failure, and fatal arrhythmias. Although most patients present with heart failure with preserved ejection fraction, our patient developed symptoms of advanced systolic heart failure prior to his diagnosis of TTR amyloidosis. As such, cardiac amyloidosis should be considered in patients with worsening heart failure symptoms despite appropriate medical therapy with subtle clinical findings associated with the disease.https://scholarlycommons.henryford.com/merf2020caserpt/1042/thumbnail.jp

SPAK and OSR1 kinases bind and phosphorylate the β2-Adrenergic receptor

SPAK and OSR1 are two cytoplasmic serine/threonine protein kinases that regulate the function of a series of sodium, potassium and chloride co-transporters via phosphorylation. Over recent years, it has emerged that these two kinases may have diverse function beyond the regulation of ion co-transporters. Inspired by this, we explored whether SPAK and OSR1 kinases impact physically and phosphorylate the β2-adrenergic receptor (β2ADR). Herein, we report that the amino acid sequence of the human β2ADR displays a SPAK/OSR1 consensus binding motif and using a series of pulldown and in vitro kinase assays we show that SPAK and OSR1 bind the β2ADR and phosphorylate it in vitro. This work provides a notable example of SPAK and OSR1 kinases binding to a G-protein coupled receptor and taps into the potential of these protein kinases in regulating membrane receptors beyond ion co-transporters

Coronavirus Disease-2019 in Heart Transplant Recipients in Southeastern Michigan: A Case Series

BACKGROUND: Since coronavirus disease 2019 (COVID-19) was first identified in Wuhan, China, in December 2019, the number of cases has risen exponentially. Clinical characteristics and outcomes among patients with orthotopic heart transplant (OHT) with COVID-19 remain poorly described. METHODS: We performed a retrospective case series of patients with OHT with COVID-19 admitted to 1 of 2 hospitals in Southeastern Michigan between March 21 and April 22, 2020. Clinical data were obtained through review of the electronic medical record. Final date of follow-up was May 7, 2020. Demographic, clinical, laboratory, radiologic, treatment, and mortality data were collected and analyzed. RESULTS: We identified 13 patients with OHT admitted with COVID-19. The mean age of patients was 61 ± 12 years, 100% were black males, and symptoms began 6 ± 4 days before admission. The most common symptoms included subjective fever (92%), shortness of breath (85%), and cough (77%). Six patients (46%) required admission to the intensive care unit. Two patients (15%) died during hospitalization. CONCLUSIONS: Black men may be at increased risk for COVID-19 among patients with OHT. Presenting signs and symptoms in this cohort are similar to those in the general population. Elevated inflammatory markers on presentation appear to be associated with more severe illness

EVALUATION OF GUIDELINE DIRECTED MEDICAL THERAPY IN A PHARMACIST-LED HEART FAILURE CLINIC

Background: Guideline directed medical therapy (GDMT) for the treatment of heart failure with reduced ejection fraction (HFrEF) improves morbidity and mortality. According to the CHAMP-HF registry, only 15% of patients with HFrEF achieve target dosing. Published literature reports increased achievement of GDMT by 25-40% through a multidisciplinary approach. However, the pharmacists’ role on the impact of GDMT is not well described. The purpose of this study is to evaluate the impact that the CVD Ambulatory Care Pharmacy Clinic has on achievement of GDMT for patients with HFrEF. Methods: This is the interim analysis of an IRB approved retrospective cohort study. This study compares achievement of GDMT in HFrEF patients managed by the pharmacy clinic versus the control group. GDMT is defined as achievement of target dosing or maximum tolerated doses. Control group represents those not seen by CVD Pharmacy clinic. Inclusion criteria includes adult patients with EF ≤ 45%, hospitalization in the previous 12 months, followed by a cardiologist within the health system, and not on maximum tolerated doses of GDMT. The primary outcome is the number of patients on GDMT 12 months after the initial visit. Secondary outcomes include days from initial visit until GDMT, number of patients on moderate dosing of GDMT and change in EF after GDMT. Patients were enrolled from October 1, 2019 through September 30, 2020. Results: Achievement of GDMT at 12 months was 67.2% (39/58) in the intervention group compared to 16.2% (7/43) in the control (P \u3c0.001). Days to GDMT was a median of 95.5 [57-175.5] days and 143 [64-214] days for the intervention and control group respectively (P = 0.493). In the intervention group, 50% (29/58) of patients achieved moderate dosing at 12 months compared to 11.6% (5/43) in the control group (P\u3c0.001). Patients in the intervention group who had an echo after achieving GDMT had a median increase in EF of 12% [5-20] after GDMT achievement. For all patients who achieved GDMT, 32.6% (15/46) achieved target dosing of medications. Conclusion: The CVD Ambulatory Care Pharmacy Clinic was associated with higher rates of GDMT achievement compared to the control and a shorter time to GDMT achievement

Candidate Selection for Durable Mechanical Circulatory Support

Severe systolic dysfunction combined with symptoms of heart failure has a high rate of morbidity and mortality. Medical management remains the mainstay of therapy but mechanical circulatory support (MCS) is one of the treatment options for end-stage heart failure. The left ventricular assist device (LVAD) is the most common type of device used for durable MCS. There have been significant improvements in the technology, surgical technique, and patient management. There is not a single model that is able to accurately assess risk in these patients due to the variety of variables. It is essential to assess all risk in the decision-making process

Pulmonary Hypertension in Heart Failure with Preserved Ejection Fraction

Heart failure with preserved ejection fraction (HFpEF) is a common medical condition associated with increased morbidity and mortality. Through different mechanisms, including passive left-sided congestion and/or vasculopathy, patients with HFpEF can develop pulmonary hypertension (PH). This association -PH-HFpEF- is linked with worsening symptomatology and long-term outcomes. Although pulmonary vasodilators have been effective in treating patients with a pulmonary vasculopathy, such as pulmonary arterial hypertension (PAH), these results have not been replicated in those with PH-HFpEF. There is an unmet need to develop effective medical therapy for this challenging population. In this article, we focus on understanding the definition, epidemiology, diagnosis, clinical implications, and treatment for PH in the setting of HFpEF