Arrhythmogenic cardiomyopathy (ACM) is an inherited heart disease marked by progressive fattyfibro replacement of the ventricular myocardium, life-threatening arrhythmias, and sudden cardiac death. To dissect epicardial contributions to ACM pathogenesis, we generated iPSC lines from patients carrying plakophilin 2 (PKP2) 1849C > T or PKP2 2013delC mutations, their CRISPR/Cas9-corrected isogenic controls, and a PKP2 knockout line. Epicardial cells (hPSC-EPCs) differentiated from mutant and knockout backgrounds exhibit enhanced epithelial-to-mesenchymal transition characteristics, increased lipid accumulation, and a pronounced fibrotic phenotype. RNA-seq performed on ACM hPSC-EPCs reveals dysregulation of Wnt, interferon, and Rho GTPase signaling, including an upregulation of insulin growth factor 2 (IGF2) and a key adipogenic transcription factor, CEBPA. Subsequent treatment of control and PKP2KO hPSC-EPCs with recombinant IGF2 enhances CEBPA expression, suggesting that insulin growth factor signaling contributes to ACM fattyfibro remodeling.

Purpose: To analyze both the allocation of heart transplants in patients based on blood type and whether durable VADs alter said distribution. Methods: Data was gathered from the Organ Procurement & Transplantation Network on blood type, status of patients at time of transplant, and if VAD was present at time of transplant nationally and for Region 5 (R5) in 2021. The percentage of each blood type for all status for all transplants and R5 were calculated, as well as the relative transplantation rates for status 4 VADS. Results: Table one shows the distribution of heart transplants by blood type for all transplants nationally, all transplants in R5, all transplants with status 4 VADs, and R5 with status 4 VADs. R5 had an increase in the percentage of status 4 VADs patients transplanted for blood types A and B and a decrease in the percentage of blood type O in comparison to all transplants that occurred in that area. Nationally all transplants and status 4 VAD patients with O and A blood type were transplanted less than the national blood type distribution. R5 transplanted more O patients overall, but less status 4 VAD patients. The opposite was true for A patients in R5. Both nationally and R5, blood type B was transplanted more frequently than the national blood type distribution. Conclusions: Blood type may matter for patients with durable VADs who are eligible for heart transplantation. VAD patients with certain blood types are more or less likely to receive a transplant than patients without a VAD. Both nationally and in R5, blood type O patients are less frequently transplanted with a VAD than without a VAD. On the other hand VAD patients with blood types A and B tend to have more transplants than patients without a VAD. Given a patient’s clinical status and end-goal of cardiac transplantation, it may be more or less beneficial to have a VAD as a bridge to transplant depending on their blood type.

A 44-year-old female with no medical history presented with 3 days of sudden-onset pleuritic chest pain at rest, exertional dyspnea, and orthopnea. She was tachycardic to 132 bpm with a blood pressure of 96/81 mmHg that was rapidly falling. She was in respiratory distress, tachypneic to 26 breaths/minute and saturating 94% on room air. Physical exam revealed cool skin with lack of peripheral edema or jugular venous distension. She had elevated high-sensitivity troponin (4069 ng/L), N-terminal-pro-brain natriuretic peptide (9871 pg/mL), C-reactive peptide (58.2 mg/L), and lactic acid despite fluid resuscitation (4.0 mmol/L). Genetic, auto-immune, endocrine, and toxic workup returned negative. Workup supported cardiogenic shock from myocarditis. Transthoracic echocardiography demonstrated a left ventricular ejection fraction of 15%. Right and left heart catheterization revealed markedly elevated right and left-sided filling pressures with a depressed cardiac index (1.1 L/min/m2) and cardiac output (2.4 L/min). The patient underwent veno-arterial extracorporeal membrane oxygenation and intra-aortic balloon pump placement with hemodynamic improvement. With intravenous methylprednisolone, the left ventricular ejection fraction improved to 35%; however, blood cultures revealed Staphylococcus epidermidis warranting glucocorticoid discontinuation. Urine drug screen returned cocaine-positive. The patient and family adamantly denied drug use but a couple days prior to presentation she had a dental procedure using local anesthesia in another country. The patient's course was complicated by multiple episodes of sustained ventricular tachycardia. Given the unclear pathogenesis of myocarditis and prolonged mechanical circulatory support requirements, endomyocardial biopsy was pursued, demonstrating marked interstitial inflammatory infiltrates with extensive myocyte damage and interstitial fibrosis (Figure A), most consistent with lymphocytic myocarditis. After negative repeat blood cultures, methylprednisolone 125 mg was reinitiated. Starting with 40 mg twice daily, a slow prednisone taper continued for months into the outpatient course. Azathioprine 100 mg daily was added to alleviate glucocorticoid requirements. On hospital day 14, extracorporeal membrane oxygenation decannulation and balloon pump removal were successful. Subsequent cardiac magnetic resonance imaging demonstrated a left ventricular ejection fraction of 63%, no late gadolinium enhancement, and mildly elevated T1 and T2 values indicating mild diffuse myocardial edema and inflammation (Figures B and C). On hospital day 29, the patient was discharged to a rehabilitation facility on guideline-directed heart failure therapy, prednisone taper, and azathioprine. Azathioprine was ultimately discontinued due to bone marrow suppression leading to severe anemia (hemoglobin of 3.0 g/dL). Six months later, the steroid taper is complete without recurrent arrhythmias and a return to baseline physical function. This case highlights the role of endomyocardial biopsy in guiding therapy when the pathogenesis of myocarditis remains nebulous. It also demonstrates the benefits of glucocorticoids and adjunctive immunosuppressive therapy in acute, fulminant lymphocytic myocarditis. Although endomyocardial biopsy is the gold standard for the diagnosis of myocarditis, it is invasive and not consistently practical1Basso C Myocarditis.New Engl J Med. 2022; 16: 1488-1500Crossref Scopus (40) Google Scholar with complication rates on veno-arterial extracorporeal membrane oxygenation of 26.1%.2van der Boon RMA den Dekker WK Meuwese CL et al.Safety of endomyocardial biopsy in new-onset acute heart failure requiring veno-arterial extracorporeal membrane oxygenation.Circ Heart Fail. 2021; 14e008387Crossref PubMed Scopus (9) Google Scholar This risk is counterbalanced with a histopathologic diagnosis rate of 78.3%.2van der Boon RMA den Dekker WK Meuwese CL et al.Safety of endomyocardial biopsy in new-onset acute heart failure requiring veno-arterial extracorporeal membrane oxygenation.Circ Heart Fail. 2021; 14e008387Crossref PubMed Scopus (9) Google Scholar In this case, endomyocardial biopsy yielded the diagnosis of fulminant lymphocytic myocarditis clinically mimicking giant-cell myocarditis. Giant-cell myocarditis typically manifests as severe left ventricular dysfunction, cardiogenic shock, and refractory ventricular arrhythmias, whereas lymphocytic myocarditis has a more benign course. Often, lymphocytic myocarditis resolves spontaneously or with guideline-directed medical therapy for heart failure, but the benefit of immunosuppressive therapy remains unclear.1Basso C Myocarditis.New Engl J Med. 2022; 16: 1488-1500Crossref Scopus (40) Google Scholar In chronic non-viral myocarditis, prednisone and azathioprine may improve left ventricular ejection fraction.1Basso C Myocarditis.New Engl J Med. 2022; 16: 1488-1500Crossref Scopus (40) Google Scholar This patient received immunosuppression due to difficulty weaning extracorporeal membrane oxygenation, refractory ventricular tachycardia warranting treatment of the underlying cause, and prior clinical response to glucocorticoids—with rapid clinical response.

Aortic valve disorders are important considerations in advanced heart failure patients being evaluated for left ventricular assist devices (LVAD) and those on LVAD support. Aortic insufficiency (AI) can be present prior to LVAD implantation or develop de novo during LVAD support. It is usually a progressive disorder and can lead to impaired LVAD effectiveness and heart failure symptoms. Severe AI is associated with worsening hemodynamics, increased hospitalizations, and decreased survival in LVAD patients. Diagnosis is made with echocardiographic, device assessment, and/or catheterization studies. Standard echocardiographic criteria for AI are insufficient for accurate diagnosis of AI severity. Management of pre-existing AI includes aortic repair or replacement at the time of LVAD implant. Management of de novo AI on LVAD support is challenging with increased risks of repeat surgical intervention, and percutaneous techniques including transcatheter aortic valve replacement are assuming greater importance. In this manuscript, we provide a comprehensive approach to contemporary diagnosis and management of aortic valve disorders in the setting of LVAD therapy.

This perspective focuses on the development of tissue engineered (TE) cell-based therapies to treat left ventricular (LV) dysfunction and chronic heart failure (CHF). The development of induced pluripotent stem cells enabled investigators to seed or co-culture human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) alone and in combination with other cells onto bioengineered scaffolds applied to the epicardial surface of the damaged left ventricle. Using our work as an example, we show how a xenograft implant of a bioengineered scaffold embedded with human neonatal fibroblasts and seeded with hiPSC-CMs partially reversed maladaptive LV remodeling and improved LV systolic/diastolic function in an immune-competent rat model of CHF. The fibroblasts lay down an extracellular matrix and secrete growth factors that increase myocardial blood flow. This approach provides an improved cell payload that covers a larger area of the damaged left ventricle as opposed to direct cell injections into the heart or down the coronary arteries. These studies combined with ongoing studies in immune-competent Yucatan mini swine treated with the same xenograft led to the preliminary design of a proposed Phase I clinical trial that will be presented to the Federal Drug Administration. For the proposed Phase I clinical, this TE patch will be implanted onto the epicardial surface of non-immunosuppressed patients undergoing elective Coronary Artery Bypass Grafting with Ejection Fractions ≥ 20% and ≤ 45%. The primary endpoints will be adverse events/severe adverse events associated with placing the TE patch on the heart. While Phase I trials are primarily safety trials, this proposed trial is designed to obtain some potential efficacy endpoints to help with the design of future Phase II/III clinical trials. These endpoints include changes in LV remodeling that were seen in the pre-clinical animal models as well as including endpoints that focus on patient well-being.

Previous reports indicate that IL18 is a novel candidate gene for diastolic dysfunction in sickle cell disease (SCD)–related cardiomyopathy. We hypothesize that interleukin-18 (IL-18) mediates the development of cardiomyopathy and ventricular tachycardia (VT) in SCD. Compared with control mice, a humanized mouse model of SCD exhibited increased cardiac fibrosis, prolonged duration of action potential, higher VT inducibility in vivo, higher cardiac NF-κB phosphorylation, and higher circulating IL-18 levels, as well as reduced voltage-gated potassium channel expression, which translates to reduced transient outward potassium current (Ito) in isolated cardiomyocytes. Administering IL-18 to isolated mouse hearts resulted in VT originating from the right ventricle and further reduced Ito in SCD mouse cardiomyocytes. Sustained IL-18 inhibition via IL-18–binding protein resulted in decreased cardiac fibrosis and NF-κB phosphorylation, improved diastolic function, normalized electrical remodeling, and attenuated IL-18–mediated VT in SCD mice. Patients with SCD and either myocardial fibrosis or increased QTc displayed greater IL18 gene expression in peripheral blood mononuclear cells (PBMCs), and QTc was strongly correlated with plasma IL-18 levels. PBMC-derived IL18 gene expression was increased in patients who did not survive compared with those who did. IL-18 is a mediator of sickle cell cardiomyopathy and VT in mice and a novel therapeutic target in patients at risk for sudden death.

"We shall fight [the COVID-19] on the beaches, we shall fight on the landing grounds, we shall fight in the fields and in the streets, we shall fight in the hills; we shall never surrender."Winston Churchill speaking to Parliament on June 4, 1940 [COVID amendment by JSA] Winston Churchill delivered the preceding quote in a speech to Parliament during one of the blackest moments in the long history of the English people.1Larson E The Splendid and the Vile. A Saga of Churchill, Family, and Defiance during the Blitz. Penguin Random House, LLC, New York, NY2020Google Scholar Nazi Germany was planning to invade England, likely London. European nations had fallen, one after the other, before the fearsome military forces of Nazi Germany. Of course, we all know that the invasion never occurred, and 5 years later, with the United States playing a major role, Adolf Hitler and the Third Reich were annihilated. Today (July 11, 2020) the world is again involved in a global conflict against a new enemy, an enemy that is harder to see and harder to define: severe acute respiratory syndrome coronavirus 19 (SARS COVID-19). Many individuals throughout the United States and the world have been sickened and many have succumbed. At this moment, the fight continues, shifting from one battleground to another. As noted in a previous commentary, we follow in the footsteps of Dr. Bernard Rieux in Albert Camus's novel, The Plague.2Camus A The Plague. Borzoi Books/Alfred A. Knopf, New York, NY1960Google Scholar Dr. Rieux felt compelled to fight the plague because, as he stated, it was a question of human decency, and it was his job. For the last 3 1/2 months, we have been 2 of the foot soldiers in the war against COVID-19. We have not been working directly on the 4 COVID wards in our university hospital, but we have been battling just behind the front lines on our internal medicine and cardiology care unit and inpatient services.3Alpert JS Life imitates art: the physician in a time of plague.Am J Med. 2020; 133: 651https://doi.org/10.1016/j.amjmed.2020.04.001Abstract Full Text Full Text PDF PubMed Scopus (7) Google Scholar We chose to continue working as inpatient doctors for the same reasons as Dr. Rieux, and we are still spending most of our days on the inpatient services of our university hospital. We are trying to lead our students and house staff during this pandemic so that they may learn from our compassion, dedication, empathy, and perseverance.4Juneman E. Leading the compassionate charge.Circ Heart Fail. 2020; 13e007085Crossref PubMed Scopus (3) Google Scholar As many of our readership know, Arizona has now become one of the major hot spots for COVID-19 both in the United States and in the world. The war against COVID-19 drags on. The hoped-for influenza-like course has not developed, and many opine that we will be fighting this scourge for many months or even years to come. The battles are being bravely waged by a variety of "health soldiers": Clinicians and other health care workers, basic science and clinical investigators, and public health personnel. The health soldiers are from across the globe, not joined by nationality, ethnicity, or uniform, but rather joined by an ethical oath to care for those in need. Like the English referred to in Churchill's quotation, we will continue to fight on many fronts and will never give up or surrender to the COVID-19 forces currently raging among us. During this pandemic, we have received many emails from clinicians throughout the country recounting their personal experiences. The information and knowledge gained about COVID-19 is being passed on, from country to country, state to state, and hospital to hospital as health soldiers fight to keep patients safe. Every morning when we wake up and prepare for another day dressed in surgical scrubs and wearing N-95 masks, we remember Joan Baez singing "We shall overcome some day." This gospel song was sung in the 1960s in support of the civil rights movement and the political forces arrayed against US involvement in Vietnam. Currently, this song represents our expectation of eventual victory over the COVID-19 pandemic. We are aware that there are individuals in the United States and abroad who mistakenly feel that the COVID-19 "war" is some form of political trickery. During World War II, there were also many Americans who opposed our involvement in that conflict. To these misguided parties, we offer only our own witnessing of the 4 COVID wards in our hospital filled with desperately sick and, at times, dying patients. Just like the Nazi Third Reich, COVID-19 also represents a real and present danger to the life we have all come to enjoy. Make no mistake about it: If we are to defeat COVID-19, then we must all rally behind our health "generals" such as Dr. Anthony Fauci and not be misled by naysayers. We are confident that in the future when we have conquered COVID-19, and conquer it we will, many stories will be told of the 2019-2020 pandemic and our various roles in the conquest. For those us born during and after World War II, the current struggle will be "our finest hour." As always, I love hearing from our readership at [email protected] or on our blog at amjmed.org.

Heart failure (HF) post-myocardial infarction (MI) presents with increased vulnerability to monomorphic ventricular tachycardia (mmVT). To appropriately evaluate new therapies for infarct-mediated reentrant arrhythmia in the preclinical setting, chronologic characterization of the preclinical animal model pathophysiology is critical. This study aimed to evaluate the rigor and reproducibility of mmVT incidence in a rodent model of HF. We hypothesize a progressive increase in the incidence of mmVT as the duration of HF increases. Adult male Sprague-Dawley rats underwent permanent left coronary artery ligation or SHAM surgery and were maintained for either 6 or 10 wk. At end point, SHAM and HF rats underwent echocardiographic and invasive hemodynamic evaluation. Finally, rats underwent electrophysiologic (EP) assessment to assess susceptibility to mmVT and define ventricular effective refractory period (ERP). In 6-wk HF rats (n = 20), left ventricular (LV) ejection fraction (EF) decreased (P < 0.05) and LV end-diastolic pressure (EDP) increased (P < 0.05) compared with SHAM (n = 10). Ten-week HF (n = 12) revealed maintenance of LVEF and LVEDP (P > 0.05), (P > 0.05). Electrophysiology studies revealed an increase in incidence of mmVT between SHAM and 6-wk HF (P = 0.0016) and ERP prolongation (P = 0.0186). The incidence of mmVT and ventricular ERP did not differ between 6- and 10-wk HF (P = 1.0000), (P = 0.9831). Findings from this rodent model of HF suggest that once the ischemia-mediated infarct stabilizes, proarrhythmic deterioration ceases. Within the 6- and 10-wk period post-MI, no echocardiographic, invasive hemodynamic, or electrophysiologic changes were observed, suggesting stable HF. This is the necessary context for the evaluation of experimental therapies in rodent HF.NEW & NOTEWORTHY Rodent model of ischemic cardiomyopathy exhibits a plateau of inducible monomorphic ventricular tachycardia incidence between 6 and 10 wk postinfarction.

BACKGROUND Mycophenolic acid is an immunosuppressive drug commonly used in solid organ transplantation to prevent acute and chronic allograft rejection. There are 2 common preparations of mycophenolic acid including mycophenolate mofetil (Cellcept), and enteric-coated mycophenolate sodium (Myfortic) which was developed to reduce the high rate of gastrointestinal side effects seen with Cellcept. Cases of mycophenolate mofetil induced colitis have been described in solid organ transplant patients and rarely in heart transplant patients, but enteric-coated mycophenolate sodium induced colitis is very rare and has not been reported in heart transplant patients. CASE REPORT A 66-year old male with an orthotopic heart transplant was admitted with diarrhea. The patient was on an immunosuppression regimen including mycophenolate mofetil for 10 weeks post-transplantation until complaining of soft stools and bloating. At this time, he was switched to enteric-coated mycophenolate sodium. At week 11 post-transplantation, the patient was admitted to the hospital with worsening diarrhea. Extensive workup was unrevealing. Colonoscopy with biopsy showed features of mycophenolic acid induced colitis. Enteric coated mycophenolate sodium was discontinued, and the patient's diarrhea markedly improved over the next 48 hours. The patient had no signs of colitis or solid organ rejection at 7-month follow up appointment. CONCLUSIONS Although a diagnosis of exclusion, enteric-coated mycophenolate sodium induced colitis should be considered in the differential of an orthotopic heart transplant patient with diarrhea as discontinuing the medication can improve symptoms and avoid costly workups, however, patients should be monitored closely for signs of rebound rejection.

Patients diagnosed with heart failure with reduced ejection fraction (HFrEF) are at increased risk of monomorphic ventricular tachycardia (VT) and ventricular fibrillation. The presence of myocardial fibrosis provides both anatomical and functional barriers that promote arrhythmias in these patients. Propagation of VT in a reentrant circuit depends on the presence of excitable myocardium and the refractoriness of the circuit. We hypothesize that myocardial refractoriness can be modulated surgically in a model of HFrEF, leading to decreased susceptibility to VT. Male Sprague-Dawley rats were infarcted via permanent left coronary artery ligation. At 3 weeks post-infarction, engineered grafts composed of human dermal fibroblasts cultured into a polyglactin-910 biomaterial were implanted onto the epicardium to cover the area of infarction. Three weeks post-graft treatment, all rats underwent a terminal electrophysiologic study to compare monophasic action potential electroanatomic maps and susceptibility to inducible monomorphic VT. HFrEF rats (n=29) demonstrated a longer (p=0.0191) ventricular effective refractory period (ERP) and a greater (p=0.0394) VT inducibility compared with sham (n=7). HFrEF rats treated with the graft (n=12) exhibited no change in capture threshold (p=0.3220), but had a longer ventricular ERP (p=0.0029) compared with HFrEF. No statistically significant change in VT incidence was found between HFrEF rats treated with the graft and untreated HFrEF rats (p=0.0834). Surgical deployment of a fibroblast-containing biomaterial in a rodent ischemic cardiomyopathy model prolonged ventricular ERP as measured by programmed electrical stimulation. This hypothesis-generating study warrants additional studies to further characterize the antiarrhythmic or proarrhythmic effects of this novel surgical therapy.

HomeCirculation: Heart FailureVol. 13, No. 4Leading the Compassionate Charge Free AccessArticle CommentaryPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessArticle CommentaryPDF/EPUBLeading the Compassionate Charge Elizabeth B. Juneman, MD Elizabeth B. JunemanElizabeth B. Juneman Correspondence to: Elizabeth B. Juneman, MD, Banner Health & Sarver Heart Center, University of Arizona College of Medicine, 1501 N. Campbell Ave, Tucson, AZ 85724. Email E-mail Address: [email protected] https://orcid.org/0000-0003-1771-562X Banner Health & Sarver Heart Center, University of Arizona College of Medicine, Tucson, AZ. Originally published7 Apr 2020https://doi.org/10.1161/CIRCHEARTFAILURE.120.007085Circulation: Heart Failure. 2020;13:e007085Compassion. I have been spending a lot of time thinking about compassion. As heart failure providers who care for one of the frailest patient populations, compassion is part of our everyday work life. We demonstrate compassion in acute care, chronic care, advanced care decisions, and end of life care. It is part of our nature. I assume that had we not believed this to be the tenant of our profession, then we would have not chosen to be heart failure providers. As an optimistic person, I have generally chosen to believe that my local community, city, and country are compassionate as well. But in this time of a pandemic, I have been thinking that compassion is not necessarily easy.Our communities were in a state of normalcy, and then with an urgent, frantic surge, supermarkets were laid barren of daily essentials like toilet paper, thermometers, and milk. There was collective "me first" mentality. I heard conversations of "blame and shame" while in the local deli. There was a collective "not me" attitude as I saw young adults gather at local bars and baby boomers plan St Patrick's Day dinners. These are the overt manifestations of primitive responses to fear that seems in my mind coupled to the ebbing of compassion.It struck me that collective compassion is hard when there is an abstract threat and no obvious signs of physical or social decay. In a most recent New York Times op-ed by David Brooks, titled "Pandemics Kill Compassion, Too," Mr Brooks points to history's account of the 17th century Plague and 1918 Spanish Flu and how dread overwhelmed the bonds of human affection.1 He poignantly writes that society often overlooks times of pandemic in our recount of history as we do not really like who we became. I just now remember, as a teenager in the 1980s, speaking with my great grandmother about her childhood. She would talk about the brilliant roaring 1920s as well as the tribulations of the Great Depression and World War II. Never did she mention about the Spanish Flu of 1918 in which roughly 675 000 Americans lost their lives to influenza. I wonder if that time in her life was most easily forgotten, and the ever-powerful defense mechanism of denial won over.Compassion often is best exhibited when we can be in the physical presence of another human when we can hold a hand and provide a hug. Physical disasters like war, hurricanes, and earthquakes bring people together physically so that compassion can thrive. Conversely, denial does not dominate when a physical disaster of pain and suffering can be seen and felt. Pandemics like the Spanish Flu and now COVID-19 cannot be tangibly seen nor felt by society. They are an invisible threat, and thus compassion may be more difficult to develop. Does social distancing contribute to a loss of physical human contact and thus threaten compassion? Professionally, as we will be required to wear personal protective equipment, will there be a cost of the loss of physical human contact? How will we maintain our compassion for our vulnerable patients during phone/virtual visits/chart consults?I have been walking the halls of my hospital with a feeling of dread and uncertainty. As healthcare providers of the frailest, we have a sense of what is yet to come. Our inherent compassion will very much be needed and frankly tested in the weeks to come. Although compassion may not be easy in pandemics, I do have hope. As the world is practicing social distancing, we are ever more connected via social media. I have seen acts of kindness and compassion on social media in support of food banks, local schools, and the elderly. Medical students have joined together to offer support to the faculty who are on the front lines with childcare, dog walking, grocery shopping, and food delivery. Neighborhoods joining together to support those who are more vulnerable, to share resources, and provide family care to healthcare providers on the front lines. Members of the community making food/personal care baskets for the health care providers at the hospitals. This gives me hope that society can come together to provide compassion and human affection.I know that heart failure healthcare workers will need to lead the compassionate charge. We will need to adapt our toolkit of compassion to calm the sickest, support families, and set an example for our colleagues and community. I believe in our heart failure community, and I trust that we will continue to be compassionate.DisclosuresNoneFootnotesGuest Editor for this article was Kenneth B. Margulies, MD.For Disclosures, see page 2.The opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.Correspondence to: Elizabeth B. Juneman, MD, Banner Health & Sarver Heart Center, University of Arizona College of Medicine, 1501 N. Campbell Ave, Tucson, AZ 85724. Email [email protected]arizona.eduReference1. Brooks D.. Pandemics Kill Compassion, Too. The New York Times.https://www.nytimes.com/2020/03/12/opinion/pandemic-coronavirus-compassion.html. Accessed March 12, 2020.Google Scholar Previous Back to top Next FiguresReferencesRelatedDetailsCited By Alpert J and Juneman E (2020) We Will Never Give Up, The American Journal of Medicine, 10.1016/j.amjmed.2020.07.002, 133:10, (1111-1112), Online publication date: 1-Oct-2020. Barbarash O, Karetnikova V, Kashtalap V, Zvereva T and Kochergina A (2020) New coronavirus disease (COVID-19) and cardiovascular disease, Complex Issues of Cardiovascular Diseases, 10.17802/2306-1278-2020-9-2-17-28, 9:2, (17-28) Sweitzer N (2020) Science in the Time of Coronavirus, Circulation: Heart Failure, 13:4, Online publication date: 1-Apr-2020. April 2020Vol 13, Issue 4 Advertisement Article InformationMetrics © 2020 American Heart Association, Inc.https://doi.org/10.1161/CIRCHEARTFAILURE.120.007085PMID: 32255660 Originally publishedApril 7, 2020 Keywordshumanspersonal protective equipmentheart failurepandemicCOVID-19PDF download Advertisement SubjectsEthics and Policy

Accurate right ventricle functional analysis prior to mechanical circulatory support continues to be valuable for preoperative stratification of patients at risk for developing right ventricular (RV) failure. While cardiac magnetic resonance imaging (CMR) remains the gold standard, CMR is limited by availability and patient-specific contraindications. Further investigation of other imaging modalities would be beneficial as it may serve as a surrogate to identifying RV systolic dysfunction. A single-center, retrospective study including 29 patients with advanced heart failure was performed. All patients underwent ventricular functional analysis with both CMR and echocardiography, and 19 patients underwent right heart catheterization. Predictability with multimodal assessment of RV function was determined using logistic regression methods. Of the 29 participants, 10 had severe RV dysfunction. Tricuspid annular plane of systolic excursion was a modest predictor of RV dysfunction with odd ratio (OR) of 0.07 (0.01-0.72) and c-statistic of 0.79. Invasive hemodynamic measurement of cardiac index by thermodilution method was also predictive of RV dysfunction but failed to reach statistical significance (OR of 0.03, <0.001-1.28) with c-statistic of 0.83. The role of invasive hemodynamic data in predicting RV function compared with CMR should be further explored among patients with advanced heart failure.

This study was designed to determine the potential therapeutic effects of a new sodium-hydrogen exchanger (NHE-1) inhibitor in the rat coronary artery ligation model of chronic heart failure. After the induction of acute myocardial infarction, rats were entered into a randomly designed pilot dose study from 0.3 mg/kg, 1.0 mg/kg, and 3.0 mg/kg. Solid state micrometer hemodynamics, echocardiographic, and pressure-volume relationships were measured after 6 weeks of treatment. Treatment with this NHE-¬1 inhibitor at 3 mg/kg increased (P<0.05) ejection fraction from 23±3% (N=6) to 33±2% (N=13), while the 1 mg/kg dose decreased (P<0.05) the infarct size in CHF rats from 21.7±1.4% (N=7) to 15.9±0.7% (N=3) and prevented (P<0.05) dilata¬tion of the left ventricle in CHF rats in diastole (1.0±0.1 cm, N=6) to 0.9±0.1 cm, N=10) and in systole (0.9±0.1 cm, N=6) to 0.8±0.1, N=10). These study results suggest that this new NHE-1 inhibitor may be potentially useful in treating CHF with an improvement in maladaptive left ventricle remodeling. Because the mechanism of action of this agent is entirely different than the currently applied approach in treating CHF that focuses on aggressive neuro-hormonal blockade and because this agent does not adversely affect important hemodynamic variables, further investigations with this agent may be warranted.

Background: Worldwide, the prevalence of heart failure (HF) is increasing and HF patients are living longer. Chronic ischemic HF presents with increased vulnerability to ventricular tachycardia and fibrillation. However, the mechanism of these arrhythmias differ between the acute infarction phase and the chronic, namely via myocyte membrane potential instability in the acute phase versus substrate-mediated reentry in the chronic phase. We propose our chronic heart failure (CHF) model to recapitulate the potentially progressive nature of arrhythmogenesis in the chronic phase. Methods: Adult male Sprague Dawley rats underwent permanent left coronary artery ligation and were maintained for six or ten weeks; SHAM operations were also performed. At each respective endpoint, SHAM and CHF rats underwent transthoracic echocardiography and invasive hemodynamic evaluation. Finally, a median sternotomy was performed for epicardial electrophysiology (EP) assessment. Programmed electrical stimulation was utilized to assess susceptibility to induced ventricular tachycardia (VT) and also to determine effective refractory period (ERP). Results: Six-week CHF (n=50) induction proved successful as evidenced by the decrease in left ventricular ejection fraction (LVEF) (76±3% to 35±2%, p<0.0001) and the increase in left ventricular end-diastolic pressure (LVEDP) (6±1 mmHg to 20±2 mmHg, p=0.0008) compared to SHAM (n=15). Progression to ten-week CHF (n=18) also proved successful via LVEF and LVEDP maintenance (35±2% to 38±3%, p=0.3909) (20±2 mmHg to 15±3 mmHg, p=0.1578). EP studies revealed an increase in the incidence of induced VT between SHAM and six-week CHF (0% to 60%, p<0.0001) and a prolongation of the ERP (54±4 milliseconds to 69±3 ms, p=0.0228). The incidence of induced VT and ERP did not continue to increase between six- and ten-week CHF (60% to 50%, p=0.5804), (69±3 ms to 68±3 ms, p=0.8221). Conclusion: Myocardial infarction-mediated arrhythmogenesis is known to exist in an acute and a chronic phase. Here, we examine the chronic phase of ischemic HF and show evidence to support that once the adverse remodeling-mediated substrate stabilizes, proarrhythmic deterioration ceases.

Although radiofrequency ablation has revolutionized the management of tachyarrhythmias, the rate of arrhythmia recurrence is a large drawback. Successful substrate identification is paramount to abolishing arrhythmia, and bipolar voltage electrogram's narrow field of view can be further reduced for increased sensitivity. In this report, we perform cardiac mapping with monophasic action potential (MAP) amplitude. We hypothesize that MAP amplitude (MAPA) will provide more accurate infarct sizes than other mapping modalities via increased sensitivity to distinguish healthy myocardium from scar tissue. Using the left coronary artery ligation Sprague-Dawley rat model of ischemic heart failure, we investigate the accuracy of in vivo ventricular epicardial maps derived from MAPA, MAP duration to 90% repolarization (MAPD90), unipolar voltage amplitude (UVA), and bipolar voltage amplitude (BVA) compared with gold standard histopathological measurement of infarct size. Numerical analysis reveals discrimination of healthy myocardium versus scar tissue using MAPD90 (P = 0.0158) and UVA (P < 0.001, n = 21). MAPA and BVA decreased between healthy and border tissue (P = 0.0218 and 0.0015, respectively) and border and scar tissue (P = 0.0037 and 0.0094, respectively). Contrary to our hypothesis, BVA mapping performed most accurately regarding quantifying infarct size. MAPA mapping may have high spatial resolution for myocardial tissue characterization but was quantitatively less accurate than other mapping methods at determining infarct size. BVA mapping's superior utility has been reinforced, supporting its use in translational research and clinical electrophysiology laboratories. MAPA may hold potential value for precisely distinguishing healthy myocardium, border zone, and scar tissue in diseases of disseminated fibrosis such as atrial fibrillation.NEW & NOTEWORTHY Monophasic action potential mapping in a clinically relevant model of heart failure with potential implications for atrial fibrillation management.

A chronic heart failure (CHF) rat underwent epicardial programmed electrical stimulation (PES). Ventricular tachycardia (VT) developed during PES. Mechanical alternans was noted despite fixed tachycardia cycle length. Anti-tachycardia pacing attempts initiated a second VT that generated pulse intermittently and then degenerated into pulseless VT with electrical alternans.To our knowledge electrical and mechanical alternans have not been recorded in animal models of CHF during VT. The distinct events of mechanical alternans and electrical alternans may be indicative of progressively worsened calcium handling in the compromised cardiomyocytes.Although ion channel differences between rodents and humans exist, this work attempts to demonstrate this rat model's usefulness in understanding cardiac electrophysiology in CHF.

Placing pregnant patients in left lateral tilt (LLT) position to avoid compression of the inferior vena cava (IVC) has long been standard obstetric practice. The American Heart Association recommends continuous manual left uterine displacement (LUD) instead of LLT position during a maternal cardiac arrest. The relationship between maternal position and proximal filling of the IVC is unknown. The hypothesis is that the maternal IVC diameter would increase in response to LLT and LUD compared to supine position. A pilot prospective observational study was performed on 60 healthy gravidas. 30 patients at 20-24 weeks and 30 patients at 37-41 weeks were recruited. Patients were placed in supine, 30 degree left lateral tilt and supine with left uterine displacement positions. The IVC was visualized by ultrasound using the subxiphoid technique. The primary outcome was IVC diameter at end expiration. Descriptive analysis and student's paired t-test were performed. In the 20-24 weeks cohort, patients in LLT position (77.5 +/- 9.8, p=0.03) and LUD position (77.3 +/-9.5, p=0.04) had a significant decrease in heart rate (bpm) compared to supine position (80.5 +/-8.5). Patients in the LUD position (80.7 +/-7.6, p<0.001) had a significant decrease in MAP compared to supine position (83.7 +/- 7.4). No significant differences were seen in the IVC diameter between all 3 positions.In the 37-41 weeks cohort, there were no significant differences in the MAP, heart rate, and IVC measurement between all 3 positions.In the 20-24 weeks cohort, 48.3%, 30%, 18.3% of patients had their largest IVC diameter in the LUD, LLT, and supine position, respectively. In the 37-41 weeks cohort, 33.3%, 28.3%, 30% of patients had their largest IVC diameter in the LUD, LLT, and supine position, respectively. 1 subject in each cohort experienced symptoms consistent with supine hypotension syndrome in the supine position (3.33%). Sonographically the IVC diameters were not statistically different between all 3 positions. Furthermore, 18% in the 20-24 weeks cohort and 30% in the 37-41 weeks cohort had their largest IVC diameter in the supine position. This observation challenges the universal belief of uterine IVC compression with associating decrease in proximal IVC filling among pregnant cohort. This study suggests that LLT or LUD may not be universally beneficial.

Background: Twenty six million people worldwide are diagnosed with chronic heart failure (CHF). With only 5000 heart transplants performed annually, the prognosis for the remaining individuals is poor and new therapeutic options are needed. Previously we have described a cardiac engineered graft comprised of human induced pluripotent stem cell (iPSC) derived cardiomyocytes co-cultured with fibroblasts in a bio-absorbable mesh. Few studies to date have examined comparatively the therapeutic benefits of different cardiac populations. In the present study we engineered grafts generated with either hiPSC derived heterogeneous cardiac myocytes (hetCMs) or ventricular pure myocyte (VMs) populations to compare functional outcomes in a rat model of CHF. Methods: Cardiac grafts were generated with hetCMs or VMs (Axiogenesis) by co-culture into a 3D bioabsorbable mesh with human dermal fibroblasts. The hetCMs contain 60% ventricular, 40% atrial and nodal-like cardiomyocytes. The VMs contain 90% ventricular and 10% atrial cardiomyocytes. Grafts were evaluated in culture out to 6 days. Adult male Sprague-Dawley rats underwent permanent left coronary artery ligation and were randomized to Sham, CHF or graft treatment. Hemodynamic pressure measurements were performed at 6 weeks post-ligation with Millar solid state micromanometer pressure catheters. Ventricular tachycardia (VT) induction studies were performed at study endpoint (3 weeks after implant) to evaluate VT susceptibility using methods developed in the laboratory. Results: Both HetCM and VM generated cardiac grafts displayed synchronous and spontaneous contractions after 48hrs in culture and maintained an average contraction rate of 67±6 (hetCM) and 71±9 (VM) beats per minute (n=10 per group). Implantation of HetCM and VM grafts lowered (p<0.05) EDP 45% and 14% (n=10) and resulted in decreased susceptibility of VT induction 54% and 65%, respectively (n=4). Conclusion: Cardiac grafts engineered with hetCMs or VMs and implanted in a rat CHF model can lower LV EDP in-vivo while decreasing susceptibility of induced VT. This approach raises the possibility that iPSC derived engineered grafts may be used as a treatment for VT in patients with CHF.

Introduction: In the United States, one in three deaths is attributed to cardiovascular disease (CVD). With CVD, sudden cardiac death is a common cause of mortality, specifically by way of ventricular tachycardia (VT) and ventricular fibrillation. We propose the application of our custom software to evaluate the electrophysiologic (EP) properties of animal models of ischemic and non-ischemic dilated cardiomyopathies. Methods: Adult male Sprague-Dawley rats with left coronary artery ligation and adult male and female transgenic Fragile X cardiomyopathic mice were sedated with Inactin and Isoflurane, respectively, and underwent hemodynamic measurements and/or EP testing. Using a PowerLab system and LabChart software, three-lead electrocardiograms were recorded. Using a pressure catheter, hemodynamic parameters were calculated. Using a concentric microelectrode (World Precision Inc.), a clinical EP catheter (Bard Inc.), and custom MATLAB software, local epicardial monophasic action potentials (MAP) and local epicardial voltages were recorded. Using custom MATLAB software for programmed electrical stimulation (PES), VT was induced epicardially with a clinically-accepted drivetrain. Animals underwent eight equidistant ‘S1’ stimulations followed by a premature ‘S2’ stimulation. The S2 stimulation was decreased by 5 milliseconds until loss of capture, indicating the effective refractory period. Sustained ventricular tachycardia (sVT) has been defined as more than fifteen consecutive premature ventricular contractions. Results: The chronic heart failure (CHF) rats had documented hemodynamic heart failure with elevated LV EDPs, and decreased EFs. Mapping and PES was performed on the two groups of rats, namely CHF and Sham-operated. In the CHF group, 71% (27/39) of the rats exhibited sVT, while 0% (0/10) of the Sham-operated rats exhibited sVT. Mapping was also performed on the two groups of mice, namely Wild-Type and Fragile X. Conclusions: We have performed clinically-relevant EP studies in CHF rats and in Fragile X dilated cardiomyopathic mice. These EP studies demonstrate our ability to evaluate and validate the phenotypes of animal models of cardiomyopathies and demonstrate the potential to evaluate the effectiveness of new therapies.

Resulting from a various etiologies, the most notable remains ischemia; heart failure (HF) manifests as the common end pathway of many cardiovascular processes and remains among the top causes for hospitalization and a major cause of morbidity and mortality worldwide. Current pharmacologic treatment for HF utilizes pharmacologic agents to control symptoms and slow further deterioration; however, on a cellular level, in a patient with progressive disease, fibrosis and cardiac remodeling can continue leading to end-stage heart failure. Cellular therapeutics have risen as the new hope for an improvement in the treatment of HF. Mesenchymal stem cells (MSCs) have gained popularity given their propensity of promoting endogenous cellular repair of a myriad of disease processes via paracrine signaling through expression of various cytokines, chemokines, and adhesion molecules resulting in activation of signal transduction pathways. While the exact mechanism remains to be completely elucidated, this remains the primary mechanism identified to date. Recently, MSCs have been incorporated as the central focus in clinical trials investigating the role how MSCs can play in the treatment of HF. In this review, we focus on the characteristics of MSCs that give them a distinct edge as cellular therapeutics and present results of clinical trials investigating MSCs in the setting of ischemic HF.