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.
Abstract
Aims
Heart failure with preserved ejection fraction (HFpEF) and pathological cardiac aging share a complex pathophysiology, including extracellular matrix remodelling (EMR). ...Protease-activated receptor 2 (PAR2) deficiency is associated with EMR. The roles of PAR1 and PAR2 have not been studied in HFpEF, age-dependent cardiac fibrosis, or diastolic dysfunction (DD).
Methods and results
Evaluation of endomyocardial biopsies from patients with HFpEF (n = 14) revealed that a reduced cardiac PAR2 expression was associated with aggravated DD and increased myocardial fibrosis (r = −0.7336, P = 0.0028). In line, 1-year-old PAR2-knockout (PAR2ko) mice suffered from DD with preserved systolic function, associated with an increased age-dependent α-smooth muscle actin expression, collagen deposition (1.7-fold increase, P = 0.0003), lysyl oxidase activity, collagen cross-linking (2.2-fold increase, P = 0.0008), endothelial activation, and inflammation. In the absence of PAR2, the receptor-regulating protein caveolin-1 was down-regulated, contributing to an augmented profibrotic PAR1 and transforming growth factor beta (TGF-β)-dependent signalling. This enhanced TGF-β/PAR1 signalling caused N-proteinase (ADAMTS3) and C-proteinase (BMP1)-related increased collagen I production from cardiac fibroblasts (CFs). PAR2 overexpression in PAR2ko CFs reversed these effects. The treatment with the PAR1 antagonist, vorapaxar, reduced cardiac fibrosis by 44% (P = 0.03) and reduced inflammation in a metabolic disease model (apolipoprotein E-ko mice). Patients with HFpEF with upstream PAR inhibition via FXa inhibitors (n = 40) also exhibited reduced circulating markers of fibrosis and DD compared with patients treated with vitamin K antagonists (n = 20).
Conclusions
Protease-activated receptor 2 is an important regulator of profibrotic PAR1 and TGF-β signalling in the heart. Modulation of the FXa/FIIa-PAR1/PAR2/TGF-β-axis might be a promising therapeutic approach to reduce HFpEF.
Inflammation in myocarditis induces cardiac injury and triggers disease progression to heart failure. NLRP3 inflammasome activation is a newly identified amplifying step in the pathogenesis of ...myocarditis. We previously have demonstrated that mesenchymal stromal cells (MSC) are cardioprotective in Coxsackievirus B3 (CVB3)-induced myocarditis. In this study, MSC markedly inhibited left ventricular (LV) NOD2, NLRP3, ASC, caspase-1, IL-1β, and IL-18 mRNA expression in CVB3-infected mice. ASC protein expression, essential for NLRP3 inflammasome assembly, increased upon CVB3 infection and was abrogated in MSC-treated mice. Concomitantly, CVB3 infection in vitro induced NOD2 expression, NLRP3 inflammasome activation and IL-1β secretion in HL-1 cells, which was abolished after MSC supplementation. The inhibitory effect of MSC on NLRP3 inflammasome activity in HL-1 cells was partly mediated via secretion of the anti-oxidative protein stanniocalcin-1. Furthermore, MSC application in CVB3-infected mice reduced the percentage of NOD2-, ASC-, p10- and/or IL-1β-positive splenic macrophages, natural killer cells, and dendritic cells. The suppressive effect of MSC on inflammasome activation was associated with normalized expression of prominent regulators of myocardial contractility and fibrosis to levels comparable to control mice. In conclusion, MSC treatment in myocarditis could be a promising strategy limiting the adverse consequences of cardiac and systemic NLRP3 inflammasome activation.
There is growing evidence that a cross-talk exists between the renin-angiotensin (Ang) system and lipoproteins. We investigated the role of high-density lipoprotein (HDL) on Ang II type 1 receptor ...(AT1R) regulation and subsequent Ang II-mediated signaling under diabetic conditions. To investigate the effect of HDL on AT1R expression in vivo, apolipoprotein A-I gene transfer was performed 5 days after streptozotocin injection. Six weeks after apolipoprotein A-I gene transfer, the 1.9-fold (P=0.001) increase of HDL cholesterol was associated with a 4.7-fold (P<0.05) reduction in diabetes mellitus-induced aortic AT1R expression. Concomitantly, NAD(P)H oxidase activity, Nox 4, and p22(phox) mRNA expression were reduced 2.6-fold, 2.0-fold, and 1.5-fold (P<0.05), respectively, whereas endothelial NO synthase dimerization was increased 3.3-fold (P<0.005). Apolipoprotein A-I transfer improved NO bioavailability as indicated by ameliorated acetylcholine-dependent vasodilation in the streptozotocin-Ad.hapoA-I group compared with streptozotocin-induced diabetes mellitus. In vitro, HDL reduced the hyperglycemia-induced upregulation of the AT1R in human aortic endothelial cells. This was associated with a 1.3-fold and 2.2-fold decreases in reactive oxygen species and NAD(P)H oxidase activity, respectively (P<0.05). Finally, HDL reduced the responsiveness to Ang II, as indicated by decreased oxidative stress in the hyperglycemia+HDL+Ang II group compared with the hyperglycemia+Ang II group. In conclusion, vascular-protective effects of HDL include the downregulation of the AT1R.
The coxsackievirus and adenovirus receptor (CAR) mediates homo- and heterotopic interactions between neighboring cardiomyocytes at the intercalated disc. CAR is upregulated in the hypoxic areas ...surrounding myocardial infarction (MI). To elucidate whether CAR contributes to hypoxia signaling and MI pathology, we used a gain- and loss-of-function approach in transfected HEK293 cells, H9c2 cardiomyocytes and CAR knockout mice. CAR overexpression increased RhoA activity, HIF-1α expression and cell death in response to chemical and physical hypoxia. In vivo, we subjected cardiomyocyte-specific CAR knockout (KO) and wild-type mice (WT) to coronary artery ligation. Survival was drastically improved in KO mice with largely preserved cardiac function as determined by echocardiography. Histological analysis revealed a less fibrotic, more compact lesion. Thirty days after MI, there was no compensatory hypertrophy or reduced cardiac output in hearts from CAR KO mice, in contrast to control mice with increased heart weight and reduced ejection fraction as signs of the underlying pathology. Based on these findings, we suggest CAR as a therapeutic target for the improved future treatment or prevention of myocardial infarction.
Graphical Abstract
Epicardial adipose tissue (EAT)-related heart failure with preserved ejection fraction (HFpEF). Obesity and type 2 diabetes mellitus (T2DM) are common triggers of HFpEF, frequently ...associated with EAT expansion. EAT plays metabolic and mechanical roles in HFpEF development
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para/vasocrine factors and pericardial restrain, respectively. Life-style modifications including healthy diet and regular exercise can quash the EAT expansion. Statins, proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors and fat-modulating antidiabetics including metformin, sodium-glucose cotransporter 2 (SGLT2) inhibitors and glucagon-like peptide-1 (GLP-1) agonists can target EAT. FFA, free fatty acids; AGEs, advanced glycation end-products; NO, nitric oxide; ROS, reactive oxygen species; Ang-II, angiotensin II; TGF-β, Transforming growth factor beta; MCP-1, monocyte chemoattractant protein 1; IL-6, interleukin 6; TNF-α, tumor necrosis factor alpha. Figure created
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Servier Medical Art and BioRender tools.
Heart failure with preserved ejection fraction (HFpEF) is a heterogeneous syndrome with diverse etiologies and pathophysiological factors. Obesity and type 2 diabetes mellitus (T2DM), conditions that coexist frequently, induce a cluster of metabolic and non-metabolic signaling derangements which are in favor to induce inflammation, fibrosis, myocyte stiffness, all hallmarks of HFpEF. In contrast to other HFpEF risk factors, obesity and T2DM are often associated with the generation of enlarged epicardial adipose tissue (EAT). EAT acts as an endocrine tissue that may exacerbate myocardial inflammation and fibrosis
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various paracrine and vasocrine signals. In addition, an abnormally large EAT poses mechanical stress on the heart
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pericardial restrain. HFpEF patients with enlarged EAT may belong to a unique phenotype that can benefit from specific EAT-targeted interventions, including life-style modifications and pharmacologically
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statins and fat modifying anti-diabetics drugs; like metformin, sodium-glucose cotransporter 2 inhibitors, or glucagon-like peptide-1 receptor agonists, respectively.
In 99mTcTc-DPD scintigraphy for myocardial ATTR amyloidosis, planar images 3 hour p.i. and SPECT/CT acquisition in L-mode are recommended. This study investigated if earlier planar images (1 hour ...p.i.) are beneficial and if SPECT/CT acquisition should be preferred in H-mode (180° detector angle) or L-mode (90°).
In SPECT/CT phantom measurements (NaI cameras, N = 2; CZT, N = 1), peak contrast recovery (CRpeak) was derived from sphere inserts or myocardial insert (cardiac phantom; signal-to-background ratio SBR, 10:1 or 5:1). In 25 positive and 38 negative patients (reference: endomyocardial biopsy or clinical diagnosis), Perugini scores and heart-to-contralateral (H/CL) count ratios were derived from planar images 1 hour and 3 hour p.i.
In phantom measurements, accuracy of myocardial CRpeak at SBR 10:1 (H-mode, 0.95-0.99) and reproducibility at 5:1 (H-mode, 1.02-1.14) was comparable for H-mode and L-mode. However, L-mode showed higher variability of background counts and sphere CRpeak throughout the field of view than H-mode. In patients, sensitivity/specificity were ≥ 95% for H/CL ratios at both time points and visual scoring 3 hour. At 1 hour, visual scores showed specificity of 89% and reduced reader’s confidence.
Early DPD images provided no additional value for visual scoring or H/CL ratios. In SPECT/CT, H-mode is preferred over L-mode, especially if quantification is applied apart from the myocardium.
En la gammagrafía con 99mTc-DPD para amiloidosis cardiaca ATTR, se recomienda la adquisición de imágenes planares a las 3h p.i y SPECT/CT en modo L. Este estudio investigó si las imágenes planares más tempranas (1h p.i.) tienen beneficios y si la adquisición del SPECT/CT debería preferirse en modo H (ángulo de detección de 180 °) o en modo L (90 °).
En las mediciones con el fantoma del SPECT/CT (cámaras de NaI, n= 2; CZT, n=1), la recuperación pico de contraste (CRpico) se derivó de inserciones de esfera o de inserciones miocárdicas (fantoma cardiaco; relación señal-fondo SBR, 10:1 o 5: 1). En 25 pacientes positivos y 38 negativos (referencia: biopsia endomiocárdica o diagnóstico clínico), el score de Perugini y la relación de cuentas corazón-contralateral (H/CL) se derivaron de imágenes planares a 1h y 3h p.i.
En mediciones con el fantoma, la precisión del CRpico miocárdico en SBR 10:1 (modo H, 0.95-0.99) y la reproducibilidad a 5:1 (modo H, 1.02-1.14) fue comparable para el modo H y el modo L. Sin embargo, el modo L mostró una mayor variabilidad de las cuentas de fondo y del CRpico de la esfera en todo el campo de visión que el modo H. En pacientes, la sensibilidad/especificidad fue ≥ 95% para las relaciones H/CL en ambos puntos de tiempo y con un score visual a las 3 h. A 1h, los scores visuales mostraron una especificidad de (89%) y disminución de la confianza del lector.
Las imágenes tempranas de DPD no proporcionaron ningún valor adicional para el score visual o las relaciones H/CL. En SPECT/CT, se prefiere el modo H sobre el modo L, especialmente si la cuantificación se aplica aparte del miocardio.
99mTcTc-DPD闪烁显像检查心肌ATTR淀粉样变性时, 建议使用3h p.i.平面图像和L模式SPECT/CT扫描。本研究探讨了早期平面图像(1h p.i.)是否有益, 以及SPECT/CT采集是否应首选H模式(探测器角度180°)或L模式(90°)。
在SPECT/CT模体测量中(NaI相机, n=2;CZT, n=1), 峰值造影剂恢复(CRpeak)来自球体插入物或心肌插入物(心脏模体; 信号与背景比SBR, 10:1 或5:1)。在25个阳性和38个阴性病人中(参考标准: 心内膜活检或临床诊断), Perugini分数和心脏/对侧 (H / CL)计数比率来自平面图像1 h和3 h p.i.。
在模体测量中, 心肌CRpeak的SBR准确性 10:1 (H-mode, 0.95 - 0.99)和可重复性5:1 (H-mode, 1.02 - 1.14), H模式和L 模式相当。然而, 与H模式相比, L模式在整个视野中表现出更高的背景计数和球形CRpeak变异性。在患者中, 两个时间点的H/CL比值以及3h视觉评分的敏感性/特异性均≥95%。1h时, 视觉评分特异性为89%, 阅读者的信心降低。
DPD早期图像对视觉评分和H/CL比值没有额外的价值。在SPECT/CT中, H模式优于L模式, 特别是心肌之外定量时。
The introduction of automated oscillometric blood pressure monitors was the basis for today's widespread use of blood pressure self-measurement. However, in atrial fibrillation, there is a ...controversial debate on the use of oscillometry because there is a high variability of heart rate and stroke volume. To date, the accuracy of oscillometric blood pressure monitoring in atrial fibrillation has only been investigated using auscultatory sphygmomanometry as reference method, which may be biased by arrhythmia as well. We performed a cross-sectional study in 102 patients (52 sinus rhythm, 50 atrial fibrillation) assessing the accuracy of an automated and validated oscillometric upper arm (M5 Professional, Omron) and wrist device (R5 Professional, Omron) to invasively assessed arterial pressure. Blood pressure values were calculated as the mean of 3 consecutive measurements. Systolic and diastolic blood pressure did not significantly differ in patients with sinus rhythm and atrial fibrillation, independent of the method of measurement (P>0.05 each). The within-subject variability of the oscillometric measurements was higher in patients with atrial fibrillation compared with sinus rhythm (P<0.01 each). The biases of systolic and diastolic blood pressure, however, did not significantly differ in presence or absence of atrial fibrillation in Bland-Altmann analysis (P>0.05 each). In conclusion, atrial fibrillation did not significantly affect the accuracy of oscillometric measurements, if 3 repeated measurements were performed.
This study investigated the spontaneous clinical course of patients with endomyocardial biopsy (EMB)-proven lymphocytic myocarditis and cardiac human herpesvirus 6 (HHV6) DNA presence, and the ...effectiveness of steroid-based intervention in HHV6-positive patients.
756 heart failure (HF) patients underwent an EMB procedure to determine the underlying cause of unexplained HF. Low levels of HHV6 DNA, detectable by nested PCR only, were found in 10.4% of the cases (
= 79) of which 62% (
= 49) showed myocardial inflammation. The spontaneous course of patients with EMB-proven HHV6 DNA-associated lymphocytic myocarditis (
= 26) showed significant improvements in the left ventricular ejection fraction (LVEF) and clinical symptoms, respectively, in 15/26 (60%) patients, 3-12 months after disease onset. EMB mRNA expression of components of the NLRP3 inflammasome pathway and protein analysis of cardiac remodeling markers, analyzed by real-time PCR and MALDI mass spectrometry, respectively, did not differ between HHV6-positive and -negative patients. In another cohort of patients with ongoing symptoms related to lymphocytic myocarditis associated with cardiac levels of HHV6-DNA copy numbers <500 copies/µg cardiac DNA, quantified by real-time PCR, the efficacy and safety of steroid-based immunosuppression for six months was investigated. Steroid-based immunosuppression improved the LVEF (≥5%) in 8/10 patients and reduced cardiac inflammation in 7/10 patients, without an increase in cardiac HHV6 DNA levels in follow-up EMBs.
Low HHV6 DNA levels are frequently detected in the myocardium, independent of inflammation. In patients with lymphocytic myocarditis with low levels of HHV6 DNA, the spontaneous clinical improvement is nearby 60%. In selected symptomatic patients with cardiac HHV6 DNA copy numbers less than 500 copies/µg cardiac DNA and without signs of an active systemic HHV6 infection, steroid-based therapy was found to be effective and safe. This finding needs to be further confirmed in large, randomized trials.
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