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

Introducing IR to Medical Students Interested in Primary Care Specialties

Introduction: Over the last several years, interventional radiologists have become increasingly recognized as part of a collaborative healthcare team. At the same time, interventional radiology (IR) is a field poorly represented in many medical school curricula. As IR management options are increasingly incorporated into the clinician’s arsenal, representation during medical education is critical. Several studies have demonstrated that interventional radiology interest group (IRIG) presentations and demonstrations increase knowledge and excitement about the specialty amongst medical students. However, current literature investigating the effect of these presentations on students interested in primary care specialties is lacking. Our study demonstrates that presenting cases specifically targeted toward students interested in primary care specialties increases their knowledge about the role of IR in their future practice.Methods: Case presentations were given to students who attended interest group meetings in family medicine, emergency medicine, pediatrics, and internal medicine. Presentations were developed specifically to consist of cases that are relevant to each interest group’s respective field. The majority of students were in their preclinical years and interested in a variety of non-radiology specialties. Surveys were administered prior to the presentation and following the presentation (7 questions each). All questions were answered on a Likert scale of 1-5 (1—disagree and 5—agree). Questions were centered around general knowledge of IR, the role of IR within their field, and the benefits of IR to their future practice. Descriptive statistics were calculated based on these results.Results: Responses from 81 participants to every question suggested an overall increase in the knowledge of the field of IR following the case presentation. The mean value to the question “I understand the role of IR in my specialty of interest” increased from 2.7 to 3.6 after the presentation. Students’ average response to the question, “I understand some IR procedures” increased 1.3 points on the scale.Conclusions: Medical students are generally not exposed to IR as a specialty despite its expanding role in clinical practice. Increasing medical student familiarity with IR is essential to producing physicians with a broad understanding of the management options at their disposal. Targeted case presentations given to pre-clinical and clerkship-level medical students interested in primary care specialties were effective in increasing understanding of the role of IR in their specialty of interest. Student-led presentations using interest groups as a networking platform are an effective method for forming first impressions and exposing future doctors to the applications of interventional radiology in their practice.https://scholarlycommons.henryford.com/merf2019edu/1001/thumbnail.jp

Diltiazem Induced Bullous Leukocytoclastic Vasculitis

Diltiazem is a calcium ion cellular influx inhibitor approved by the U.S. Food and Drug Administration for the management of hypertension and chronic stable angina. Diltiazem is commonly used off label for chronic ventricular rate control in atrial fibrillation. Very few cases of widespread cutaneous vasculitis have been described in association with diltiazem since 1988. We report on a patient developing diffuse petechiae with overlying palpable purpura and tense bullae in both lower extremities, which progressed to the thighs, buttocks, abdomen, and upper extremities 6 days after starting diltiazem for management of atrial fibrillation. Skin biopsy revealed leukocytoclastic vasculitis.https://scholarlycommons.henryford.com/merf2020caserpt/1009/thumbnail.jp

Increasing Diversity in Cardiology: A Fellowship Director\u27s Perspective

Introduction: Under-represented minority (URM) physicians, specifically African American, Asian (Filipino, Hmong, Vietnamese), Native American, Hispanic, and/or Pacific Islander, constitute only about 10% of practicing cardiologists. Although cardiology programs may face challenges recruiting under-represented minority applicants, concerted efforts to increase diversity may increase the likelihood of graduating minority cardiologists. However, there remains uncertainty regarding how best to recruit under-represented minorities and incentivize minority applicants to apply for cardiology fellowship training. As a result, the goal of this study is to survey current cardiology fellowship program directors regarding their views of diversity and recruitment of URMs. Methods: A questionnaire containing items that assess cardiology fellowship program demographics and characteristics, attitudes regarding diversity in cardiology, strategies to increase diversity, and responsibility to increase diversity was developed for submission to cardiology fellowship program directors. The list of cardiology program directors was abstracted from the FREIDA AMA Residency & Fellowship Database. An email containing a link to the electronic survey was submitted to current program directors. Data was collected from September to November 2020. Data was analyzed using standard statistical methods. Results: A total of 58 program directors (PDs) responded from 250 cardiology fellowship programs, constituting a 23.2% response rate. The majority of PDs (n=40, 69%) strongly endorsed the importance of diversity in their fellowship programs. The majority of the PDs (n=38,65.5%) believed that allowing applicants the opportunity to interact with URM cardiology fellows, directly recruiting URM to apply to their fellowship program (n=33,56.9%), and involving current program fellows in informal recruitment of URMs (n=32,55.2%) increased diversity. These strategies were implemented by 58.6% (n=34), 51.7% (n=30), and 63.8% (n=37) of PDs, respectively. Most PDs (n=40,70.2%) agreed that holistic review of applicants played an important role in diversifying the cardiology applicant pool and 75.4% (n=43) implemented this method. However, deemphasizing USMLE scores when reviewing URM applications (n=19,32.8%), expanding the fellowship selection committee to include URM reviewers (n=22,37.9%), and considering more IMG applicants (n=15,25.9%) were supported by fewer PDs. Furthermore, the majority of PDs (n=35, 60.3%) reported actively increasing the number of URM faculty members. Lastly, 66.7% (n=38) and 75.4% (n=43) of respondents indicated that residency and fellowship programs have the most responsibility to increase URM representation in cardiology fellowships respectively, while the ACGME, attending physicians, physician professional organizations, and government have less responsibility. Conclusion: The results of this study underscore the importance of diversity and inclusion in cardiology fellowship programs nationwide according to the views of program directors. Several of the strategies endorsed and implemented to increase URMs may be used to inform cardiology fellowship program directors of which interventions are being used in other programs, which programs are most supported by their peers, and which initiatives may yet need to be implemented. These findings may also be of value to medical students and resident physicians interested in applying to cardiology fellowships. Future research is needed to determine which strategies are most effective to increase URMs in cardiology fellowship programs in the United States

Inhibition of HIF-1 alpha by PX-478 enhances the anti-tumor effect of gemcitabine by inducing immunogenic cell death in pancreatic ductal adenocarcinoma

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SURVIVAL OF PATIENTS WITH RHEUMATIC AND NON-RHEUMATIC MITRAL VALVE STENOSIS AFTER VALVULOPLASTY

Background: Non-rheumatic (NR) mitral stenosis (MS) due to mitral annular calcification (MAC) presents in elderly patients and is difficult to treat due elevated surgical risk. In search for alternative treatments, mitral balloon valvuloplasty (MBV) has been performed in non-rheumatic mitral stenosis but no outcomes have been described in this cohort. Methods: Single center retrospective review of 85 consecutive MBV cases at Henry Ford from 3/2013 to 4/2021. Clinical and procedural outcome variables are reported as median and interquartile ranges (IQR). Kaplan-Meier method was used to estimate survival. Chi-squared and Wilcoxon-signed rank tests were used to compare categorical and continuous variables respectively using 95% confidence intervals for statistical significance. Results: Of 85 MBV cases, 50 and 35 were performed for rheumatic (R) and NR MS respectively. NR patients tended to be older and were more likely to have hypertension, diabetes, coronary artery disease, chronic kidney disease, aortic valve procedures. Rates of ≥moderate-severe mitral regurgitation (MR) (R 18% vs. NR 12% p=0.4) and procedure success (R 57% vs NR 42.9% p=0.2) were similar. Median follow up for the entire cohort was 0.5 yrs [0.1, 2.1]. Survival was significantly better for rheumatic cases (Figure). Conclusion: Survival of NR MS post-valvuloplasty is significantly attenuated as compared to those with R MS. Larger prospective studies are necessary in understanding optimal bridging therapies for patients with MAC

INITIAL EXPERIENCE WITH LITHOTRIPSY FOR MITRAL BALLOON VALVULOPLASTY

Background: Mitral annular calcification (MAC) causes degeneration of the mitral valve function. Since these patients are poor surgical candidates, options are limited to percutaneous solutions. Use of balloon lithotripsy (BL) to augment mitral balloon valvuloplasty (MBV) is a novel technique for treatment of MAC-related mitral stenosis (MS). Methods: Single-center retrospective review of 35 consecutive MBV for MAC cases at Henry Ford from 3/2013 to 4/2021. Outcome variables are reported as median and interquartile ranges (IQR). Chi-squared and Wilcoxon-signed rank tests were used to compare categorical and continuous variables respectively using 95% confidence intervals for statistical significance. Procedural success was defined as a final mitral valve area ≥1.5 cm2 or ≥50% reduction in gradient. Results: Of 35 MBV cases done for MAC, 5 utilized lithotripsy balloons to augment valvuloplasty results (Table). Mean baseline gradients were similar and right ventricular systolic pressures trended higher for BL cases. Cases utilizing lithotripsy were longer and utilized more fluoroscopy time but the final invasive gradient trended lower (non-BL 7mmHg [4, 9] vs. BL 1 mmHg [0,5] p=0.113), therefore, higher rates of procedural success were seen (non-BL 47% vs. BL 80%, p=0.2). Survival analysis was hampered due to loss of follow-up in the BL group. Conclusion: BL appears to augment immediate valvuloplasty results. Further studies regarding the durable impact of balloon lithotripsy on MBV are warranted

Cerenkov Radiation Energy Transfer (CRET) Imaging: A Novel Method for Optical Imaging of PET Isotopes in Biological Systems

Positron emission tomography (PET) allows sensitive, non-invasive analysis of the distribution of radiopharmaceutical tracers labeled with positron (β(+))-emitting radionuclides in small animals and humans. Upon β(+) decay, the initial velocity of high-energy β(+) particles can momentarily exceed the speed of light in tissue, producing Cerenkov radiation that is detectable by optical imaging, but is highly absorbed in living organisms.To improve optical imaging of Cerenkov radiation in biological systems, we demonstrate that Cerenkov radiation from decay of the PET isotopes (64)Cu and (18)F can be spectrally coupled by energy transfer to high Stokes-shift quantum nanoparticles (Qtracker705) to produce highly red-shifted photonic emissions. Efficient energy transfer was not detected with (99m)Tc, a predominantly γ-emitting isotope. Similar to bioluminescence resonance energy transfer (BRET) and fluorescence resonance energy transfer (FRET), herein we define the Cerenkov radiation energy transfer (CRET) ratio as the normalized quotient of light detected within a spectral window centered on the fluorophore emission divided by light detected within a spectral window of the Cerenkov radiation emission to quantify imaging signals. Optical images of solutions containing Qtracker705 nanoparticles and [(18)F]FDG showed CRET ratios in vitro as high as 8.8±1.1, while images of mice with subcutaneous pseudotumors impregnated with Qtracker705 following intravenous injection of [(18)F]FDG showed CRET ratios in vivo as high as 3.5±0.3.Quantitative CRET imaging may afford a variety of novel optical imaging applications and activation strategies for PET radiopharmaceuticals and other isotopes in biomaterials, tissues and live animals

Computed Tomography Imaging of Primary Lung Cancer in Mice Using a Liposomal-Iodinated Contrast Agent

To investigate the utility of a liposomal-iodinated nanoparticle contrast agent and computed tomography (CT) imaging for characterization of primary nodules in genetically engineered mouse models of non-small cell lung cancer.Primary lung cancers with mutations in K-ras alone (Kras(LA1)) or in combination with p53 (LSL-Kras(G12D);p53(FL/FL)) were generated. A liposomal-iodine contrast agent containing 120 mg Iodine/mL was administered systemically at a dose of 16 µl/gm body weight. Longitudinal micro-CT imaging with cardio-respiratory gating was performed pre-contrast and at 0 hr, day 3, and day 7 post-contrast administration. CT-derived nodule sizes were used to assess tumor growth. Signal attenuation was measured in individual nodules to study dynamic enhancement of lung nodules.A good correlation was seen between volume and diameter-based assessment of nodules (R(2)>0.8) for both lung cancer models. The LSL-Kras(G12D);p53(FL/FL) model showed rapid growth as demonstrated by systemically higher volume changes compared to the lung nodules in Kras(LA1) mice (p<0.05). Early phase imaging using the nanoparticle contrast agent enabled visualization of nodule blood supply. Delayed-phase imaging demonstrated significant differential signal enhancement in the lung nodules of LSL-Kras(G12D);p53(FL/FL) mice compared to nodules in Kras(LA1) mice (p<0.05) indicating higher uptake and accumulation of the nanoparticle contrast agent in rapidly growing nodules.The nanoparticle iodinated contrast agent enabled visualization of blood supply to the nodules during the early-phase imaging. Delayed-phase imaging enabled characterization of slow growing and rapidly growing nodules based on signal enhancement. The use of this agent could facilitate early detection and diagnosis of pulmonary lesions as well as have implications on treatment response and monitoring

Human Tumor Cell Proliferation Evaluated Using Manganese-Enhanced MRI

Tumor cell proliferation can depend on calcium entry across the cell membrane. As a first step toward the development of a non-invasive test of the extent of tumor cell proliferation in vivo, we tested the hypothesis that tumor cell uptake of a calcium surrogate, Mn(2+) [measured with manganese-enhanced MRI (MEMRI)], is linked to proliferation rate in vitro.Proliferation rates were determined in vitro in three different human tumor cell lines: C918 and OCM-1 human uveal melanomas and PC-3 prostate carcinoma. Cells growing at different average proliferation rates were exposed to 1 mM MnCl(2) for one hour and then thoroughly washed. MEMRI R(1) values (longitudinal relaxation rates), which have a positive linear relationship with Mn(2+) concentration, were then determined from cell pellets. Cell cycle distributions were determined using propidium iodide staining and flow cytometry. All three lines showed Mn(2+)-induced increases in R(1) compared to cells not exposed to Mn(2+). C918 and PC-3 cells each showed a significant, positive correlation between MEMRI R(1) values and proliferation rate (p≤0.005), while OCM-1 cells showed no significant correlation. Preliminary, general modeling of these positive relationships suggested that pellet R(1) for the PC-3 cells, but not for the C918 cells, could be adequately described by simply accounting for changes in the distribution of the cell cycle-dependent subpopulations in the pellet.These data clearly demonstrate the tumor-cell dependent nature of the relationship between proliferation and calcium influx, and underscore the usefulness of MEMRI as a non-invasive method for investigating this link. MEMRI is applicable to study tumors in vivo, and the present results raise the possibility of evaluating proliferation parameters of some tumor types in vivo using MEMRI