Standard Heart Failure Medications Research Articles

A biopsy-based pilot clinical study: monitoring the effectiveness of tafamidis treatment of patients with transthyretin amyloid cardiomyopathy

Abstract Background Transthyretin amyloid cardiomyopathy (ATTR-CM) is a rare and progressive disease associated with high mortality. It is caused by the accumulation of TTR amyloid protein in various tissues, including the myocardium. Tafamidis is currently the only approved therapy for ATTR-CM. The results of the phase III ATTR-ACT trial showed lower rates of mortality and hospitalization, besides lower rate of decline for both quality of life (QoL), and 6-minute walk test (6mwt) distance [1]. Whether the reported clinical outcomes represent a change in myocardial ATTR-accumulation and remodeling remains unclear. Here we monitor the clinical outcome and the corresponding myocardial histological changes of tafamidis-treated patients using endomyocardial biopsy (EMB). Methods Eleven patients with EMB-proven ATTR-CM, 10 wild type, 1 hereditary, 9 males, 2 females age= 77±9 years, were prescribed with 61 mg tafamidis once daily indefinitely. The course of the disease was evaluated via EMB, 99mTc-DPD scintigraphy, cardiac magnetic resonance imaging (cMRI), echocardiography, 6mwt, Minnesota QoL questionnaire and serum N-terminal pro brain natriuretic peptide (NT-proBNP) analysis, at baseline and after 321±72 days of treatment (ethics application number EA2/140/16). EMBs were examined via immunohistochemistry and Imaging mass spectrometry. All patients received standard heart failure medications. Paired clinical measurements were compared via paired t test for parametric data or Wilcoxon rank test for non-parametric data. Results Following the course of treatment, EMB ATTR-positive area measured via immunohistochemistry increased by 7.7±9.5% (p<0.05). Myocardial CD3+ and CD68+ cell counts remained within normal limits. The EMB peak intensities of ATTR, collagen and macrophage migration inhibitory factor, measured via imaging mass spectrometry were increased by 23% (AUC= 0.677, p<0.001), 25% (AUC= 0.620, p<0.001) and 18% (AUC= 0.609, p<0.001), respectively. Echocardiography measured left ventricular (LV) ejection fraction and LV end-diastolic diameter, as well as 6mwt distance, QoL and serum NT-proBNP showed no significant changes. cMRI did not show any significant changes in fibrosis/amyloidosis markers (N=9). 99mTc-DPD scintigraphy-derived Perugini score (N=10) improved by one-point in two patients and remained stable in the rest. The New York Heart Association (NYHA) functional class improved in one patient and remained stable in 10/11 patients. Conclusion Our findings demonstrate, for the first time, the persistence of myocardial ATTR-accumulation and remodeling despite a clinically stable disease course. Whether this finding is relevant in terms of disease-progression or indicate a need for more intensive treatment warrants further investigation.

Sex and gender differences in myocarditis and dilated cardiomyopathy: An update.

In the past decade there has been a growing interest in understanding sex and gender differences in myocarditis and dilated cardiomyopathy (DCM), and the purpose of this review is to provide an update on this topic including epidemiology, pathogenesis and clinical presentation, diagnosis and management. Recently, many clinical studies have been conducted examining sex differences in myocarditis. Studies consistently report that myocarditis occurs more often in men than women with a sex ratio ranging from 1:2-4 female to male. Studies reveal that DCM also has a sex ratio of around 1:3 women to men and this is also true for familial/genetic forms of DCM. Animal models have demonstrated that DCM develops after myocarditis in susceptible mouse strains and evidence exists for this progress clinically as well. A consistent finding is that myocarditis occurs primarily in men under 50 years of age, but in women after age 50 or post-menopause. In contrast, DCM typically occurs after age 50, although the age that post-myocarditis DCM occurs has not been investigated. In a small study, more men with myocarditis presented with symptoms of chest pain while women presented with dyspnea. Men with myocarditis have been found to have higher levels of heart failure biomarkers soluble ST2, creatine kinase, myoglobin and T helper 17-associated cytokines while women develop a better regulatory immune response. Studies of the pathogenesis of disease have found that Toll-like receptor (TLR)2 and TLR4 signaling pathways play a central role in increasing inflammation during myocarditis and in promoting remodeling and fibrosis that leads to DCM, and all of these pathways are elevated in males. Management of myocarditis follows heart failure guidelines and there are currently no disease-specific therapies. Research on standard heart failure medications reveal important sex differences. Overall, many advances in our understanding of the effect of biologic sex on myocarditis and DCM have occurred over the past decade, but many gaps in our understanding remain. A better understanding of sex and gender effects are needed to develop disease-targeted and individualized medicine approaches in the future.

Impact of interventional therapy on top of standard drug therapy on left ventricular structure and function in HFrEF patients complicating with middle aortic syndrome caused by Takayasu arteritis

Objective: To evaluate the impact of interventional therapy on top of drug therapy on cardiac function and structure in heart failure with reduced ejection fraction (HFrEF) patients complicating with middle aortic syndrome caused by Takayasu arteritis (TA-MAS). Methods: It was a retrospective longitudinal study. The data of patients with TA-MAS and HFrEF, who received interventional therapy on top of drug therapy in Fuwai Hospital from January 2010 to September 2020, were collected and analyzed. Baseline clinical data (including demographic data, basic treatment, etc.) were collected through the electronic medical record system. Changes of indexes such as New York Heart Association (NYHA) classification, N-terminal pro-brain natriuretic peptide (NT-proBNP), left ventricular end diastolic diameter (LVEDD), left ventricular ejection fraction (LVEF), left ventricular mass index (LVMI) before and after therapy were analyzed. Results: A total of 10 patients were collected. There were 8 females in this patient cohort, age was (18.4±5.0) years and onset age was (15.3±5.0) years. All 10 patients received standard heart failure medication therapy in addition to hormone and/or immunosuppressive anti-inflammatory therapy, but cardiac function was not improved, so aortic balloon dilatation and/or aortic stenting were performed in these patients. The median follow-up was 3.3(1.3, 5.6) years. On the third day after interventional therapy, the clinical symptoms of the 10 patients were significantly improved, NYHA classfication was restored from preoperative Ⅲ/Ⅳ to Ⅱ at 6 months post intervention(P<0.05). Compared with preoperation, NT-proBNP (P=0.028), LVEDD (P=0.011) and LVMI (P=0.019) were significantly decreased, LVEF was significantly increased (P<0.001) at 6 months after operation. Compared with preoperation, NT-proBNP (P=0.016), LVEDD (P=0.023) and LVMI (P=0.043) remained decreased, LVEF remained increased (P<0.001) at 1 year after operation. Conclusion: Results from short and medium term follow-up show that interventional therapy on top of heart failure drug therpay can effectively improve left cardiac function and attenuate cardiac remodeling in patients with TA-MAS comorbid with HFrEF.

Heart Failure and Cardiorenal Syndrome: A Narrative Review on Pathophysiology, Diagnostic and Therapeutic Regimens-From a Cardiologist's View.

In cardiorenal syndrome (CRS), heart failure and renal failure are pathophysiologically closely intertwined by the reciprocal relationship between cardiac and renal injury. Type 1 CRS is most common and associated with acute heart failure. A preexistent chronic kidney disease (CKD) is common and contributes to acute kidney injury (AKI) in CRS type 1 patients (acute cardiorenal syndrome). The remaining CRS types are found in patients with chronic heart failure (type 2), acute and chronic kidney diseases (types 3 and 4), and systemic diseases that affect both the heart and the kidney (type 5). Establishing the diagnosis of CRS requires various tools based on the type of CRS, including non-invasive imaging modalities such as TTE, CT, and MRI, adjuvant volume measurement techniques, invasive hemodynamic monitoring, and biomarkers. Albuminuria and Cystatin C (CysC) are biomarkers of glomerular filtration and integrity in CRS and have a prognostic impact. Comprehensive "all-in-one" magnetic resonance imaging (MRI) approaches, including cardiac magnetic resonance imaging (CMR) combined with functional MRI of the kidneys and with brain MRI are proposed for CRS. Hospitalizations due to CRS and mortality are high. Timely diagnosis and initiation of effective adequate therapy, as well as multidisciplinary care, are pertinent for the improvement of quality of life and survival. In addition to the standard pharmacological heart failure medication, including SGLT2 inhibitors (SGLT2i), renal aspects must be strongly considered in the context of CRS, including control of the volume overload (diuretics) with special caution on diuretic resistance. Devices involved in the improvement of myocardial function (e.g., cardiac resynchronization treatment in left bundle branch block, mechanical circulatory support in advanced heart failure) have also shown beneficial effects on renal function.

Role of immunosuppression in patients with lymphocytic myocarditis and myocardial parvovirus B19 with or without human herpesvirus 6 co-presence

Abstract Background Parvovirus B19 (B19V) and Human Herpesvirus 6 (HHV6) are commonly detected in endomyocardial biopsy (EMB) specimens of patients with myocarditis symptoms. Whether B19V- and HHV6-DNA belong to the cardiac bio-portfolio remains unclear [1,2]. Until today, the role of B19V-/HHV6-DNA presence in myocarditis is doubtful. Both viruses have been detected in the myocardium, even independent of cardiac inflammation. Yet, their contribution to myocarditis remains controversial. The European Society of Cardiology guidelines exclude the use of immunosuppression in patients with virus-associated myocarditis [3]. Whether myocarditis patients with the presence of B19V-DNA alone or with HHV6-DNA in EMB findings can be treated using immunosuppression, remains a delicate question for clinicians. Methods 931 patients with unexplained heart failure symptoms underwent EMB investigation to determine the underlying cause. Patients with low-levels (&amp;lt;1000 copies/μg DNA) of B19V-DNA and HHV6-DNA were identified. A sub-cohort of 28 patients who suffered from chronic-persistent lymphocytic myocarditis with ongoing symptoms was treated with azathioprine 100 mg once daily and prednisolone 1 mg/kg/day tapered down by 10 mg every two weeks followed by a second EMB. Twenty out of 28 patients had B19V-DNA only (mean LVEF=38%, age=47±15) and eight patients had B19V-/HHV6-DNA copresence (mean LVEF=39%, age=42±10). Patients with systemic infections were excluded. Both cohorts received standard heart failure medications. Continuous variables are expressed as mean±SD. Results B19V-DNA alone and in the presence of HHV6-DNA was detectable in the EMB of 377 and 63 patients, respectively. Following the immunosuppression course, the patients with B19V-DNA only and those with B19V-/HHV6-DNA showed complete resolution of inflammation in 12/20 and 5/8 patients, New York Heart Association (NYHA) functional class improvement in 9/20 and 4/8 patients, LVEF improvement by 8.0±13.8% (p&amp;lt;0.05) and 8.4±9.6% (p&amp;lt;0.05), and a reduction of LVEDD by 3.8±6.1mm (p&amp;lt;0.05) and 1.0±7.7mm (p&amp;gt;0.05), respectively. Importantly, following immunosuppression B19V and HHV6-DNA copy numbers went down from 186±266 to 130±186 copies/μg DNA and from 71±141 to 58±143 copies/μg DNA, respectively. Conclusion Chronic lymphocytic myocarditis patients with persistent B19V-DNA even in co-presence of HHV6-DNA may benefit from combined immunosuppression therapy. The therapy is clinically effective and safe to reduce cardiac inflammation independent of B19V- and HHV6-DNA copy numbers. In conclusion, we show for the first time that cases with chronic lymphocytic myocarditis can be principally treated with immunosuppression, despite B19V-/HHV6-DNA EMB presence. Funding Acknowledgement Type of funding sources: Public Institution(s). Main funding source(s): Berlin Institute of Health-Center for Regenerative Therapies

Homoarginine treatment of rats improves cardiac function and remodeling in response to pressure overload

Low serum concentrations of the amino acid homoarginine (HA) are associated with increased cardiovascular mortality by incompletely understood mechanisms. This study sought to assess the influence of HA on cardiac remodeling in rats undergoing either transaortic banding or inhibition of nitric oxide synthesis by Nω-Nitro-L-arginine methyl ester hydrochloride (L-NAME). Male Wistar rats (n= 136) underwent sham operation (SH) or aortic banding (AB). Both groups were equally divided into 14 subgroups, receiving different doses of HA alone or in combination with lisinopril, spironolactone, or L-NAME for 4weeks. HA treatment in AB animals resulted in a dose-dependent improvement of cardiac function up to a concentration of 800 mg·kg-1 ·day-1 . Combining 800 mg·kg-1 ·day-1 HA with spironolactone or lisinopril yielded additional effects, showing a positive correlation with LV ejection fraction (+33%, p= 0.0002) and fractional shortening (+41%, p= 0.0014). An inverse association was observed with collagen area fraction (-41%, p< 0.0001), myocyte cross-sectional area (-22%, p< 0.0001) and the molecular markers atrial natriuretic factor (-74%, p= 0.0091), brain natriuretic peptide (-42%, p =0.0298), beta-myosin heavy chain (-46%, p =0.0411), and collagen type V alpha 1 chain (-73%, p =0.0257) compared to placebo-treated AB animals. Co-administration of HA and L-NAME was found to attenuate cardiac remodeling and prevent NO-deficient hypertension following AB. HA treatment has led to a dose-dependent improvement of myocardial function and marked histological and molecular changes in cardiac remodeling following AB. Combining HA with standard heart failure medication resulted in additional beneficial effects boosting its direct impact on heart failure pathophysiology.

Treatment of Transthyretin Amyloid Cardiomyopathy: The Current Options, the Future, and the Challenges.

Transthyretin amyloid cardiomyopathy (ATTR-CM) is a progressively debilitating, rare disease associated with high mortality. ATTR-CM occurs when TTR amyloid protein builds up in the myocardium along with different organs, most commonly the peripheral and the autonomic nervous systems. Managing the cardiac complications with standard heart failure medications is difficult due to the challenge to maintain a balance between the high filling pressure associated with restricted ventricular volume and the low cardiac output. To date, tafamidis is the only agent approved for ATTR-CM treatment. Besides, several agents, including green tea, tolcapone, and diflunisal, are used off-label in ATTR-CM patients. Novel therapies using RNA interference also offer clinical promise. Patisiran and inotersen are currently approved for ATTR-polyneuropathy of hereditary origin and are under investigation for ATTR-CM. Monoclonal antibodies in the early development phases carry hope for amyloid deposit clearance. Despite several drug candidates in the clinical development pipeline, the small ATTR-CM patient population raises several challenges. This review describes current and future therapies for ATTR-CM and sheds light on the clinical development hurdles facing them.

Circulating and Myocardial Cytokines Predict Cardiac Structural and Functional Improvement in Patients With Heart Failure Undergoing Mechanical Circulatory Support.

BackgroundRecent prospective multicenter data from patients with advanced heart failure demonstrated that left ventricular assist device (LVAD) support combined with standard heart failure medications, induced significant cardiac structural and functional improvement, leading to high rates of LVAD weaning in selected patients. We investigated whether preintervention myocardial and systemic inflammatory burden could help identify the subset of patients with advanced heart failure prone to LVAD‐mediated cardiac improvement to guide patient selection, treatment, and monitoring.Methods and ResultsNinety‐three patients requiring durable LVAD were prospectively enrolled. Myocardial tissue and blood were acquired during LVAD implantation, for measurement of inflammatory markers. Cardiac structural and functional improvement was prospectively assessed via serial echocardiography. Eleven percent of the patients showed significant reverse remodeling following LVAD support (ie, responders). Circulating tumor necrosis factor alpha, interleukin (IL)‐4, IL‐5, IL‐6, IL‐7, IL‐13, and interferon gamma were lower in responders, compared with nonresponders (P<0.05, all comparisons). The myocardial tissue signal transducer and activator of transcription‐3, an inflammatory response regulator, was less activated in responders (P=0.037). Guided by our tissue studies and a multivariable dichotomous regression analysis, we identified that low levels of circulating interferon gamma (odds ratio [OR], 0.06; 95% CI, 0.01–0.35) and tumor necrosis factor alpha (OR, 0.05; 95% CI, 0.00–0.43), independently predict cardiac improvement, creating a 2‐cytokine model effectively predicting responders (area under the curve, 0.903; P<0.0001).ConclusionsBaseline myocardial and systemic inflammatory burden inversely correlates with cardiac improvement following LVAD support. A circulating 2‐cytokine model predicting significant reverse remodeling was identified, warranting further investigation as a practical preintervention tool in identifying patients prone to LVAD‐mediated cardiac improvement and device weaning.

Bioenergetic and metabolic impairments in Duchenne Muscular Dystrophy (DMD) patients' iPSC-derived cardiomyocytes

Abstract Introduction DMD, an X-linked muscle degenerative fatal disease, is caused by mutations in the dystrophin gene. Dilated cardiomyopathy (DCM) is a major cause of morbidity and mortality in DMD patients. Treatments for DCM in DMD are limited to steroids and standard heart failure medications such as β-blockers and ACE-inhibitors, and therefore novel therapeutic modalities are urgently needed. Purpose We hypothesized that dystrophin mutations in DMD lead to cardiomyopathy-causing bioenergetic/metabolic impairments, which can be therapeutically targeted for improving cardiac function. Methods Induced Pluripotent Stem Cell-derived cardiomyocytes (iPSC-CMs) were generated from healthy volunteer and 3 DMD patients: young male (YM), adult male (AM) and adult female (AF). We investigated the bioenergetics, electrophysiology, mitochondrial and metabolic features of healthy and DMD iPSC-CMs using the Seahorse Flux analyzer, patch clamp, confocal fluorescence microscopy and Liquid chromatography mass spectrometry (LC-MS) technologies, respectively. Results To test the hypothesis, we measured respiration and glycolytic rates of healthy and DMD iPSC-CMs. Compared to healthy iPSC-CMs, in both AM and AF DMD, but not in YM DMD cardiomyocytes, there was a 75% decrease in ATP production, and 80% and 45% decrease in basal respiration, respectively. In agreement with the healthy-like bioenergetic status of YM, the iPSC-CMs showed no arrhythmias, in contrast to the prominent arrhythmias in AM and AF cardiomyocytes. To determine whether the impairment in the phosphorylation pathway (OXPHOS) affects glycolysis, we measured the cardiomyocytes' response to glycolytic stress test. These experiments showed that the glycolytic rates were similar in healthy and DMD iPSC-CMs. In agreement with impaired OXPHOS, mitochondrial activity measured by 3D life confocal microscopy was attenuated in the DMD male by 35%, compared to healthy cardiomyocytes. Furthermore, the metabolomic LC-MS analyses demonstrated significant differences in metabolite levels in YM, AM and AF DMD iPSC-CMs relative to healthy iPSC-CMs. For example, compared to healthy iPSC-CMs, there was a dramatic fall to undetected levels in phosphocreatine in both AM and AF, but not in YM DMD, indicating a dysfunctional phosphocreatine energy system. Conclusions DMD iPSC-CMs exhibit bioenergetic/metabolic impairments, which constitute novel targets for alleviating the cardiomyopathy in DMD patients. Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): ISF - Israel Science Foundation

Novel Neuromodulation Approach to Improve Left Ventricular Contractility in Heart Failure: A First-in-Human Proof-of-Concept Study.

Morbidity and mortality outcomes for patients admitted for acute decompensated heart failure are poor and have not significantly changed in decades. Current therapies are focused on symptom relief by addressing signs and symptoms of congestion. The objective of this study was to test a novel neuromodulation therapy of stimulation of epicardial cardiac nerves passing along the posterior surface of the right pulmonary artery. Fifteen subjects admitted for defibrillator implantation and ejection fraction ≤35% on standard heart failure medications were enrolled. Through femoral arterial access, high fidelity pressure catheters were placed in the left ventricle and aortic root. After electro anatomic rendering of the pulmonary artery and branches, either a circular or basket electrophysiology catheter was placed in the right pulmonary artery to allow electrical intravascular stimulation at 20 Hz, 4 ms pulse width, and ≤20 mA. Changes in maximum positive dP/dt (dP/dtMax) indicated changes in ventricular contractility. Of 15 enrolled subjects, 5 were not studied due to equipment failure or abnormal pulmonary arterial anatomy. In the remaining subjects, dP/dtMax increased significantly by 22.6%. There was also a significant increase in maximum negative dP/dt (dP/dtMin), mean arterial pressure, systolic pressure, diastolic pressure, and left ventricular systolic pressure. There was no significant change in heart rate or left ventricular diastolic pressure. In this first-in-human study, we demonstrated that in humans with stable heart failure, left ventricular contractility could be accentuated without an increase in heart rate or left ventricular filling pressures. This benign increase in contractility may benefit patients admitted for acute decompensated heart failure.

The Role of AMPK Activation for Cardioprotection in Doxorubicin-Induced Cardiotoxicity

Doxorubicin is a commonly used chemotherapeutic agent for the treatment of a range of cancers, but despite its success in improving cancer survival rates, doxorubicin is cardiotoxic and can lead to congestive heart failure. Therapeutic options for this patient group are limited to standard heart failure medications with the only drug specific for doxorubicin cardiotoxicity to reach FDA approval being dexrazoxane, an iron-chelating agent targeting oxidative stress. However, dexrazoxane has failed to live up to its expectations from preclinical studies while also bringing up concerns about its safety. Despite decades of research, the molecular mechanisms of doxorubicin cardiotoxicity are still poorly understood and oxidative stress is no longer considered to be the sole evil. Mitochondrial impairment, increased apoptosis, dysregulated autophagy and increased fibrosis have also been shown to be crucial players in doxorubicin cardiotoxicity. These cellular processes are all linked by one highly conserved intracellular kinase: adenosine monophosphate–activated protein kinase (AMPK). AMPK regulates mitochondrial biogenesis via PGC1α signalling, increases oxidative mitochondrial metabolism, decreases apoptosis through inhibition of mTOR signalling, increases autophagy through ULK1 and decreases fibrosis through inhibition of TGFβ signalling. AMPK therefore sits at the control point of many mechanisms shown to be involved in doxorubicin cardiotoxicity and cardiac AMPK signalling itself has been shown to be impaired by doxorubicin. In this review, we introduce different agents known to activate AMPK (metformin, statins, resveratrol, thiazolidinediones, AICAR, specific AMPK activators) as well as exercise and dietary restriction, and we discuss the existing evidence for their potential role in cardioprotection from doxorubicin cardiotoxicity.

Takotsubo Cardiomyopathy presenting with different morphological patterns in the same patient: a case report and review of the literature

Takotsubo Cardiomyopathy is characterized by transient left ventricular systolic dysfunction, which often mimics a myocardial infarction and is usually triggered by emotional or physical stress. There are four variants of Takotsubo Cardiomyopathy, based on the affected left ventricular area. We report a 75-year-old female with a past medical history of diabetes mellitus, hypertension, hyperlipidemia, and chronic kidney disease who presented with chest pain that had started after a stressful, emotional event. Her electrocardiogram showed no ischemic changes, troponin was mildly elevated, and cardiac catheterization revealed nonobstructive coronary artery disease. Echocardiogram showed a decreased ejection fraction and apical akinesia with basal hyperkinesia consistent with classical Takotsubo Cardiomyopathy. The patient symptomatically improved on optimal heart failure therapy, and a follow-up echocardiogram showed improvement in her systolic function. Over a year later, the patient was readmitted with chest pain, which also began after an emotional event. ECG showed nonspecific ST-T wave changes, and troponin was mildly elevated. Echocardiogram demonstrated a reduced ejection fraction and inferior akinesia with apical hyperkinesia consistent with reverse Takotsubo Cardiomyopathy. A repeat cardiac catheterization exhibited mild nonobstructive coronary artery disease unchanged from her previous report. A follow-up echocardiogram showed full recovery of her systolic function. Classical and reverse Takotsubo Cardiomyopathy due to different stressors have been reported in the literature individually, but up to our knowledge, both variants of Takotsubo Cardiomyopathy occurring in the same patient has not been reported previously.

Dilated cardiomyopathy in an adolescent – a diagnostic challenge

Background. Heart failure is a rare but serious diagnosis in pediatric patients. While in newborns and infants con­ge­ni­tal heart disease is commonly the cause, in older chil­dren and in adolescents cardiomyopathies (primary or se­con­dary) take the lead. The diagnosis may be difficult to establish, as the symptoms are nonspecific (especially in young ages). Case presentation. A previously healthy 16-year-old girl had been experiencing heart failure symp­toms for the past 10 months, with gradual worsening of symp­tom severity. Upon evaluation, a diagnosis of class III Ross/NYHA heart failure due to dilated cardiomyopathy with severe left ventricular systolic dysfunction was es­ta­blished. Standard heart failure medication was initiated, al­le­via­ting congestion and partially controlling symptoms. There was no family or personal history of heart disease. The patient reported excellent exercise tolerance previously. No exposure to potentially toxic agents has been identified. The initial tests could not establish a definite cause, al­though a possible respiratory tract infection at the onset of symptoms and certain cardiac magnetic resonance ima­ging features could suggest previous eosinophilic myo­car­di­tis. Current literature to guide the diagnosis pro­cess and treatment options are discussed. Conclusions. Di­la­ted cardiomyopathy is rare but severe in children. Even the ty­pi­cal symptoms may be downplayed or ignored for long pe­riods, delaying the diagnosis; a high index of suspicion is therefore required when other more common disorders seem unlikely or have been ruled out. The possible underlying cau­ses vary with age and differ from the adult population. An etiological diagnosis is frequently difficult to achieve, but must nonetheless be sought out, as it may allow for tar­ge­ted therapy and improve prognosis. However, long-term out­come is usually grim.

Sacubitril-Valsartan versus Standard Anti-Hypertensives in Left Ventricular Assist Device Patients

Introduction Hypertension is a common comorbidity affecting patients with left ventricular assist devices (LVAD). Left uncontrolled, it may lead to a decrease in LVAD support and increase the risk for stroke. The ISHLT defines hypertension in LVAD patients as a mean arterial pressure (MAP) of > 90 mmHg and recommends aggressive management utilizing standard heart failure medications. Sacubitril-valsartan (Entresto®) is an angiotension II blocker-neprilysin inhibitor with potent anti-hypertensive effects approved for the treatment of heart failure with a reduced ejection fraction. Our aim was to assess blood pressure control with sacubitril-valsartan versus standard anti-hypertensive therapy in our LVAD patients. Methods This is a single center evaluation of MAP reduction, stroke and readmission rates associated with sacubitril-valsartan versus standard anti-hypertensives in our HeartMate II (HMII) LVAD patients with a diagnosis of hypertension. Initial MAP measured by Doppler was assessed prior to initiation or intensification of therapy post LVAD implant and compared to the most recent clinic visit MAP. Patients were excluded if they did not have a recent MAP, were on intravenous inotropic therapy, were non-compliant or were implanted with an LVAD other than HMII. Results Due to exclusion criteria, only 26 patients were assessed, with 12 treated with sacubitril-valsartan. Patients treated with sacubitril-valsartan had an average MAP reduction of 20 mmHg. Those on standard anti-hypertensives had an average MAP reduction of 12 mmHg. Of the patients in the standard group, 46% had a documented stroke whereas no patients in the sacubitril-valsartan group had a stroke. Readmissions were also lower in the sacubitril-valsartan group with these patients requiring an average of three fewer hospitalizations. Adverse effects associated with sacubitril-valsartan were reported in three patients and included hypovolemia and lightheadedness leading to two discontinuations. Discussion In this single center retrospective analysis of HMII LVAD patients, sacubitril-valsartan provided a larger reduction in MAP when compared to standard anti-hypertensive therapy. Patients in the sacubitril-valsartan group were less likely to have a stroke and required fewer readmissions than those on standard therapies. Due to the non-randomized, retrospective nature of this study, confounding factors cannot be ruled out. Randomized trials are ongoing to assess the clinical benefits of its use on a larger scale.

Viral genome changes and the impact of viral genome persistence in myocardium of patients with inflammatory cardiomyopathy.

IntroductionViral infections are considered the most frequent cause of myocarditis and dilated cardiomyopathy (DCM).Material and methodsWe investigated the changes in viral presence and the impact of viral genome persistence in the myocardium on echocardiographic parameters, functional status and some laboratory parameters in a 6-month follow-up. Fifty-four patients with recent onset DCM, left ventricular ejection fraction < 40% and biopsy-proven myocarditis (> 14 mononuclear leukocytes/mm2 and/or > 7 T-lymphocytes/mm2) were enrolled. Polymerase chain reaction (PCR) was performed to detect pathogens in the myocardium. Patients were divided according to the administered therapy: standard heart failure medication (46 patients) and immunosuppressive therapy (8 patients).ResultsIn the standard heart failure medication group viral clearance was observed in 13 patients and viral persistence in 24 patients in the follow-up period. Comparing both groups, there was no statistically significant difference – LVEF improvement of 12.0 ±11.4% vs. 18.3 ±12.6%, decrease in NYHA class of 0.7 ±0.7 vs. 1.0 ±0.7, decline in NT-proBNP of 1335 ±1933 ng/l vs. 1942 ±3242 ng/l and decrease in infiltrating leukocytes of 11.1 ±15.8 vs. 6.7 ±23.0 cells/mm2 and T-lymphocytes of 5.8 ±15.1 vs. 1.8 ±10.9 cells/mm2 (all p = NS). A decrease in PCR positive patients from 37 to 29 was observed. The number of PVB19 positive PCR findings decreased from 5 to 4 in patients with immunosuppressive therapy.ConclusionsA decrease in the number of positive PCR findings in control endomyocardial biopsy was observed. Viral genome persistence was not associated with worse outcome in short-term follow-up.

MODELING THE DILATED CARDIOMYOPATHY WITH ATAXIA SYNDROME (DCMA), A PEDIATRIC MITOCHONDRIAL CARDIOMYOPATHY, USING CARDIOMYOCYTES DERIVED FROM INDUCED PLURIPOTENT STEM CELLS

Cardiomyopathy is a predominant and lethal feature of many inborn metabolic disorders but results from derangements in cellular energetics rather than ischemic myocardial injury. This fundamental difference is likely why standard heart failure medications appear to be ineffective. This problem is exemplified by the dilated cardiomyopathy with ataxia syndrome (DCMA). DCMA is related to Barth syndrome with abnormal cardiolipin and mitochondria causing heart failure, conduction defects and other systemic features. Isolated cases of DCMA have been identified worldwide but the largest known group of patients is found in the Hutterites of southern Alberta. No effective therapy exists and in our cohort there is 39% mortality in early childhood related to cardiac dysfunction despite recommended optimal medical therapy. The lack of useful drugs for mitochondrial cardiomyopathies means that there are few therapies available outside of mechanical circulatory support or heart transplantation. Since the rarity and heterogeneity of the pediatric cardiomyopathies preclude randomized drug trials, the use of patient cells and in vitro drug modeling represents the best possible option to identify effective therapeutics. Here, we describe the creation and characterization of cardiomyocytes derived from induced pluripotent stem cells (iPSC-CMs) (as an in vitro model of DCMA) from 4 children with DCMA and varying severity of cardiac dysfunction. Purified peripheral blood mononuclear cells derived from 4 DCMA patients (Table 1) were reprogrammed into induced pluripotent stem cells (iPSCs) using Sendai virus and the 4 Yamanaka factors, and characterized using standard pluripotency tests. Our iPSCs expressed markers of pluripotency including SSEA4 and OCT4. The DCMA-derived iPSCs were sequenced to detect the DCMA related mutation in their genomic DNA. Results showed that the iPSCs carried the DNAJC19 mutation (rs137854888) responsible for the abnormal splicing causing the disease phenotype. These iPSCs were successfully differentiated into beating cardiomyocytes using a modified protocol and lactate as a sole carbon source to enrich purified iPSC-CMs. The resulting iPSC-CMs expressed the cardiac-specific markers TNNT2 and NKX2.5. We describe the development of iPSC-CMs for DCMA which represent a novel in vitro model for mitochondrial cardiomyopathy and provide a platform to study the efficacy of potential therapeutics and genome editing approaches.

Ivabradine Improves Symptoms and Quality of Life in Chronic Systolic Heart Failure Patients With Different Baseline Symptom Severity

Introduction: The prospective, open-label, multicenter INTENSIfY study evaluated the effectiveness, tolerability, and effect on quality of life (QoL) of ivabradine treatment over a 4-month period in patients with chronic systolic heart failure (CHF). We performed a subgroup analysis to characterize the effectiveness and safety of ivabradine in addition to standard heart failure medication in patients with different severity of CHF symptoms. Methods: Resting heart rate (HR), heart failure symptoms (NYHA class, signs of decompensation), and concomitant medication were documented in ambulatory CHF patients. BNP measurements were tracked in subset of patients. Treatment with flexible doses of ivabradine twice daily was initiated for 4 months; dose adjustment was possible after 1 month. QoL was evaluated by the EQ-5D patient questionnaire at each visit. A descriptive statistical analysis of the results was performed for four subgroups defined by NYHA class at baseline (NYHA I-IV). Results: In total, 1956 patients (intention to treat, mean age 67.2611.7 years, 56% male) were analyzed. Etiology was ischemic for 62%; diagnosis had been known for more than 6 months for 85% of all patients. Overall, 78% received beta blockers: 33% metoprolol, mean daily dose (mdd) 102.9 mg; 28% bisoprolol, mdd 6.2 mg; 9% nebivolol, mdd 5.4 mg; and 7% carvedilol, mdd 27.1 mg). Other concomitant medication included ACEI/ARB (83%), diuretics (61%), aldosterone antagonists (18%), cardiac glycosides (8%), aspirin (58%), and statins (56%). After 4 months of ivabradine treatment (overall mdd 12.44 mg), patients had decreases in heart rate (17-21%) and increases in QoL scores (0.1-0.24), and most responded to

Low systolic blood pressure and high resting heart rate as predictors of outcome in patients with peripartum cardiomyopathy

BackgroundPatients with peripartum cardiomyopathy (PPCM) present with low blood pressure (SBP) often preventing uptitration of heart failure medication. We aimed to study prediction of risk and the contribution of high resting heart rate (HR) and low SBP to risk in recent onset of PPCM. MethodsClinical assessment with HR and SBP, echocardiography and laboratory results were obtained at baseline and at six months on 206 patients with recent onset PPCM enrolled at two tertiary care centers in South Africa. Poor outcome was defined as the combined endpoint of death, LVEF<35% or remaining in New York Heart Association (NYHA) functional class III/IV at six months. Complete LV recovery was defined as LVEF≥55% at six months. ResultsPoor outcome was observed in 110 of 220 patients (53%), with 26 patients dying at six months (12.6%). There were 98 (47.5%) patients with SBP≤110mmHg. Patients with high HR (HR≥100) and low SBP (<110mmHg) tended to have worse outcomes than patients below the HR median and high SBP. PPCM patients with low SBP and high HR were less likely to be on ACE-inhibitors (n=35, 69% versus n=129, 84%, p=0.024) and on the beta blocker carvedilol (n=24, 47% versus n=98, 64%, p=0.047). Low SBP, high HR and left ventricular end diastolic diameter at baseline were predictors of poor outcome. Patients with low SBP and high HR had the highest mortality (p=0.0023). ConclusionsThese findings suggest increased risk in patients with PPCM presenting with low SBP and high HR on standard heart failure medication possibly having implications on HF management.

Novel CHF Drug Shows Great Promise

Novel CHF Drug Shows Great Promise

Heart Failure with Preserved Ejection Fraction and Therapeutic Approaches: A Systematic Review and Meta-analysis

Aims: Evidence is still lacking regarding optimal treatment for patients with heart failure with preserved ejection fraction (HfPEF). Our objective is to present an individual evaluation foreach of the current available heart failure medications using a meta analytical model. Methods and Results: Using meta-analytical techniques we assessed the impact of standard systolic heart failure medications on the combined endpoint of all -cause mortality and/or hospitalization for heart failure as a primary endpoint and on mortality and heart failure hospitalization as separate secondary endpoints for patients with HfPEF. Studies were heterogeneous (Q test, p