Post-capillary pulmonary hypertension in heart failure: impact of current definition in the PH-HF multicentre study.

BACKGROUND AND AIMS: Based on retrospective studies, the 2022 European guidelines changed the definition of post-capillary pulmonary hypertension (pcPH) in heart failure (HF) by lowering the level of mean pulmonary artery pressure (mPAP) and pulmonary vascular resistance (PVR). However, the impact of this definition and its prognostic value has never been evaluated prospectively. METHODS: Stable left HF patients with the need for right heart catheterization were enrolled from 2010 to 2018 and prospectively followed up in this multicentre study. The impact of the successive pcPH definitions on pcPH prevalence and subgroup [i.e. isolated (IpcPH) vs. combined pcPH (CpcPH)] was evaluated. Multivariable Cox regression analysis was used to assess the prognostic value of mPAP and PVR on all-cause death or hospitalization for HF (primary outcome). RESULTS: Included were 662 HF patients were (median age 63 years, 60% male). Lowering mPAP from 25 to 20 mmHg resulted in +10% increase in pcPH prevalence, whereas lowering PVR from 3 to 2 resulted in +60% increase in CpcPH prevalence (with significant net reclassification improvement for the primary outcome). In multivariable analysis, both mPAP and PVR remained associated with the primary outcome [hazard ratio (HR) 1.02, 95% confidence interval (CI) 1.00-1.03, P = .01; HR 1.07, 95% CI 1.00-1.14, P = .03]. The best PVR threshold associated with the primary outcome was around 2.2 WU. Using the 2022 definition, pcPH patients had worse survival compared with HF patients without pcPH (log-rank, P = .02) as well as CpcPH compared with IpcPH (log-rank, P = .003). CONCLUSIONS: This study is the first emphasizing the impact of the new pcPH definition on CpcPH prevalence and validating the prognostic value of mPAP > 20 mmHg and PVR > 2 WU among HF patients.

Latent Pulmonary Vascular Disease May Alter the Response to Therapeutic Atrial Shunt Device in Heart Failure.

BACKGROUND: In REDUCE LAP-HF II (A Study to Evaluate the Corvia Medical, Inc IASD System II to Reduce Elevated Left Atrial Pressure in Patients With Heart Failure), implantation of an atrial shunt device did not provide overall clinical benefit for patients with heart failure with preserved or mildly reduced ejection fraction. However, prespecified analyses identified differences in response in subgroups defined by pulmonary artery systolic pressure during submaximal exercise, right atrial volume, and sex. Shunt implantation reduces left atrial pressures but increases pulmonary blood flow, which may be poorly tolerated in patients with pulmonary vascular disease (PVD). On the basis of these results, we hypothesized that patients with latent PVD, defined as elevated pulmonary vascular resistance during exercise, might be harmed by shunt implantation, and conversely that patients without PVD might benefit. METHODS: REDUCE LAP-HF II enrolled 626 patients with heart failure, ejection fraction ≥40%, exercise pulmonary capillary wedge pressure ≥25 mm Hg, and resting pulmonary vascular resistance <3.5 Wood units who were randomized 1:1 to atrial shunt device or sham control. The primary outcome-a hierarchical composite of cardiovascular death, nonfatal ischemic stroke, recurrent HF events, and change in health status-was analyzed using the win ratio. Latent PVD was defined as pulmonary vascular resistance ≥1.74 Wood units (highest tertile) at peak exercise, measured before randomization. RESULTS: Compared with patients without PVD (n=382), those with latent PVD (n=188) were older, had more atrial fibrillation and right heart dysfunction, and were more likely to have elevated left atrial pressure at rest. Shunt treatment was associated with worse outcomes in patients with PVD (win ratio, 0.60 [95% CI, 0.42, 0.86]; P=0.005) and signal of clinical benefit in patients without PVD (win ratio, 1.31 [95% CI, 1.02, 1.68]; P=0.038). Patients with larger right atrial volumes and men had worse outcomes with the device and both groups were more likely to have pacemakers, heart failure with mildly reduced ejection fraction, and increased left atrial volume. For patients without latent PVD or pacemaker (n=313; 50% of randomized patients), shunt treatment resulted in more robust signal of clinical benefit (win ratio, 1.51 [95% CI, 1.14, 2.00]; P=0.004). CONCLUSIONS: In patients with heart failure with preserved or mildly reduced ejection fraction, the presence of latent PVD uncovered by invasive hemodynamic exercise testing identifies patients who may worsen with atrial shunt therapy, whereas those without latent PVD may benefit.

Time to onset of cardiovascular and cerebrovascular outcomes after hypertensive disorders of pregnancy: a nationwide, population-based retrospective cohort study.

BACKGROUND: The increased maternal cardiocerebrovascular risk after a pregnancy complicated by hypertensive disorders of pregnancy, is well documented in the literature. Recent evidence has suggested a shorter timeframe for the development of these postnatal outcomes, which could have major clinical implications. OBJECTIVE: This study aimed to determine the risk of and time to onset of maternal cardiovascular and cerebrovascular outcomes after a pregnancy complicated by hypertensive disorders of pregnancy. STUDY DESIGN: This study included 2,227,711 women, without preexisting chronic hypertension, who delivered during the period 2008 to 2010: 37,043 (1.66%) were diagnosed with preeclampsia, 34,220 (1.54%) were diagnosed with gestational hypertension, and 2,156,448 had normotensive pregnancies. Hospitalizations for chronic hypertension, heart failure, coronary heart disease, cerebrovascular disease, and peripheral arterial disease were studied. A classical Cox regression was performed to estimate the average effect of hypertensive disorders of pregnancy over 10 years compared with normotensive pregnancy; moreover, an extended Cox regression was performed with a step function model to estimate the effect of the exposure variable in different time intervals: <1, 1 to 3, 3 to 5, and 5 to 10 years of follow-up. RESULTS: The risk of chronic hypertension after a pregnancy complicated by preeclampsia was 18 times higher in the first year (adjusted hazard ratio, 18.531; 95% confidence interval, 16.520-20.787) to only 5 times higher at 5 to 10 years after birth (adjusted hazard ratio, 4.921; 95% confidence interval, 4.640-5.218). The corresponding risks of women with gestational hypertension were 12 times higher (adjusted hazard ratio, 11.727; 95% confidence interval, 10.257-13.409]) and 6 times higher (adjusted hazard ratio, 5.854; 95% confidence interval, 5.550-6.176), respectively. For other cardiovascular and cerebrovascular outcomes, there was also a significant effect with preeclampsia (heart failure: adjusted hazard ratio, 6.662 [95% confidence interval, 4.547-9.762]; coronary heart disease: adjusted hazard ratio, 3.083 [95% confidence interval, 1.626-5.844]; cerebrovascular disease: adjusted hazard ratio, 3.567 [95% confidence interval, 2.600-4.893]; peripheral arterial disease: adjusted hazard ratio, 4.802 [95% confidence interval, 2.072-11.132]) compared with gestational hypertension in the first year of follow-up. A dose-response effect was evident for the severity of preeclampsia with the averaged 10-year adjusted hazard ratios for developing chronic hypertension after early, preterm, and late preeclampsia being 10, 7, and 6 times higher, respectively. CONCLUSION: The risks of cardiovascular and cerebrovascular outcomes were the highest in the first year after a birth complicated by hypertensive disorders of pregnancy. We found a significant relationship with both the severity of hypertensive disorders of pregnancy and the gestational age of onset suggesting a possible dose-response relationship for the development of cardiovascular and cerebrovascular outcomes. These findings call for an urgent focus on research into effective postnatal screening and cardiocerebrovascular risk prevention for women with hypertensive disorders of pregnancy.

Prognostic value of cardiovascular magnetic resonance T1 mapping and extracellular volume fraction in nonischemic dilated cardiomyopathy.

BACKGROUND: Heart failure- (HF) and arrhythmia-related complications are the main causes of morbidity and mortality in patients with nonischemic dilated cardiomyopathy (NIDCM). Cardiovascular magnetic resonance (CMR) imaging is a noninvasive tool for risk stratification based on fibrosis assessment. Diffuse interstitial fibrosis in NIDCM may be a limitation for fibrosis assessment through late gadolinium enhancement (LGE), which might be overcome through quantitative T1 and extracellular volume (ECV) assessment. T1 and ECV prognostic value for arrhythmia-related events remain poorly investigated. We asked whether T1 and ECV have a prognostic value in NIDCM patients. METHODS: This prospective multicenter study analyzed 225 patients with NIDCM confirmed by CMR who were followed up for 2 years. CMR evaluation included LGE, native T1 mapping and ECV values. The primary endpoint was the occurrence of a major adverse cardiovascular event (MACE) which was divided in two groups: HF-related events and arrhythmia-related events. Optimal cutoffs for prediction of MACE occurrence were calculated for all CMR quantitative values. RESULTS: Fifty-eight patients (26%) developed a MACE during follow-up, 42 patients (19%) with HF-related events and 16 patients (7%) arrhythmia-related events. T1 Z-score (p = 0.008) and global ECV (p = 0.001) were associated with HF-related events occurrence, in addition to left ventricular ejection fraction (p < 0.001). ECV > 32.1% (optimal cutoff) remained the only CMR independent predictor of HF-related events occurrence (HR 2.15 [1.14-4.07], p = 0.018). In the arrhythmia-related events group, patients had increased native T1 Z-score and ECV values, with both T1 Z-score > 4.2 and ECV > 30.5% (optimal cutoffs) being independent predictors of arrhythmia-related events occurrence (respectively, HR 2.86 [1.06-7.68], p = 0.037 and HR 2.72 [1.01-7.36], p = 0.049). CONCLUSIONS: ECV was the sole independent predictive factor for both HF- and arrhythmia-related events in NIDCM patients. Native T1 was also an independent predictor in arrhythmia-related events occurrence. The addition of ECV and more importantly native T1 in the decision-making algorithm may improve arrhythmia risk stratification in NIDCM patients. Trial registration NCT02352129. Registered 2nd February 2015-Retrospectively registered, https://clinicaltrials.gov/ct2/show/NCT02352129.

Scapular renal cell carcinoma metastasis as a cause of high-output heart failure: a case report.

BACKGROUND: High-output heart failure is a rare condition that occurs when the heart is unable to respond to a sustained increase in blood demand. On echocardiography, a cardiac index of > 4 L/min/m2 (or 6 L/min) is a clear indicator of this disorder. The causes of high-output heart failure vary, but they all involve peripheral vasodilation or arteriovenous shunting. Renal cell carcinoma is well known for producing high levels of angiogenic growth factors that induce arteriovenous shunts. The decrease in peripheral arterial resistance and the increase in venous return result in a permanent high cardiac output, followed by congestive heart failure. Single bone metastases of renal clear cell carcinoma tumours causing high cardiac output and heart failure symptoms have been reported less than ten times in the medical literature. CASE PRESENTATION: Before a right-shoulder painful lump with a murmur when auscultated, magnetic resonance imaging revealed a large scapular mass, which was biopsied and found to be a bone metastasis of renal cell carcinoma. Two months later, the patient developed heart failure for the first time. There was no evidence of cardiac disease on echocardiography. The cardiac output was 9.8 L/min and the cardiac index was 5.1 L/min/m2. Doppler ultrasound revealed numerous arteriovenous shunts in the large scapular metastasis and a right axillary artery flow of 24% of cardiac output. Sustained lower cardiac output was obtained following lesion-focused radiotherapy and systemic antiangiogenic treatment with axitinib and pembrolizumab. CONCLUSIONS: Herein, we present a unique case of high-output heart failure in a 70-year-old man diagnosed by echocardiography and upper-limb Doppler ultrasound in the context of metastatic renal cell carcinoma without pre-existing cardiac disease. We stress the potentially life-threatening hemodynamic consequences of hypervascularity associated with arteriovenous shunts within a single metastatic renal cell carcinoma implant, the importance of auscultating any progressing bone mass, and the utility of non-invasive Doppler ultrasound assessment in this setting.

Impact of nutritional status on heart failure mortality: a retrospective cohort study.

BACKGROUND: Chronic heart failure (CHF) is one of the most common causes of mortality in industrialized countries despite regular therapeutic advances. Numerous factors influence mortality in CHF patients, including nutritional status. It is known that malnutrition is a risk factor for mortality, whereas obesity may play a protective role, a phenomenon dubbed the "obesity paradox". However, the effect of the obesity-malnutrition association on mortality has not been previously studied for CHF. Our aim was to study the effect of nutritional status on overall mortality in CHF patients. METHODS: This retrospective, multicenter study was based on a French nationwide database (PMSI). We included all CHF patients aged ≥18 years admitted to all public and private hospitals between 2012 and 2016 and performed a survival analysis over 1 to 4 years of follow-up. RESULTS: Malnutrition led to a significant decrease in life expectancy in CHF patients when compared with normal nutritional status (aHR=1.16 [1.14-1.18] at one year and aHR=1.04 [1.004-1.08] at four years), obese, and obese-malnutrition groups. In contrast, obesity led to a significant increase in life expectancy compared with normal nutritional status (aHR=0.75 [0.73-0.78] at one year and aHR=0.85 [0.81-0.90] at four years), malnutrition, and obese-malnutrition groups. The mortality rate was similar in patients presenting both malnutrition and obesity and patients with normal nutritional status. CONCLUSIONS: Our results indicate that the protective effect on mortality observed in obese CHF patients seems to be linked to fat massincrease. Furthermore, malnourished obese and normal nutritional status patients had similar mortality rates. Further studies should be conducted to confirm our results and to explore the physiopathological mechanisms behind these effects.

Impact of Systematic Whole-body 18F-Fluorodeoxyglucose PET/CT on the Management of Patients Suspected of Infective Endocarditis: The Prospective Multicenter TEPvENDO Study.

BACKGROUND: Diagnostic and patients' management modifications induced by whole-body 18F-FDG-PET/CT had not been evaluated so far in prosthetic valve (PV) or native valve (NV) infective endocarditis (IE)-suspected patients. METHODS: In sum, 140 consecutive patients in 8 tertiary care hospitals underwent 18F-FDG-PET/CT. ESC-2015-modified Duke criteria and patients' management plan were established jointly by 2 experts before 18F-FDG-PET/CT. The same experts reestablished Duke classification and patients' management plan immediately after qualitative interpretation of 18F-FDG-PET/CT. A 6-month final Duke classification was established. RESULTS: Among the 70 PV and 70 NV patients, 34 and 46 were classified as definite IE before 18F-FDG-PET/CT. Abnormal perivalvular 18F-FDG uptake was recorded in 67.2% PV and 24.3% NV patients respectively (P < .001) and extracardiac uptake in 44.3% PV and 51.4% NV patients. IE classification was modified in 24.3% and 5.7% patients (P = .005) (net reclassification index 20% and 4.3%). Patients' managements were modified in 21.4% PV and 31.4% NV patients (P = .25). It was mainly due to perivalvular uptake in PV patients and to extra-cardiac uptake in NV patients and consisted in surgery plan modifications in 7 patients, antibiotic plan modifications in 22 patients and both in 5 patients. Altogether, 18F-FDG-PET/CT modified classification and/or care in 40% of the patients (95% confidence interval: 32-48), which was most likely to occur in those with a noncontributing echocardiography (P < .001) or IE classified as possible at baseline (P = .04), while there was no difference between NV and PV. CONCLUSIONS: Systematic 18F-FDG-PET/CT did significantly and appropriately impact diagnostic classification and/or IE management in PV and NV-IE suspected patients. CLINICAL TRIALS REGISTRATION: NCT02287792.

Phenotype/Genotype Relationship in Left Ventricular Noncompaction: Ion Channel Gene Mutations Are Associated With Preserved Left Ventricular Systolic Function and Biventricular Noncompaction: Phenotype/Genotype of Noncompaction.

BACKGROUND: Few data exist concerning genotype-phenotype relationships in left ventricular noncompaction (LVNC). METHODS AND RESULTS: From a multicenter French Registry, we report the genetic and clinical spectrum of 95 patients with LVNC, and their genotype-phenotype relationship. Among the 95 LVNC, 45 had at least 1 mutation, including 14 cases of mutation in ion channel genes. In a complementary analysis including 16 additional patients with ion channel gene mutations, for a total of 30 patients with ion channel gene mutation, we found that those patients had higher median LV ejection fraction (60% vs 40%; P < .001) and more biventricular noncompaction (53.1% vs 18.5%; P < .001) than the 81 other patients with LVNC. Among them, both the 19 patients with an HCN4 mutation and the 11 patients with an RYR2 mutation presented with a higher LV ejection fraction and more frequent biventricular noncompaction than the 81 patients with LVNC but with no mutation in the ion channel gene, but only patients with HCN4 mutation presented with a lower heart rate. CONCLUSIONS: Ion channel gene mutations should be searched systematically in patients with LVNC associated with either bradycardia or biventricular noncompaction, particularly when LV systolic function is preserved. Identifying causative mutations is of utmost importance for genetic counselling of at-risk relatives of patients affected by LVNC.

Whole MYBPC3 NGS sequencing as a molecular strategy to improve the efficiency of molecular diagnosis of patients with hypertrophic cardiomyopathy.

Hypertrophic cardiomyopathy (HCM) is the most common heritable cardiomyopathy, historically believed to affect 1 of 500 people. MYBPC3 pathogenic variations are the most frequent cause of familial HCM and more than 90% of them introduce a premature termination codon. The current study aims to determine the prevalence of deep intronic MYBPC3 pathogenic variations that could lead to splice mutations. To improve molecular diagnosis, a next-generation sequencing (NGS) workflow based on whole MYBPC3 sequencing of a cohort of 93 HCM patients, for whom no putatively causative point mutations were identified after NGS sequencing of a panel of 48 cardiomyopathy-causing genes, was performed. Our approach led us to reconsider the molecular diagnosis of six patients of the cohort (6.5%). These HCM probands were carriers of either a new large MYBPC3 rearrangement or splice intronic variations (five cases). Four pathogenic intronic variations, including three novel ones, were detected. Among them, the prevalence of one of them (NM_000256.3:c.1927+ 600 C>T) was estimated at about 0.35% by the screening of 1,040 unrelated HCM individuals. This study suggests that deep MYBPC3 splice mutations account for a significant proportion of HCM cases (6.5% of this cohort). Consequently, NGS sequencing of MYBPC3 intronic sequences have to be performed systematically.

Cardiomyopathy due to PRDM16 mutation: First description of a fetal presentation, with possible modifier genes.

PRDM16 (positive regulatory domain 16) is localized in the critical region for cardiomyopathy in patients with deletions of chromosome 1p36, as defined by Gajecka et al., American Journal of Medical Genetics, 2010, 152A, 3074-3083, and encodes a zinc finger transcription factor. We present the first fetal case of left ventricular non-compaction (LVNC) with a PRDM16 variant. The third-trimester obstetric ultrasound revealed a hydropic fetus with hydramnios and expanded hypokinetic heart. After termination of pregnancy, foetopathology showed a eutrophic fetus with isolated cardiomegaly. Endocardial fibroelastosis was associated with non-compaction of the myocardium of the left ventricle. Exome sequencing (ES) identified a de novo unreported p.(Gln353*) heterozygous nonsense variant in PRDM16. ES also identified two rare variants of unknown significance, according to the American College of Medical Genetics and Genomics guidelines, in the titin gene (TTN): a de novo missense p.(Lys14773Asn) variant and a c.33043+5A>G variant inherited from the mother. Along with the PRDM16 de novo probably pathogenic variant, TTN VOUS variants could possibly contribute to the severity and early onset of the cardiac phenotype. Because of the genetic heterogeneity of cardiomyopathies, large panels or even ES could be considered as the main approaches for the molecular diagnosis, particularly in fetal presentations, where multiple hits seem to be common.

Patent Foramen Ovale Closure or Anticoagulation vs. Antiplatelets after Stroke.

BACKGROUND: Trials of patent foramen ovale (PFO) closure to prevent recurrent stroke have been inconclusive. We investigated whether patients with cryptogenic stroke and echocardiographic features representing risk of stroke would benefit from PFO closure or anticoagulation, as compared with antiplatelet therapy. METHODS: In a multicenter, randomized, open-label trial, we assigned, in a 1:1:1 ratio, patients 16 to 60 years of age who had had a recent stroke attributed to PFO, with an associated atrial septal aneurysm or large interatrial shunt, to transcatheter PFO closure plus long-term antiplatelet therapy (PFO closure group), antiplatelet therapy alone (antiplatelet-only group), or oral anticoagulation (anticoagulation group) (randomization group 1). Patients with contraindications to anticoagulants or to PFO closure were randomly assigned to the alternative noncontraindicated treatment or to antiplatelet therapy (randomization groups 2 and 3). The primary outcome was occurrence of stroke. The comparison of PFO closure plus antiplatelet therapy with antiplatelet therapy alone was performed with combined data from randomization groups 1 and 2, and the comparison of oral anticoagulation with antiplatelet therapy alone was performed with combined data from randomization groups 1 and 3. RESULTS: A total of 663 patients underwent randomization and were followed for a mean (±SD) of 5.3±2.0 years. In the analysis of randomization groups 1 and 2, no stroke occurred among the 238 patients in the PFO closure group, whereas stroke occurred in 14 of the 235 patients in the antiplatelet-only group (hazard ratio, 0.03; 95% confidence interval, 0 to 0.26; P<0.001). Procedural complications from PFO closure occurred in 14 patients (5.9%). The rate of atrial fibrillation was higher in the PFO closure group than in the antiplatelet-only group (4.6% vs. 0.9%, P=0.02). The number of serious adverse events did not differ significantly between the treatment groups (P=0.56). In the analysis of randomization groups 1 and 3, stroke occurred in 3 of 187 patients assigned to oral anticoagulants and in 7 of 174 patients assigned to antiplatelet therapy alone. CONCLUSIONS: Among patients who had had a recent cryptogenic stroke attributed to PFO with an associated atrial septal aneurysm or large interatrial shunt, the rate of stroke recurrence was lower among those assigned to PFO closure combined with antiplatelet therapy than among those assigned to antiplatelet therapy alone. PFO closure was associated with an increased risk of atrial fibrillation. (Funded by the French Ministry of Health; CLOSE ClinicalTrials.gov number, NCT00562289 .).

Targeted panel sequencing in adult patients with left ventricular non-compaction reveals a large genetic heterogeneity.

Left ventricular non-compaction (LVNC) is a cardiomyopathy that may be of genetic origin; however, few data are available about the yield of mutation, the spectrum of genes and allelic variations. The aim of this study was to better characterize the genetic spectrum of isolated LVNC in a prospective cohort of 95 unrelated adult patients through the molecular investigation of 107 genes involved in cardiomyopathies and arrhythmias. Fifty-two pathogenic or probably pathogenic variants were identified in 40 patients (42%) including 31 patients (32.5%) with single variant and 9 patients with complex genotypes (9.5%). Mutated patients tended to have younger age at diagnosis than patients with no identified mutation. The most prevalent genes were TTN, then HCN4, MYH7, and RYR2. The distribution includes 13 genes previously reported in LVNC and 10 additional candidate genes. Our results show that LVNC is basically a genetic disease and support genetic counseling and cardiac screening in relatives. There is a large genetic heterogeneity, with predominant TTN null mutations and frequent complex genotypes. The gene spectrum is close to the one observed in dilated cardiomyopathy but with specific genes such as HCN4. We also identified new candidate genes that could be involved in this sub-phenotype of cardiomyopathy.

Incomplete Timothy syndrome secondary to a mosaic mutation of the CACNA1C gene diagnosed using next-generation sequencing.

Autosomal dominant genetic diseases can occur de novo and in the form of somatic mosaicism, which can give rise to a less severe phenotype, and make diagnosis more difficult given the sensitivity limits of the methods used. We report the case of female child with a history of surgery for syndactyly of the hands and feet, who was admitted at 6 years of age to a pediatric intensive care unit following cardiac arrest. The electrocardiogram (ECG) showed a long QT interval that on occasions reached 500 ms. Despite the absence of facial dysmorphism and the presence of normal psychomotor development, a diagnosis of Timothy syndrome was made given the association of syndactyly and the ECG features. Sanger sequencing of the CACNA1C gene, followed by sequencing of the genes KCNQ1, KCNH2, KCNE1, KCNE2, were negative. The subsequent analysis of a panel of genes responsible for hereditary cardiac rhythm disorders using Haloplex technology revealed a recurrent mosaic p.Gly406Arg missense mutation of the CACNA1C gene in 18% of the cells. This mosaicism can explain the negative Sanger analysis and the less complete phenotype in this patient. Given the other cases in the literature, mosaic mutations in Timothy syndrome appear more common than previously thought. This case demonstrates the importance of using next-generation sequencing to identify mosaic mutations when the clinical picture supports a specific mutation that is not identified using conventional testing. © 2016 Wiley Periodicals, Inc.

High prevalence of arrhythmic and myocardial complications in patients with cardiac glycogenosis due to PRKAG2 mutations.

AIMS: Mutations in PRKAG2, the gene encoding for the γ2 subunit of 5'-AMP-activated protein kinase (AMPK), are responsible for an autosomal dominant glycogenosis with a cardiac presentation, associating hypertrophic cardiomyopathy (HCM), ventricular pre-excitation (VPE), and progressive heart block. The aim of this study was to perform a retrospective time-to-event study of the clinical manifestations associated with PRKAG2 mutations. METHODS AND RESULTS: A cohort of 34 patients from 9 families was recruited between 2001 and 2010. DNA were sequenced on all exons and flanking sequences of the PRKAG2 gene using Sanger sequencing. Overall, four families carried the recurrent p.Arg302Gln mutation, and the five others carried private mutations among which three had never been reported. In the total cohort, at 40 years of age, the risk of developing HCM was 61%, VPE 70%, conduction block 22%, and sudden cardiac death (SCD) 20%. The global survival at 60 years of age was 66%. Thirty-two per cent of patients (N = 10) required a device implantation (5 pacemakers and 5 defibrillators) at a median age of 66 years, and two patients required heart transplant. Only one patient presented with significant skeletal muscle symptoms. No significant differences regarding the occurrence of VPE, ablation complications, or death incidence were observed between different mutations. CONCLUSION: This study of patients with PRKAG2 mutations provides a more comprehensive view of the natural history of this disease and demonstrates a high risk of cardiac complications. Early recognition of this disease appears important to allow an appropriate management.

Prevalence and clinical phenotype of hereditary transthyretin amyloid cardiomyopathy in patients with increased left ventricular wall thickness.

AIMS: Increased left ventricular wall thickness (LVWT) is a common finding in cardiology. It is not known how often hereditary transthyretin-related familial amyloid cardiomyopathy (mTTR-FAC) is responsible for LVWT. Several therapeutic modalities for mTTR-FAC are currently in clinical trials; thus, it is important to establish the prevalence of TTR mutations (mTTR) and the clinical characteristics of the patients with mTTR-FAC. METHODS AND RESULTS: In a prospective multicentre, cross-sectional study, the TTR gene was sequenced in 298 consecutive patients diagnosed with increased LVWT in primary cardiology clinics in France. Among the included patients, median (25-75th percentiles) age was 62 [50;74]; 74% were men; 23% were of African origin; and 36% were in NYHA Class III-IV. Median LVWT was 18 (16-21) mm. Seventeen (5.7%; 95% confidence interval [CI]: [3.4;9.0]) patients had mTTR of whom 15 (5.0%; 95% CI [2.9;8.2]) had mTTR-FAC. The most frequent mutations were V142I (n = 8), V50M (n = 2), and I127V (n = 2). All mTTR-FAC patients were older than 63 years with a median age of 74 [69;79]. Of the 15 patients with mTTR-FAC, 8 were of African descent while 7 were of European descent. In the African descendants, mTTR-FAC median age was 74 [72;79] vs. 55 [46;65] years in non-mTTR-FAC (P < 0.001). In an adjusted multivariate model, African origin, neuropathy, carpal tunnel syndrome, electrocardiogram (ECG) low voltage, and late gadolinium enhancement (LGE) at cardiac-magnetic resonance imaging were all independently associated with mTTR-FAC. CONCLUSION: Five per cent of patients diagnosed with hypertrophic cardiomyopathy have mTTR-FAC. Mutated transthyretin genetic screening is warranted in elderly subjects with increased LVWT, particularly, those of African descent with neuropathy, carpal tunnel syndrome, ECG low voltage, or LGE.

Socioeconomic factors and mortality in diastolic heart failure.

BACKGROUND: Mortality in patients with heart failure with preserved ejection fraction (HFPEF) has remained stable over recent decades. Few studies have explored prognostic characteristics specifically in HFPEF, and none of them has assessed the potential impact of socioeconomic factors. We aimed to evaluate the impact of socioeconomic factors on all-cause and cardiovascular mortality in HFPEF patients. MATERIALS AND METHODS: We used data from the French ODIN cohort. All patients with heart failure and a left ventricular ejection fraction (LVEF) > 45%, included in ODIN between July 2007 and July 2010, were eligible here. Socioeconomic, demographic, clinical, biological and therapeutic data were collected at inclusion. The endpoints were all-cause and cardiovascular mortality between inclusion and 30 September 2011. The impact of patient socioeconomic characteristics on mortality was assessed using Cox regression models. RESULTS: Of 575 HFPEF patients considered, 58·6% were male; their mean age was 71·1 ± 13·5 years, and their mean LVEF was 58·1 ± 8·5%. After adjustment for confounders, living alone and limitations on activities of daily living were associated with all-cause mortality [HR = 1·77, 95%CI(1·11-2·81) and 2·61(1·35-5·03), respectively] and cardiovascular mortality [2·26 (1·24-4·10) and 3·16 (1·33-7·54), respectively]. Having a professional occupation was associated with a lower cardiovascular mortality only [0·37(0·15-0·94)]. CONCLUSIONS: Poor social conditions impair survival in patients with HFPEF. These findings may shed new light on how best to detect HFPEF patients with high health-care needs.

Randomised study for the Optimal Treatment of symptomatic patients with low-gradient severe Aortic valve Stenosis and preserved left ventricular ejection fraction (ROTAS trial).

BACKGROUND: The best management of symptomatic patients with low-gradient (LG) severe aortic stenosis (AS) and preserved left ventricular ejection fraction (LVEF) has not been established. The Randomised study for the Optimal Treatment of symptomatic patients with low-gradient severe Aortic valve Stenosis (ROTAS) trial aimed to assess the superiority of aortic valve replacement (AVR) versus medical treatment (MT) in this specific group of AS patients. METHODS: Patients with symptomatic LG severe AS and preserved LVEF (>50%) underwent dobutamine stress echocardiography and/or CT-aortic calcium score to confirm AS severity and were then randomised 1:1 to AVR or MT. The primary endpoint was a composite of overall death and/or cardiovascular hospitalisation. RESULTS: The ROTAS study was stopped early because of insufficient recruitment. In the end, only 52 patients (age 79±7 years; women 54%; NYHA III-IV 27%; median STS score 3.3%) were included in the study. During follow-up (mean: 14±7 months), the primary endpoint occurred in 12 (23%) patients. Compared with MT, AVR was not associated with a significant prognostic benefit (events: 5/26 (19%) vs 7/26 (27%) (HR 0.76, 95% CI 0.24 to 2.39, p=0.63). During follow-up, 11 (42%) patients in the MT group developed class I criteria for AVR or severe symptoms justifying a cross-over to the AVR group. CONCLUSIONS: Because of the small number of included patients and short follow-up the ROTAS trial was underpowered and unable to demonstrate a difference in the study endpoint between treatment arms. In patients in the MT arm, a regular echocardiographic and clinical assessment might be useful to disclose those developing class I indications of AVR or severe AS-related symptoms. TRIAL REGISTRATION NUMBER: NCT01835028.

Clinical outcomes for 2788 patients with transthyretin amyloidosis: Tafamidis meglumine early access program in France.

BACKGROUND: Early access experience in France with tafamidis meglumine, a selective transthyretin stabilizer for transthyretin-related amyloidosis cardiomyopathy (ATTR-CM), following transthyretin-related amyloidosis (ATTR) polyneuropathy approval and positive ATTR-ACT study results. AIM: To describe the characteristics and clinical outcomes for patients in the French ATTR-CM tafamidis meglumine early access programme (28 Nov 2018 to 01 Jun 2021). METHODS: Patients with confirmed ATTR-CM received tafamidis meglumine 20mg/day or 80mg/day. Demographic and clinical data were collected prospectively until patients discontinued treatment or died, or the programme ended. RESULTS: Overall, 222 physicians from 126 centres enrolled 2788 patients. The median age was 82years, 81.6% were male and New York Heart Association severity was class I for 12.8%, class II for 60.1% and class III for 27.0%. Overall, 1943 (74.6%) had genetic testing, and the results were available at tafamidis start for 1208 (62.2%) patients: 995 (82.4%) had wild-type ATTR and 213 (17.6%) had hereditary ATTR. Most patients started treatment≤12months after diagnosis (88.3%): 2268 (81.3%) at 20mg/day, with 401 (17.7%) increasing to 80mg/day. Median follow-up duration was 11.8months. New York Heart Association class improved or remained stable for 1299 (77.6%), whereas 376 (22.4%) worsened between inclusion and last follow-up. Among patients initiated at 80mg, 297 (81.1%) improved or remained stable and 69 (18.9%) worsened. New York Heart Association class progression did not vary with age. The 18-month survival rates were 89.8% (95% confidence interval: 87.0-92.0) among patients aged<80years, and 86.5% (95% confidence interval: 83.9-88.7) among those aged≥80years. CONCLUSIONS: Early tafamidis meglumine access was given to 2788 patients with ATTR-CM. New York Heart Association class progression and survival were consistent with previously published data.

Obesity in heart failure with preserved ejection fraction: Insights from the REDUCE LAP-HF II trial.

AIMS: Obesity is causally related to the development of heart failure with preserved ejection fraction (HFpEF) but complicates the diagnosis and treatment of this disorder. We aimed to determine the relationship between severity of obesity and clinical, echocardiographic and haemodynamic parameters in a large cohort of patients with documented HFpEF. METHODS AND RESULTS: The REDUCE LAP-HF II trial randomized 626 patients with ejection fraction ≥40% and exercise pulmonary capillary wedge pressure (PCWP) ≥25 mmHg to atrial shunt or sham procedure. We tested for associations between body mass index (BMI), clinical characteristics, cardiac structural and functional abnormalities, physical limitations, quality of life and outcomes with atrial shunt therapy. Overall, 60.9% of patients had BMI ≥30 kg/m2 . As the severity of obesity increased, symptoms (Kansas City Cardiomyopathy Questionnaire score) and 6-min walk distance worsened. More severe obesity was associated with lower natriuretic peptide levels despite more cardiac remodelling, higher cardiac filling pressures, and higher cardiac output. Lower cut points for E/e' were needed to identify elevated PCWP in more obese patients. Strain measurements in all four chambers were maintained as BMI increased. Pulmonary vascular resistance at rest and exercise decreased with higher BMI. Obesity was associated with more first and recurrent heart failure events. However, there was no significant interaction between obesity and treatment effects of the atrial shunt. CONCLUSIONS: Increasing severity of obesity was associated with greater cardiac remodelling, higher right and left ventricular filling pressures, higher cardiac output and increased subsequent heart failure events. Despite significant obesity, many HFpEF patients have preserved right heart and pulmonary vascular function and thus, may be appropriate candidates for atrial shunt therapy.

Feasibility and accuracy of linking a heart failure registry to the national claims database using indirect identifiers.

BACKGROUND: Heart failure (HF) registries include rich data on patient inclusion characteristics, but follow-up information is often incomplete. Medicoadministrative databases may provide less clinical information than registries, e.g. on left ventricular ejection fraction (LVEF), but long-term data are exhaustive and reliable. The combination of the two types of database is therefore appealing, but the feasibility and accuracy of such linking are largely unexplored. AIMS: To assess the feasibility and accuracy of linking an HF registry (FRESH; FREnch Survey on Heart Failure) with the French National Healthcare System database (SNDS). METHODS: A probabilistic algorithm was developed to link and match patient data included in the FRESH HF registry with anonymized records from the SNDS, which include: hospitalizations and diagnostic codes; all care-related reimbursements by national health system; and deaths. Consistency was assessed between deaths recorded in the registry and in the SNDS. A comparison between the two databases was carried out on several identifiable clinical characteristics (history of HF hospitalization, diabetes, atrial fibrillation, chronic bronchopneumopathy, severe renal failure and stroke) and on events during 1-year follow-up after inclusion. RESULTS: Of 2719 patients included in the FRESH registry (1049 during decompensation; 1670 during outpatient follow-up), 1885 could be matched with a high accuracy of 94.3% for deaths. Mortality curves were superimposable, including curves according to type of HF and LVEF. The rates of missing data in the FRESH registry were 2.3-8.4% for clinical characteristics and 17.5% for hospitalizations during follow-up. The discrepancy rate for clinical characteristics was 3-13%. Hospitalization rates were significantly higher in the SNDS than in the registry cohort. CONCLUSIONS: The anonymous matching of an HF research cohort with a national health database is feasible, with a significant proportion of patients being accurately matched, and facilitates combination of clinical data and a reduced rate of losses to follow-up.