Long-term outcomes of autologous skeletal myoblast cell-sheet transplantation for end-stage ischemic cardiomyopathy.

We evaluated the cardiac function recovery following skeletal myoblast cell-sheet transplantation and the long-term outcomes after applying this treatment in 23 patients with ischemic cardiomyopathy. We defined patients as "responders" when their left ventricular ejection fraction remained unchanged or improved at 6 months after treatment. At 6 months, 16 (69.6%) patients were defined as responders, and the average increase in left ventricular ejection fraction was 4.9%. The responders achieved greater improvement degrees in left ventricular and hemodynamic function parameters, and they presented improved exercise capacity. During the follow-up period (56 ± 28 months), there were four deaths and the overall 5-year survival rate was 95%. Although the responders showed higher freedom from mortality and/or heart failure admission (5-year, 81% versus 0%; p = 0.0002), both groups presented an excellent 5-year survival rate (5-year, 93% versus 100%; p = 0.297) that was higher than that predicted using the Seattle Heart Failure Model. The stepwise logistic regression analysis showed that the preoperative estimated glomerular filtration rate and the left ventricular end-systolic volume index were independently associated with the recovery progress. Approximately 70% of patients with "no-option" ischemic cardiomyopathy responded well to the cell-sheet transplantation. Preoperative renal and left ventricular function might predict the patients' response to this treatment.

Cardiomyopathy and altered integrin-actin signaling in Fhl1 mutant female mice.

X-linked scapuloperoneal myopathy (X-SM), one of Four-and-a-half LIM 1 (FHL1) related diseases, is an adult-onset slowly progressive myopathy, often associated with cardiomyopathy. We previously generated a knock-in mouse model that has the same mutation (c.365 G > C, p.W122S) as human X-SM patients. The mutant male mouse developed late-onset slowly progressive myopathy without cardiomyopathy. In this study, we observed that heterozygous (Het) and homozygous (Homo) female mice did not show alterations of skeletal muscle function or histology. In contrast, 20-month-old mutant female mice showed signs of cardiomyopathy on echocardiograms with increased systolic diameter [wild-type (WT): 2.74 ± 0.22 mm, mean ± standard deviation (SD); Het: 3.13 ± 0.11 mm, P < 0.01; Homo: 3.08 ± 0.37 mm, P < 0.05) and lower fractional shortening (WT: 31.1 ± 4.4%, mean ± SD; Het: 22.7 ± 2.5%, P < 0.01; Homo: 22.4 ± 6.9%, P < 0.01]. Histological analysis of cardiac muscle revealed frequent extraordinarily large rectangular nuclei in mutant female mice that were also observed in human cardiac muscle from X-SM patients. Western blot demonstrated decreased Fhl1 protein levels in cardiac muscle, but not in skeletal muscle, of Homo mutant female mice. Proteomic analysis of cardiac muscle from 20-month-old Homo mutant female mice indicated abnormalities of the integrin signaling pathway (ISP) in association with cardiac dysfunction. The ISP dysregulation was further supported by altered levels of a subunit of the ISP downstream effectors Arpc1a in Fhl1 mutant mice and ARPC1A in X-SM patient muscles. This study reveals the first mouse model of FHL1-related cardiomyopathy and implicates ISP dysregulation in the pathogenesis of FHL1 myopathy.

Elevated dual specificity protein phosphatase 4 in cardiomyopathy caused by lamin A/C gene mutation is primarily ERK1/2-dependent and its depletion improves cardiac function and survival.

Mutations in the lamin A/C gene (LMNA) encoding the nuclear intermediate filament proteins lamins A and C cause a group of tissue-selective diseases, the most common of which is dilated cardiomyopathy (herein referred to as LMNA cardiomyopathy) with variable skeletal muscle involvement. We previously showed that cardiomyocyte-specific overexpression of dual specificity protein phosphatase 4 (DUSP4) is involved in the pathogenesis of LMNA cardiomyopathy. However, how mutations in LMNA activate Dusp4 expression and whether it is necessary for the development of LMNA cardiomyopathy are currently unknown. We now show that female LmnaH222P/H222P mice, a model for LMNA cardiomyopathy, have increased Dusp4 expression and hyperactivation of extracellular signal-regulated kinase (ERK) 1/2 with delayed kinetics relative to male mice, consistent with the sex-dependent delay in the onset and progression of disease. Mechanistically, we show that the H222P amino acid substitution in lamin A enhances its binding to ERK1/2 and increases sequestration at the nuclear envelope. Finally, we show that genetic deletion of Dusp4 has beneficial effects on heart function and prolongs survival in LmnaH222P/H222P mice. These results further establish Dusp4 as a key contributor to the pathogenesis of LMNA cardiomyopathy and a potential target for drug therapy.

Recovery From Exhaustion of the Frank-Starling Mechanism by Mechanical Unloading With a Continuous-Flow Ventricular Assist Device.

BACKGROUND: We describe our original left ventricular assist device (LVAD) speed ramp and volume loading test designed to evaluate native heart function under continuous-flow LVAD support.Methods and Results:LVAD speed was decreased in 4 stages from the patient's optimal speed to the minimum setting for each device. Under minimal LVAD support, patients were subjected to saline loading (body weight [kg]×10 mL in 15 min). Echocardiographic and hemodynamic data were obtained at each stage of the LVAD speed ramp and every 3 min during saline loading. Patients were divided into Recovery (with successful LVAD removal; n=8) and Non-recovery (others; n=31) groups. During testing, increased pulmonary capillary wedge pressure caused by volume loading was milder in the Recovery than Non-recovery group (repeated measures analysis of variance; group effect, P=0.0069; time effect, P<0.0001; interaction effect, P=0.0173). Increased cardiac output from volume loading was significantly higher in the Recovery than Non-recovery group (group effect, P=0.0124; time effect, P<0.0001; interaction effect, P=0.0091). Therefore, the Frank-Starling curve of the Recovery group was located upward and to the left of that of the Non-recovery group. CONCLUSIONS: The LVAD speed ramp and volume loading test facilitates the precise evaluation of native heart function during continuous-flow LVAD support.

Jarvik 2000 with postauricular cable as destination therapy: first clinical case in Japan.

Currently in Japan, a left ventricular assist device powered by an abdominal driveline is the only type of left ventricular assist device available. The driveline is vulnerable to infection secondary to inappropriate fixation and the traditional Japanese custom of bathing is prohibited in patients with an abdominal driveline. The Jarvik 2000 with postauricular cable is a left ventricular assist device in which the driveline exits the body behind the ear (postauricular) instead of exiting through an abdominal site. This case report is the first to describe the implantation of Jarvik 2000 with postauricular cable as destination therapy in a Japanese patient. This device enables patients to take a bath and may reduce the incidence of driveline infection.

Decreased WNT/ß-catenin signalling contributes to the pathogenesis of dilated cardiomyopathy caused by mutations in the lamin a/C gene.

Cardiomyopathy caused by lamin A/C gene (LMNA) mutations (hereafter referred as LMNA cardiomyopathy) is characterized by cardiac conduction abnormalities and left ventricular systolic dysfunction predisposing to heart failure. Previous cardiac transcriptional profiling of LmnaH222P/H222P mouse, a small animal model of LMNA cardiomyopathy, suggested decreased WNT/ß-catenin signalling. We confirmed decreased WNT/ß-catenin signalling in the hearts of these mice by demonstrating decreased ß-catenin and WNT proteins. This was correlated with increased expression of soluble Frizzled-related proteins that modulate the WNT/ß-catenin signalling pathway. Hearts of LmnaH222P/H222P mice also demonstrated lowered expression of the gap junction connexin 43. Activation of WNT/ß-catenin activity with 6-bromoindirubin-3'-oxime improved cardiac contractility and ameliorated intraventricular conduction defects in LmnaH222P/H222P mice, which was associated with increased expression of myocardial connexin 43. These results indicate that decreased WNT/ß-catenin contributes to the pathophysiology of LMNA cardiomyopathy and that drugs activating ß-catenin may be beneficial in affected individuals.

Old-Age Onset Progressive Cardiac Contractile Dysfunction in a Patient with Polycystic Kidney Disease Harboring a PKD1 Frameshift Mutation.

A 70-year-old man with dyspnea was admitted to our department and received standard therapy for recurrent heart failure. He was diagnosed with polycystic kidney disease (PKD) in his thirties and received hemodialysis for 4 years before undergoing renal transplantation at age 45. Although his left ventricular ejection fraction (LVEF) was preserved in his 50s, LVEF decreased progressively from 61% to 24%, while left ventricular diastolic dimension (LVDd) increased from 54 mm to 65 mm between 63 and 69 years of age. Right ventricular endomyocardial biopsy demonstrated myocardial disarray and interstitial fibrosis. Genetic analysis identified a heterozygous frameshift mutation in PKD1, which encodes polycystin-1, a major causative gene of PKD. We detected PKD1 protein expression in myocardial tissue by immunostaining. Recent epidemiological studies and animal models have clarified the pathological correlation between ventricular contractile dysfunction and PKD1 function. Here, we present a case of old-age onset progressive cardiac contractile dysfunction with a PKD1 gene mutation.

ERK1/2 directly acts on CTGF/CCN2 expression to mediate myocardial fibrosis in cardiomyopathy caused by mutations in the lamin A/C gene.

Cardiomyopathy caused by lamin A/C gene mutations (LMNA cardiomyopathy) is characterized by increased myocardial fibrosis, which impairs left ventricular relaxation and predisposes to heart failure, and cardiac conduction abnormalities. While we previously discovered abnormally elevated extracellular signal-regulated kinase 1/2 (ERK1/2) activities in heart in LMNA cardiomyopathy, its role on the development of myocardial fibrosis remains unclear. We now showed that transforming growth factor (TGF)-ß/Smad signaling participates in the activation of ERK1/2 signaling in LMNA cardiomyopathy. ERK1/2 acts on connective tissue growth factor (CTGF/CCN2) expression to mediate the myocardial fibrosis and left ventricular dysfunction. Studies in vivo demonstrate that inhibiting CTGF/CCN2 using a specific antibody decreases myocardial fibrosis and improves the left ventricular dysfunction. Together, these findings show that cardiac ERK1/2 activity is modulated in part by TGF-ß/Smad signaling, leading to altered activation of CTGF/CCN2 to mediate fibrosis and alter cardiac function. This identifies a novel mechanism in the development of LMNA cardiomyopathy.

Macrocyclic MEK1/2 inhibitor with efficacy in a mouse model of cardiomyopathy caused by lamin A/C gene mutation.

Signaling mediated by extracellular signal-regulated kinases 1 and 2 (ERK1/2) is involved in numerous cellular processes. Mitogen-activated protein kinase kinases (MEK1/2) catalyze the phosphorylation of ERK1/2, converting it into an active kinase that regulates the expression of numerous genes and cellular processes. Inhibitors of MEK1/2 have demonstrated preclinical and clinical efficacy in certain cancers and types of cardiomyopathy. We report the synthesis of a novel, allosteric, macrocyclic MEK1/2 inhibitor that potently inhibits ERK1/2 activity in cultured cells and tissues of mice after systemic administration. Mice with dilated cardiomyopathy caused by a lamin A/C gene mutation have abnormally increased cardiac ERK1/2 activity. In these mice, this novel MEK1/2 inhibitor is well tolerated, improves left ventricular systolic function, decreases left ventricular fibrosis, has beneficial effects on skeletal muscle structure and pathology and prolongs survival. The novel MEK1/2 inhibitor described herein may therefore find clinical utility in the treatment of this rare cardiomyopathy, other types of cardiomyopathy and cancers in humans.

Mitogen-activated protein kinase kinase 1/2 inhibition and angiotensin II converting inhibition in mice with cardiomyopathy caused by lamin A/C gene mutation.

BACKGROUND: Mutations in the LMNA gene encoding A-type nuclear lamins can cause dilated cardiomyopathy with or without skeletal muscular dystrophy. Previous studies have shown abnormally increased extracellular signal-regulated kinase 1/2 activity in hearts of Lmna(H222P/H222P) mice, a small animal model. Inhibition of this abnormal signaling activity with a mitogen-activated protein kinase kinase 1/2 (MEK1/2) inhibitor has beneficial effects on heart function and survival in these mice. However, such treatment has not been examined relative to any standard of care intervention for dilated cardiomyopathy or heart failure. We therefore examined the effects of an angiotensin II converting enzyme (ACE) inhibitor on left ventricular function in Lmna(H222P/H222P) mice and assessed if adding a MEK1/2 inhibitor would provide added benefit. METHODS: Male Lmna(H222P/H222P) mice were treated with the ACE inhibitor benazepril, the MEK1/2 inhibitor selumetinib or both. Transthoracic echocardiography was used to measure left ventricular diameters and fractional shortening was calculated. RESULTS: Treatment of Lmna(H222P/H222P) mice with either benazepril or selumetinib started at 8weeks of age, before the onset of detectable left ventricular dysfunction, lead to statistically significantly increased fractional shortening compared to placebo at 16weeks of age. There was a trend towards a great value for fractional shortening in the selumetinib-treated mice. When treatment was started at 16weeks of age, after the onset of left ventricular dysfunction, the addition of selumetinib treatment to benazepril lead to a statistically significant increase in left ventricular fractional shortening at 20weeks of age. CONCLUSIONS: Both ACE inhibition and MEK1/2 inhibition have beneficial effects on left ventricular function in Lmna(H222P/H222P) mice and both drugs together have a synergistic benefit when initiated after the onset of left ventricular dysfunction. These results provide further preclinical rationale for a clinical trial of a MEK1/2 inhibitor in addition to standard of care in patients with dilated cardiomyopathy caused by LMNA mutations.

Left ventricular longitudinal strain by speckle-tracking echocardiography is associated with treatment-requiring cardiac allograft rejection.

BACKGROUND: Noninvasive detection of rejection is a major objective in the management of heart transplant recipients. METHODS AND RESULTS: To investigate the utility of 2-dimensional speckle-tracking echocardiography (2D-STE), we retrospectively evaluated 160 sets of endomyocardial biopsies and echocardiograms from 59 asymptomatic heart transplant recipients. Conventional International Society for Heart and Lung Transplantation grade 1B or higher rejection was considered as treatment-requiring rejection (group R), whereas International Society for Heart and Lung Transplantation grade 0 or 1A was classified as group Non-R. Left ventricular global longitudinal strain (GLS), global circumferential strain, and global radial strain were assessed by 2D-STE. Twenty-five specimens were classified into group R. GLS was significantly associated with treatment-requiring rejection, whereas neither global radial strain nor global circumferential strain were. Lower GLS remained significantly associated with an increased risk of treatment-requiring rejection (odds ratio, 1.15 [95% CI, 1.01-1.30]; P=0.03) even in multivariate analysis. GLS with the absolute value of less than 14.8% showed sensitivity and specificity of 64% and 63%, respectively, for detection of treatment-requiring rejection. CONCLUSION: The 2D-STE-derived left ventricular GLS was associated with treatment-requiring rejection. Two-dimensional STE might be useful as a noninvasive supplemental tool for monitoring heart transplant recipients for possible treatment-requiring rejection.

Novel indices representing heterogeneous distributions of myocardial perfusion imaging.

INTRODUCTION: Heterogeneous distribution in myocardial perfusion images (MPI) obtained by scintigraphy is often observed in cardiac diseases with normal myocardial perfusion. However, quantitative assessments of such heterogeneity have not been established. We hypothesized that the heterogeneity in MPI can be quantitatively evaluated through histogram analysis, calculating the standard deviation (SD), the 95% bandwidth (BW95%), and entropy. METHODS: We examined resting 99mTc-MIBI images in 20 healthy subjects and 29 patients with cardiac disease who had none or very-mild reduced myocardial perfusion evaluated as a low summed rest score (0 to 4, the range of the studied healthy subjects). Two nuclear medicine specialists blindly divided them into two groups: non-heterogeneity or heterogeneity group, based solely on their visual assessments of heterogeneity on splash and polar maps generated from single-photon emission computed tomography (SPECT) images. The %uptake was determined by dividing the tracer count of each pixel by the tracer count of the pixel with the highest value in the LV myocardium. SD, BW95%, and entropy from histogram patterns were analyzed from the polar map data array of each %uptake. We investigated whether heterogeneity could be assessed using SD, BW95, and entropy in two groups classified by visual assessments. Additionally, we evaluated the area under the curve (AUC) to identify heterogeneity in the receiver operating characteristic curve analysis. RESULTS: Based solely on visual assessments, 11 (22%) and 38 (78%) cases were classified into the non-heterogeneity and heterogeneity groups, respectively. The non-heterogeneity group consisted of only healthy subjects, and all patients with cardiac disease were classified into the heterogeneity group. The cases in the heterogeneity group had significantly higher values of heterogeneity indices (SD, BW95%, and entropy) in %uptake than those in the non-heterogeneity group (p < 0.05 for all). The AUCs of the heterogeneity indices were sufficiently high (AUCs > 0.90 for all) in distinguishing cases with visually heterogeneous distribution or patients with cardiac disease. CONCLUSIONS: Heterogeneity in MPI can be evaluated using SD, BW95%, and entropy through histogram analysis. These novel indices may help identify patients with subtle myocardial changes, even in images that show preserved perfusion (345/350).

Diverse distribution patterns of segmental longitudinal strain are associated with different clinical features and outcomes in dilated cardiomyopathy.

BACKGROUND: Dilated cardiomyopathy (DCM) presents with diverse clinical courses, hardly predictable solely by the left ventricular (LV) ejection fraction (EF). Longitudinal strain (LS) offers distinct information from LVEF and exhibits various distribution patterns. This study aimed to evaluate the clinical significance of LS distribution patterns in DCM. METHODS: We studied 139 patients with DCM (LVEF ≤ 35%) who were admitted for heart failure (HF). LS distribution was assessed using a bull's eye map and the relative apical LS index (RapLSI), calculated by dividing apical LS by the sum of basal and mid-LS values. We evaluated the associations of LS distribution with cardiac events (cardiac death, LV assist device implantation, or HF hospitalization) and LV reverse remodeling (LVRR), as indicated by subsequent LVEF changes. RESULTS: Twenty six (19%) and 29 (21%) patients exhibited a pattern of relatively apical impaired or preserved LS (defined by RapLSI < 0.25 or > 0.75, signifying a 50% decrease or increase in apical LS compared to other segments), and the remaining patients exhibited a scattered/homogeneously impaired LS pattern. The proportion of new-onset heart failure and LVEF differed between the three groups. During the median 595-day follow-up, patients with relatively-impaired apical LS had a higher rate of cardiac events (both log-rank p < 0.05) and a lower incidence of LVRR (both p < 0.01) compared to patients with other patterns. RapLSI was significantly associated with cardiac event rates after adjusting for age, sex, and new-onset HF or global LS. CONCLUSION: DCM patients with reduced EF and distinct distribution patterns of impaired LS experienced different outcomes.

Switching from Beraprost to Selexipag in the Treatment of Pulmonary Arterial Hypertension: Insights from a Phase IV Study of the Japanese Registry (The EXCEL Study: EXChange from bEraprost to seLexipag Study).

Pulmonary arterial hypertension (PAH) remains a significant challenge in cardiology, necessitating advancements in treatment strategies. This study explores the safety and efficacy of transitioning patients from beraprost to selexipag, a novel selective prostacyclin receptor agonist, within a Japanese cohort. Employing a multicenter, open-label, prospective design, 25 PAH patients inadequately managed on beraprost were switched to selexipag. Key inclusion criteria included ongoing beraprost therapy for ≥3 months, a diagnosis of PAH confirmed by mean pulmonary artery pressure (mPAP) ≥ 25 mmHg, and current treatment with endothelin receptor antagonists and/or phosphodiesterase type 5 inhibitors. Outcomes assessed were changes in hemodynamic parameters (mPAP, cardiac index, pulmonary vascular resistance) and the 6 min walk distance (6-MWD) over 3-6 months. The study found no statistically significant changes in these parameters post-switch. However, a subset of patients, defined as responders, demonstrated improvements in all measured hemodynamic parameters, suggesting a potential benefit in carefully selected patients. The transition was generally well-tolerated with no serious adverse events reported. This investigation underscores the importance of personalized treatment strategies in PAH, highlighting that certain patients may benefit from switching to selexipag, particularly those previously on higher doses of beraprost. Further research is needed to elucidate the predictors of positive response to selexipag and optimize treatment regimens for this complex condition.

Arterial repair 4 months after zotarolimus-eluting stent implantation observed on angioscopy.

BACKGROUND: Arterial repair in the early phase following implantation of a zotarolimus-eluting stent (ZES) remains unknown. METHODS AND RESULTS: Following implantation of 49 Endeavor ZES in 33 patients, follow-up angioscopy was performed in 13 patients (26 ZES) in the early phase (EP; 123±24 days) and in 20 patients (23 ZES) in the middle phase (MP; 247±17 days). Neointimal coverage (NIC) was graded as follows: grade 0, stent struts exposed; grade 1, struts bulging into the lumen, although covered; grade 2, struts were embedded by the neointima but were seen translucently; grade 3, struts fully embedded and invisible. NIC was defined as heterogeneous for NIC grade variation≥1. The presence of thrombus and yellow plaque was also investigated. Although NIC heterogeneity tended to be more frequent in EP than in MP (50% vs. 22%, P=0.070), and yellow plaque significantly more frequent (58% vs. 13%, P=0.0025), the majority of stents were dominant NIC grade 3 at both follow-up periods (73% in EP vs. 78% in MP, P=0.75). There was no significant difference in thrombus (23% in EP vs. 4% in MP, P=0.10) between the follow-ups. CONCLUSIONS: Sufficient arterial repair may have occurred by 4 months after ZES implantation.

Pulmonary hypertension with a precapillary component in heart failure with preserved ejection fraction.

OBJECTIVES: Heart failure with preserved ejection fraction (HFpEF) is often complicated by pulmonary hypertension (PH), which is mainly characterised by postcapillary PH and occasionally accompanied by a precapillary component of PH. Haemodynamic changes in worsening heart failure (HF) can modify the characteristics of PH. However, the clinical features of PH after HF treatment in HFpEF remain unclear. We investigated the prevalence and clinical significance of the precapillary component of PH after HF treatment in HFpEF, using data from the Prospective Multicentre Observational Study of Patients with HFpEF (PURSUIT-HFpEF). METHODS: From the PURSUIT-HFpEF registry, 219 patients hospitalised with acute HF who underwent right heart catheterisation after initial HF treatment were divided into four groups according to the 2015 and 2018 PH definitions: non-PH, isolated postcapillary pulmonary hypertension (Ipc-PH), precapillary PH and combined postcapillary and precapillary pulmonary hypertension (Cpc-PH). The latter two were combined as PH with the precapillary component. RESULTS: Using the 2015 definition, we found that the prevalence of PH after HF treatment was 27% (Ipc-PH: 20%, precapillary PH: 3%, Cpc-PH: 4%). Applying the 2018 definition resulted in a doubled frequency of precapillary PH (6%). PH with a precapillary component according to the 2015 definition was associated with poor clinical outcomes and characterised by small left ventricular dimension and high early diastolic mitral inflow velocity/early diastolic mitral annular tissue velocity. CONCLUSION: After initial HF treatment, 7% of hospitalised patients with HFpEF had precapillary component of PH according to the 2015 definition. Echocardiographic parameters of the left ventricle can contribute to the risk stratification of patients with HFpEF with a precapillary component of PH.

End-stage Hypertrophic Cardiomyopathy with Advanced Heart Failure in Patients Carrying MYH7 R453 Variants: A Case Series.

The MYH7 R453 variant has been identified in inherited hypertrophic cardiomyopathy (HCM) and is associated with sudden death and a poor prognosis. The detailed clinical course of HCM with the MYH7 R453 variant, from a preserved to a reduced left ventricular ejection fraction, has not been reported. We identified the MYH7 R453C and R453H variants in three patients who progressively developed advanced heart failure requiring circulatory support and summarized the clinical course and echocardiographic parameters of these patients over the years. Because of the rapid disease progression, we consider genetic screening for patients with HCM imperative for future prognosis stratification.

A spinal muscular atrophy modifier implicates the SMN protein in SNARE complex assembly at neuromuscular synapses.

Reduced survival motor neuron (SMN) protein triggers the motor neuron disease, spinal muscular atrophy (SMA). Restoring SMN prevents disease, but it is not known how neuromuscular function is preserved. We used model mice to map and identify an Hspa8G470R synaptic chaperone variant, which suppressed SMA. Expression of the variant in the severely affected mutant mice increased lifespan >10-fold, improved motor performance, and mitigated neuromuscular pathology. Mechanistically, Hspa8G470R altered SMN2 splicing and simultaneously stimulated formation of a tripartite chaperone complex, critical for synaptic homeostasis, by augmenting its interaction with other complex members. Concomitantly, synaptic vesicular SNARE complex formation, which relies on chaperone activity for sustained neuromuscular synaptic transmission, was found perturbed in SMA mice and patient-derived motor neurons and was restored in modified mutants. Identification of the Hspa8G470R SMA modifier implicates SMN in SNARE complex assembly and casts new light on how deficiency of the ubiquitous protein causes motor neuron disease.