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Background: Materials extracted from atherosclerotic arteries can disclose data about the molecular pathology of cardiovascular disease, but obtaining such samples is complex and requires invasive surgery. To overcome this barrier, this study investigated whether angioplasty balloons inflated during standard percutaneous coronary interventions retain proteins from treated (dilated) atherosclerotic lesions and whether proteomic analysis of this material could provide data on lesion protein profiles and distinguish between patients with stable and unstable coronary artery disease. Methods: Patients with ST-segment–elevation myocardial infarction and stable angina pectoris were subjected to routine percutaneous coronary interventions. All angioplasty balloons inflated in a coronary artery were collected. Proteins retained on the balloons were extracted and analyzed using shotgun proteomic analysis. Results: Proteomics identified and quantified 1365 unique proteins captured on percutaneous coronary intervention balloons. Control balloons inflated in the ascending aorta showed minimal nonspecific protein binding, indicating specificity to the luminal region of atherosclerotic lesions of the diseased artery wall. Clustering and principal component analyses showed that ST-segment–elevation myocardial infarction and stable angina pectoris subjects could be separated by variations in protein content and abundance. We identified 206 proteins as differentially abundant between ST-segment–elevation myocardial infarction and stable angina pectoris subjects. Pathway analysis indicated several enriched processes in the ST-segment–elevation myocardial infarction group involved in neutrophil-mediated immunity and platelet activation. Conclusions: Disease-related proteins from coronary artery lesions adhere to angioplasty balloons and constitute a source of material for proteomic analysis. This approach can identify proteins and processes occurring in unstable coronary atherosclerotic lesions and suggest novel therapeutic approaches.

Introduction: Preeclampsia is a multifactorial disease and a cause of maternal and neonatal morbidity and mortality. Women with preeclampsia have increased risk of cardiovascular diseases in later life. The impact on the offspring is, however, still uncertain. Lipid traits in newborns are considered to reflect the child’s own production. Hypothesis: We assessed the hypothesis that preeclampsia increases risk of future cardiovascular disease in both mother and offspring. Methods: For this purpose, we used the Copenhagen General Population Study comprising 59,571 women of which 1,365 had a diagnosis of preeclampsia to investigate the association between preeclampsia and risk of cardiovascular diseases. Further, we used the Copenhagen Baby Heart Study comprising more than 13,000 umbilical cord blood samples and assessed the impact of preeclampsia on atherogenic lipid traits in cord blood. Results: Age adjusted hazard ratios for preeclampsia versus no preeclampsia (95% CI) were 1.48 (1.13-1.94) for ischemic heart disease, 1.50 (1.07-2.12) for ischemic cerebrovascular disease, and 1.53 (1.22-1.91) for composite vascular disease. Corresponding multivariable adjusted hazard ratios (95% CI) were 1.31 (1.00-1.72), 1.44 (1.02-2.02), and 1.39 (1.11-1.74). Concentrations of non-HDL cholesterol, total cholesterol, LDL cholesterol, apolipoprotein B, and triglycerides in cord blood increased stepwise from no preeclampsia (n=11,221) to mild/moderate preeclampsia (n=253) to severe preeclampsia (n=104) (p for trends th percentile were 2.09 (1.67-2.61) for non-HDL cholesterol, 1.58 (1.25-2.01) for total cholesterol, 1.72 (1.37-2.16) for LDL cholesterol, 1.38 (1.07-1.78) for apolipoprotein B, and 2.64 (2.07-3.35) for triglycerides. Conclusion: Women with preeclampsia had increased risk of future cardiovascular disease and lipid traits in umbilical cord blood of their offspring were elevated. This indicates that preeclampsia affects lipid metabolism during fetal life and potentially contributes to an increased risk of future cardiovascular disease in offspring of mothers with preeclampsia.

Background: β3-AR (β3-adrenergic receptor) stimulation improved systolic function in a sheep model of systolic heart failure (heart failure with reduced ejection fraction [HFrEF]). Exploratory findings in patients with New York Heart Association functional class II HFrEF treated with the β3-AR-agonist mirabegron supported this observation. Here, we measured the hemodynamic response to mirabegron in patients with severe HFrEF. Methods: In this randomized, double-blind, placebo-controlled trial we assigned patients with New York Heart Association functional class III–IV HFrEF, left ventricular ejection fraction Results: We randomized 22 patients (age 66±11 years, 18 men, 16, New York Heart Association functional class III), left ventricular ejection fraction 20±7%, median NT-proBNP 1953 ng/L. No significant changes were seen after 3 hours, but after 1 week, there was a significantly larger increase in cardiac index in the mirabegron group compared with the placebo group (mean difference, 0.41 [CI, 0.07–0.75] L/min/BSA; P =0.039). Pulmonary vascular resistance decreased significantly more in the mirabegron group compared with the placebo group (−1.6 [CI, −0.4 to −2.8] Wood units; P =0.02). No significant differences were seen during exercise. There were no differences in changes in heart rate, systemic vascular resistance, blood pressure, or renal function between groups. Mirabegron was well-tolerated. Conclusions: Oral treatment with the β3-AR-agonist mirabegron for 1 week increased cardiac index and decreased pulmonary vascular resistance in patients with moderate to severe HFrEF. Mirabegron may be useful in patients with worsening or terminal HF. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: 2016-002367-34.

Background: Left ventricular noncompaction (LVNC) is characterized by excessive trabeculations of the LV and may be associated with reduced systolic function or severe adverse outcomes. Several aspects remain to be elucidated; there is controversy to whether LVNC cardiomyopathy is a distinct cardiomyopathy caused by failure of the spongy fetal myocardium to condense during fetal development or acquired later in life as a morphological trait associated with other types of cardiomyopathy; the prevalence in unselected populations is unknown and the distinction between normal variation and pathology remains to be defined. In this study, we aimed to determine the prevalence of LVNC and the association to LV systolic function in a large, population-based cohort of neonates. In addition, we assessed the normal ratio of noncompact to compact (NC:C) myocardium in 150 healthy neonates. Methods: Echocardiographic data were prospectively collected in the population study Copenhagen Baby Heart Study. The ratio of NC:C was measured in 12 ventricular segments. LVNC was defined as NC:C ≥2 in at least one segment. Neonates with LVNC were matched 1:10 to controls on sex, gestational age, and weight and age at the examination day. Results: In total, 25 590 neonates (52% males, median age 11 [interquartile range, 7–15] days) underwent echocardiography. Among 21 133 with satisfactory visualization of ventricular segments, we identified a prevalence of LVNC of 0.076% (95% CI, 0.047–0.123). LV ejection fraction was lower in neonates with LVNC compared with matched controls (median 49.5 versus 59.0%; P Conclusions: The prevalence of LVNC based on neonatal echocardiography was 0.076%. LVNC was associated with lower LV systolic function. The findings in normal newborns support the cutoff NC:C ≥2 as an appropriate diagnostic criterion. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT02753348.

Background: Cardiac troponins (cTns) are the cornerstone of diagnosing acute myocardial infarction. There is limited knowledge on the duration of ischemia necessary to induce a measurable release of cTns or the very-early-release kinetics of cTns after an ischemic event. Copeptin may have a supplementary role in ruling out myocardial infarction early. We investigated the release of cTns and copeptin in the first hours after experimental balloon-induced ischemia in humans. Methods: Thirty-four patients (median age, 60 years [interquartile range, 51–64]; 15 men, 43%) with angiographically normal coronary arteries were randomly assigned into 4 groups with different durations of induced myocardial ischemia (0, 30, 60, 90 s). Ischemia was induced by inflating a balloon in the left anterior descending artery between the first and second diagonal branch. Blood was collected before balloon inflation (baseline) every 15 minutes for the first 3 hours, and every 30 minutes for the next 3 hours. The cTns were analyzed by 3 high-sensitivity (hs) cTn assays: hs-cTnT (Roche), hs-cTnI (Siemens), and hs-cTnI (Abbott). Copeptin was analyzed by a sandwich immunoluminometric assay. Results: None of the patients had any complications. Increased cTn concentrations were detected by all 3 assays, and the magnitude of the increase was associated with the duration of ischemia. Increased hs-cTnI (Siemens) concentrations were first detectable 15 minutes after 90-s ischemia (median 43.7% increase) and increased more steeply and had a higher peak than the other assays. Copeptin levels did not significantly change. Using the cTnT, hs-cTnI (Siemens), and hs-cTnI (Abbott) concentrations at 0 and 180 minutes, 1 (11%), 0, and 0 patients from the 60-s ischemia group and 5 (63%), 2 (25%), and 1 (11%) from the 90-s ischemia group, respectively, fulfilled criteria for a biochemical myocardial infarction. Conclusions: This study is the first to report the early-release kinetics of cTn concentrations after different durations of experimental coronary balloon occlusion in humans. All assays detected a cTn increase after only 30 s of ischemia. hs-cTnI (Siemens) rose faster and reached a higher peak. Copeptin levels did not change significantly. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT03203057.

Objective: The interpretation of the neonatal electrocardiogram (ECG) is challenging and reflects the underlying developing physiology. The possible effects of gestational age (GA) on the ECG has never been evaluated in a large general population study. We aimed at investigating the effect of GA on neonatal electrocardiographic parameters and create GA-specific reference values. Methods: The Copenhagen Baby Heart Study is a prospective, general population study that offered cardiac evaluation of neonates. ECGs and echocardiograms were obtained and systematically analyzed. GA, weight, height, and other baseline variables were registered. Results: We included 16,462 neonates (52% boys) with normal echocardiograms. Median postnatal age was 11 days (range 0-30 days) and median GA was 281 days (range 238-301 days). Analyzing the ECG parameters as a function of GA we found a significant effect of GA on heart rate (HR), PR-, QRS-, and QT intervals, QRS axis, and maximum amplitudes of R-waves in V1/V6 and maximum S-wave in V6 (all pBox plots of ECG parameters subdivided by gestational age intervals and sex ). The effect of GA generally persisted after adjustment for HR, weight, postnatal age, and sex. In addition, when comparing HR, PR interval, QRS axis, QRS duration, uncorrected QT interval, and QTcBazett subdivided into postnatal age intervals, we found a significant effect of gestational age on most ECG parameters within these postnatal age intervals. Conclusion: Gestational age was associated with significant differences in multiple neonatal ECG parameters and the effect generally persisted after multifactorial adjustment. Our results indicate a direct effect of GA on the developing neonatal cardiac conduction system. Use of GA-specific reference values may be useful.

Introduction: Left ventricular non-compaction (LVNC) is characterized by excessive trabeculations of the left ventricular wall and may be associated with reduced systolic function. It is debated whether LVNC is congenital or may develop later as part of other cardiomyopathies. The clinical importance and heredity of LVNC with normal systolic function is unclear. We aimed to describe the cardiac development in children with LVNC from birth to 2-4 years of age, compared to matched controls. Additionally, we aimed to describe the prevalence of LVNC in first-degree relatives. Methods: A follow-up transthoracic echocardiography was performed in children at 2-4 years of age diagnosed with LVNC at birth ( Results: Of the 16 children diagnosed with LVNC at birth, 10 have been reevaluated (age 3.5 (interquartile range (IQR) 3, 4) years, 80% male) together with 20 matched controls (age 4 (IQR 3, 4) years, 70% male), 29 first-degree relatives in case group (age 29 (IQR 4, 35) years, 45% male) and 55 first-degree relatives in control group (age 32 (IQR 11, 36) years, 51% male). In probands, the extent of trabeculation (13% vs. 12%, p=0.97) and fractional shortening (FS) (29% vs. 31%, p=0.24) were unchanged from birth to follow-up. At follow-up, the median left ventricular FS was significantly lower in probands compared to matched controls (31% vs. 33%, p=0.03). Ten (35%) first-degree relatives to probands fulfilled criteria for LVNC compared to 0 (0%) of first-degree relatives to controls (p Conclusions: Children with LVNC diagnosed neonatally as part of a population study had no further progression of left ventricular dysfunction or extent of trabeculation at the age of 2-4 years, but systolic function was reduced compared to matched controls. One third of first-degree relatives to children with LVNC fulfilled criteria for LVNC.

Introduction: Guidelines recommend family screening in dilated cardiomyopathy (DCM) to uncover pre-symptomatic familial DCM (FDC). So far, no guidelines provide specific recommendations on the intensity and frequency of follow-up screening. This study sought to provide the first detailed estimates of the incidence of FDC during follow-up and identify baseline markers which could inform future follow-up of relatives. Methods: The study was a retrospective, observational, longitudinal cohort study of relatives to DCM probands screened at a regional assembly of family screening clinics in Copenhagen, Denmark, from 2006 to 2020. Results: In total, 563 relatives (50% women) from 211 families were included. At baseline, 124 relatives (22%) were diagnosed with FDC: 97 (18%) as a result of screening and 27 (5%) with symptom-onset prior to screening. Genetic sequencing identified the etiology of DCM in 35% of families and classified 90 relatives (17%) as unaffected carriers (n=44) or relatives not at risk of FDC (n=46). As such, the combined clinical and genetic baseline-yield was 31%. In 439 relatives considered unaffected at baseline, 45 (10%) were diagnosed with FDC during follow-up (median 5.0 years). The age-standardized incidence rate of FDC was 2.0% per person-year [CI: 1.4-2.8%] with higher rates in men vs women (3.0% vs 1.4% per person-year). In relatives without predictive genetic findings (n=349), non-diagnostic abnormal baseline-findings on ECG or echocardiography was associated with a higher incidence rate of FDC (figure A), while the risk was low in relatives with normal findings (0.4% vs 4.7% per person-year; figure B). Conclusion: Systematic family screening identified FDC or genetic predisposition to FDC in 1 out of 3 relatives at baseline. Relatives without predictive genetic findings and with normal findings on ECG and echocardiography at baseline had a low risk of developing FDC. Follow-up can be limited and may not be warranted in these relatives.

Background: The recently reported Familial ST-depression syndrome is a distinct inherited cardiac disease entity characterized by persistent, non-ischemic ST-depressions and risk of arrhythmias and heart failure. We aimed at further characterizing the features associated with the syndrome. Methods: Retrospective analysis of demographics, electrocardiographic, arrhythmic and imaging data from families with Familial ST-depression syndrome in Denmark. Results: Forty affected individuals (43% men; mean age at diagnosis 49.1 years) from 14 apparently unrelated families with ≥2 affected members were included. Pedigree analyses were consistent with autosomal dominant inheritance in all families. The ST-depressions were most pronounced in leads V4, V5, and II and persisted over time (mean follow-up 9.3 years), i.e. no temporary normalization was seen. The ECG phenotype seemed to develop in pre-puberty. Exercise accentuated the ST-depressions with a maximum difference between rest/stress (mean) of -117μV in lead V5. Six (15%) patients developed ventricular arrhythmias or (aborted) sudden cardiac death, seven (18%) were diagnosed with left ventricular ejection fraction ≤50%, and 10 (25%) developed atrial fibrillation. Seven patients had at least one catheter ablation; five for supraventricular arrhythmias and two for ventricular arrhythmias. Males experienced more arrhythmic endpoints than females (Figure, p Conclusions: We identified 14 families with the novel syndrome showing autosomal dominant inheritance. The phenotype was associated with arrhythmias, aborted sudden cardiac death, or heart failure in about half of the cases. Families with Familial ST-depression syndrome should undergo cascade screening like in other inherited arrhythmia syndromes.

Introduction: AV nodal re-entry tachycardia (AVNRT) is the most common type of paroxysmal supraventricular tachycardia. At present, the underlying etiology of AVNRT is unclear. Hypothesis: In a genome-wide association study (GWAS), we aimed to identify common genetic variants associated with AVNRT. Methods: We performed a GWAS meta-analysis of Danish patients diagnosed with AVNRT verified by invasive electrophysiological study. An Icelandic population of AVNRT patients was used for replication. We performed conditional analysis by adjusting our analysis for atrial fibrillation (AF) genetics and transcriptome-wide analyses (TWAS) to assess associations between gene expression and AVNRT. Electrophysiological consequences were investigated in CRISPR-Cas9 modified zebrafish. Results: A total of 1,515 AVNRT patients and 38,428 controls were available for meta-analysis. Two genetic loci associated with AVNRT; at chromosome 5q35.1, close to the NKX2-5 gene (odds ratio [OR] 1.48, 95% confidence interval [CI] 1.38-1.58, P = 2.6 х 10 -13 ), and at 14q11.2 in the MYH6 gene (OR 1.26, 95% CI 1.18-1.34, P = 2.3 х 10 -8 ). We found similar effect sizes and direction of effect for both loci in the Icelandic AVNRT cohort. Using conditional analyses, we found that these loci were associated with AVNRT independent of AF. Analyses of loss of Nkx2-5 zebrafish showed no difference with regards to electrocardiographic parameters and transmission electron microscopy of atrial tissue compared with wildtype. Conclusion: This is, to our knowledge, the first GWAS on AVNRT. We identified two genetic loci that associated with AVNRT.

Background: Abnormally high cytosolic Na + concentrations in advanced heart failure impair myocardial contractility. Stimulation of the membrane Na + -K + pump should lower Na + concentrations, and the β3 adrenoceptor (β3 AR) mediates pump stimulation in myocytes. We examined if β3 AR-selective agonists given in vivo increase myocyte Na + -K + pump activity and reverse organ congestion in severe heart failure (HF). Methods: Indices for HF were lung-, heart-, and liver: body weight ratios and ascites after circumflex coronary artery ligation in rabbits. Na + -K + pump current, I p , was measured in voltage-clamped myocytes from noninfarct myocardium. Rabbits were treated with the β3 AR agonists CL316,243 or ASP9531, starting 2 weeks after coronary ligation. Results: Coronary ligation caused ascites in most rabbits, significantly increased lung-, heart-, and liver: body weight ratios, and decreased I p relative to that for 10 sham-operated rabbits. Treatment with CL316,243 for 3 days significantly reduced lung-, heart-, and liver: body weight ratios and prevalence of ascites in 8 rabbits with HF relative to indices for 13 untreated rabbits with HF. It also increased I p significantly to levels of myocytes from sham-operated rabbits. Treatment with ASP9531 for 14 days significantly reduced indices of organ congestion in 6 rabbits with HF relative to indices of 6 untreated rabbits, and it eliminated ascites. β3 AR agonists did not significantly change heart rates or blood pressures. Conclusions: Parallel β3 AR agonists-induced reversal of Na + -K + pump inhibition and indices of congestion suggest pump inhibition is a useful target for treatment with β3 AR agonists in congestive HF.

Background: Late gadolinium enhancement (LGE) on cardiac magnetic resonance imaging (CMR) is believed to represent dense replacement fibrosis. It is seen in ≈60% of adult patients with hypertrophic cardiomyopathy (HCM). However, the prevalence of LGE in children and adolescents with HCM is not well established. In addition, longitudinal studies describing the development and evolution of LGE in pediatric HCM are lacking. This study assesses the prevalence, progression, and clinical correlations of LGE in children and adolescents with, or genetically predisposed to, HCM. Methods: CMR scans from 195 patients ≤21 years of age were analyzed in an observational, retrospective study, including 155 patients with overt HCM and 40 sarcomere mutation carriers without left ventricular (LV) hypertrophy. The extent of LGE was quantified by measuring regions with signal intensity >6 SD above nulled remote myocardium. Results: Patients were 14.3±4.5 years of age at baseline and 68% were male. LGE was present in 70 (46%) patients with overt HCM (median extent, 3.3%; interquartile range, 0.8–7.1%), but absent in mutation carriers without LV hypertrophy. Thirty-one patients had >1 CMR (median interval between studies, 2.4 years; interquartile range, 1.5–3.2 years). LGE was detected in 13 patients (42%) at baseline and in 16 patients (52%) at follow-up CMR. The median extent of LGE increased by 2.4 g/y (range, 0–13.2 g/y) from 2.9% (interquartile range, 0.8–3.2%) of LV mass to 4.3% (interquartile range, 2.9–6.8%) ( P =0.02). In addition to LGE, LV mass and left atrial volume, indexed to body surface area, and z score for LV mass, as well, increased significantly from first to most recent CMR. Conclusions: LGE was present in 46% of children and adolescents with overt HCM, in contrast to ≈60% typically reported in adult HCM. In the subset of patients with serial imaging, statistically significant increases in LGE, LV mass, and left atrial size were detected over 2.5 years, indicating disease progression over time. Further prospective studies are required to confirm these findings and to better understand the clinical implications of LGE in pediatric HCM.

Background— Knowledge of the burden and causes of sudden cardiac death (SCD) is sparse in persons aged Methods and Results— All deaths in persons aged 1 to 49 years were included in 2007 to 2009. Death certificates were reviewed by 2 physicians. History of previous admissions to hospital was assessed, and discharge summaries were read. Sudden unexpected death cases were identified and autopsy reports were collected. In the 3-year study period, there were 7849 deaths of which we identified 893 (11%) SCD cases. The annual incidence rate per 100 000 persons increased from 2.3 (95% confidence interval, 2.0–2.7) to 21.7 (95% confidence interval, 20.2–23.4) in persons aged 1 to 35 and 36 to 49 years, respectively. Coronary artery disease was the most common cause of death and was found in 158 (36%) autopsied cases, followed by 135 (31%) cases of sudden unexplained death. Conclusions— In a nationwide cohort of persons aged

Aims Lesion of the atrioventricular conduction system is a well known adverse effect of alcohol septal ablation (ASA) in patients with obstructive hypertrophic cardiomyopathy (HCM). We assessed the atrioventricular conduction at long-term follow-up after ASA. Methods In patients with a pacemaker implanted for high-grade atrioventricular block after ASA, the atrioventricular conduction was assessed prospectively by ECGs and 48-h Holter recordings. In the remaining patients, the atrioventricular conduction was analysed retrospectively for comparison. Results A total of 24 (28%) of 87 patients with obstructive HCM without a pacemaker at baseline had a pacemaker implanted due to high-grade atrioventricular block after ASA. Ten of these patients were not available for follow-up. Holter recordings in the remaining 14 patients revealed normalized atrioventricular conduction in 6 patients 6.2 years (range 2.1-9.4) after ASA. Patients with high-grade atrioventricular block at follow-up had longer PR intervals at baseline [205 ms (200-230)] than the rest of the cohort [180 ms (140-200), P = 0.004] and a higher incidence of acute complete heart block (63 vs. 15%; P = 0.007) during ASA. A PR interval of at least 200 ms at baseline was associated with higher prevalence of high-grade atrioventricular block at follow-up (30 vs. 2%; P = 0.0013). The incidence of late-onset complete heart block was 1.5% per year after ASA. Conclusion We found normalized atrioventricular conduction at long-term follow-up, suggesting recovery in 6 of 14 patients with a pacemaker implanted in relation to ASA. Permanent atrioventricular conduction abnormalities were associated with baseline PR intervals of at least 200 ms and acute persistent complete heart block during ASA.

Background— Because of the nephrotoxic effects of aminoglycosides, the Danish guidelines on infective endocarditis were changed in January 2007, reducing gentamicin treatment in enterococcal infective endocarditis from 4 to 6 weeks to only 2 weeks. In this pilot study, we compare outcomes in patients with Enterococcus faecalis infective endocarditis treated in the years before and after endorsement of these new recommendations. Methods and Results— A total of 84 consecutive patients admitted with definite left-sided E faecalis endocarditis in the period of 2002 to 2011 were enrolled. Forty-one patients were treated before and 43 patients were treated after January 1, 2007. There were no significant differences in baseline characteristics. At hospitalization, the 2 groups had similar estimated glomerular filtration rates of 66 and 75 mL/min ( P =0.22). Patients treated before January 2007 received gentamicin for a significantly longer period (28 versus 14 days; P P =0.75). At discharge, the patients treated before 2007 had a lower estimated glomerular filtration rate (45 versus 66 mL/min; P =0.008) and a significantly greater decrease in estimated glomerular filtration rate (median, 11 versus 1 mL/min; P =0.009) compared with those treated after 2007. Conclusions— Our present pilot study suggests that the recommended 2-week treatment with gentamicin seems adequate and preferable in treating non–high-level aminoglycoside-resistant E faecalis infective endocarditis. The longer duration of gentamicin treatment is associated with worse renal function. Although the certainty of the clinical outcomes is limited by the sample size, outcomes appear to be no worse with the shorter treatment duration. Randomized, controlled studies are warranted to substantiate these results.

Background— Pregnancy losses and atherosclerotic disease may be etiologically linked through underlying pathology. We examined whether miscarriage and stillbirth increase later risk of myocardial infarction, cerebral infarction, and renovascular hypertension. Methods and Results— Among women pregnant at least once between 1977 and 2008, we identified a cohort of women with miscarriages, stillbirths, or live singleton births. These women were followed from the end of pregnancy for incident myocardial infarction, cerebral infarction, and renovascular hypertension. Using Poisson regression, we estimated incidence rate ratios for each of the outcomes by history of miscarriage and stillbirth. Among 1 031 279 women followed for >15 928 900 person-years, we identified 27 98 myocardial infarctions, 40 53 cerebral infarctions, and 1269 instances of renovascular hypertension. Women with stillbirths had 2.69 (95% confidence interval, 2.06–3.50), 1.74 (1.32–2.28), and 2.42 (1.59–3.69) times the rates of myocardial infarction, cerebral infarction, and renovascular hypertension, respectively, as women with no stillbirths. Compared with women with no miscarriages, women with miscarriages had 1.13 (1.03–1.24), 1.16 (1.07–1.25), and 1.20 (1.05–1.38) times the rates of these same outcomes, respectively; these associations were dose dependent, with each additional miscarriage increasing the rates of myocardial and cerebral infarction and renovascular hypertension by 9% (3% to 16%), 13% (7% to 19%), and 19% (9% to 30%), respectively. Associations were strongest in younger women ( Conclusions— Pregnancy losses were associated with subsequent risks of myocardial infarction, cerebral infarction, and renovascular hypertension, consistent with either shared etiology or the initiation of pathological processes by a pregnancy loss leading to atherosclerosis.

Background— The penetrance of hypertrophic cardiomyopathy (HCM) during childhood and adolescence has been only sparsely described. We studied the penetrance of HCM and the short- and long-term outcomes of clinical screening and predictive genetic testing of child relatives of patients with HCM. Methods and Results— Ninety probands and 361 relatives were included in a family screening program for HCM (1994–2001). Eleven sarcomere genes, CRYAB, α-GAL, and titin were screened. Sixty-six relatives and 4 probands were Conclusions— The penetrance of HCM in phenotype-negative child relatives at risk of developing HCM was 6% after 12 years of follow-up. The finding of phenotype conversion in the mid-20s warrants continued screening into adulthood. Forty-two percent of the child relatives were noncarriers, and repeat clinical follow-up could be safely limited to the remaining children.

Background— We assessed the influence of interventricular septal thickness (IVSd) on the clinical outcome and survival after alcohol septal ablation (ASA) in patient with hypertrophic cardiomyopathy. Methods and Results— We analyzed 531 patients with hypertrophic cardiomyopathy (age: 56±14 years, men 55%) treated with ASA. Survival status was obtained 7.9±4.0 years after ASA. Baseline IVSd was inversely associated with survival (hazard ratio [HR] for 1 mm increment, 1.13; confidence interval, 1.05–1.21; P P =0.883) or during Valsalva maneuver ( P =0.885). The proportion of patients in New York Heart Association class 3 to 4 was reduced from 86% to 10%; in Canadian Cardiology Society class 3 to 4 from 26% to 2%; and with syncope from 25% to 2%. There were no correlations between baseline IVSd and New York Heart Association class ( P =0.067), Canadian Cardiology Society class ( P =0.106), or syncope ( P =0.426) after ASA. Conclusions— ASA had equal effects on left ventricular outflow tract gradients and symptoms throughout the spectrum of septal hypertrophy. Severe septal hypertrophy before ASA remained a marker of reduced survival after ASA with a 5-fold increased risk of all-cause mortality in patients with baseline IVSd >25 mm compared with patients with baseline IVSd

Background— Single-center reports on percutaneous transluminal septal myocardial ablation (PTSMA) in patients with hypertrophic obstructive cardiomyopathy have shown considerable differences in outcome. Methods and Results— We report the long-term outcome of 313 PTSMA procedures performed in 279 patients with hypertrophic obstructive cardiomyopathy aged 59±14 years from 1999 to 2010 in 4 Scandinavian centers. Sixty-nine percent of patients had ≥1 comorbidity at baseline. The median (interquartile range) of left ventricular outflow tract gradient at rest was reduced from 58 mm Hg (34 to 89 mm Hg) at baseline to 12 mm Hg (8 to 24 mm Hg) at 1-year ( P P P P P =0.03), chronic obstructive pulmonary disease ( P =0.02), and valve disease unrelated to hypertrophic cardiomyopathy ( P P =0.06 versus an age- and sex-matched background population) in all patients and 99%, 94%, and 88%, respectively ( P =0.12) in patients aged Conclusions— In this multicenter study, the in-hospital mortality after PTSMA was low despite considerable comorbidities. The hemodynamic and symptomatic effects were sustained long term. The long-term symptomatic outcome was associated with baseline comorbidities. The 10-year survival rate was comparable to that in an age- and sex-matched background population, and age was the only predictor of survival.

Importance Women with hypertensive disorders of pregnancy, preeclampsia in particular, have an increased risk of cardiomyopathy during the peripartum period. Whether hypertensive disorders of pregnancy are also associated with cardiomyopathy later in life is unknown. Objective To determine whether hypertensive disorders of pregnancy are associated with cardiomyopathy beyond the peripartum period. Design, Setting, and Participants Nationwide register–based cohort study using Cox regression to compare rates of cardiomyopathy in women with and without a history of hypertensive disorders of pregnancy in a cohort of 1 075 763 women with at least 1 pregnancy ending in live birth or stillbirth in Denmark, 1978-2012, with follow-up through December 31, 2012. Exposures A hypertensive disorder of pregnancy (severe or moderate preeclampsia or gestational hypertension) registered in the National Patient Register. Main Outcomes and Measures Cardiomyopathy more than 5 months after delivery (outside the peripartum period) up to 34 years 7 months. Result The women in the primary cohort had 2 067 633 eligible pregnancies during the study period, 76 108 of which were complicated by a hypertensive disorder of pregnancy. During follow-up, 1577 women (mean age, 48.5 years at cardiomyopathy diagnosis; 2.6% with multiple pregnancies) developed cardiomyopathy. Compared with women with normotensive pregnancies (18 211 603 person-years of follow-up; n = 1408 cardiomyopathy events, 7.7/100 000 person-years [95% CI, 7.3-8.2]), women with a history of hypertensive disorders of pregnancy had significantly increased rates of cardiomyopathy (in 173 062 person-years of follow-up among women with severe preeclampsia, n = 27 cardiomyopathy events; 15.6/100 000 person-years [95% CI, 10.7-22.7]; adjusted hazard ratio [HR], 2.20 [95% CI, 1.50-3.23]; in 697 447 person-years of follow-up among women with moderate preeclampsia, n = 102 cardiomyopathy events; 14.6/100 000 person-years [95% CI, 12.0-17.8]; adjusted HR, 1.89 [95% CI, 1.55-2.23]; in 213 197 person-years of follow-up among women with gestational hypertension, n = 40 cardiomyopathy events; 17.3/100 000 person-years [95% CI, 12.7-23.6]; adjusted HR, 2.06 [95% CI, 1.50-2.82]). These increases persisted more than 5 years after the latest pregnancy. Mediation analyses suggested that only about 50% of the association was an indirect association through postpregnancy chronic hypertension. In this cohort, 11% of all cardiomyopathy events occurred in women with a history of hypertensive disorders of pregnancy. Conclusions and Relevance Women with a history of hypertensive disorders of pregnancy, compared with women without such a history, had a small but statistically significant increased risk of cardiomyopathy more than 5 months after delivery. Further research is necessary to understand whether there is a causal mechanism behind this association.

Background— Genetic testing identifies sarcomere mutation carriers (G+) before clinical diagnosis of hypertrophic cardiomyopathy (HCM), allowing characterization of initial disease manifestations. Previous studies demonstrated that impaired relaxation develops before left ventricular hypertrophy (LVH). The precise impact of sarcomere mutations on systolic function in early and late disease is unclear. Methods and Results— Comprehensive echocardiography with strain imaging was performed on 146 genotyped individuals with mutations in 5 sarcomere genes. Contractile parameters were compared in 68 preclinical (G+/LVH−), 40 overt (G+/LVH+) subjects with HCM, and 38 mutation (−) normal control relatives. All subjects had normal left ventricular ejection fraction. In preclinical HCM, global and regional peak systolic strain (ε sys ) and longitudinal systolic strain rate were not significantly different from controls, but early diastolic mitral annular velocity (Ea) was reduced by 13%. In overt HCM, there was a significant 27% and 14% decrease in global longitudinal ε sys and systolic strain rate, respectively, compared with both preclinical HCM and controls ( P Conclusions— Sarcomere mutations have disparate initial effects on diastolic and systolic functions. Preclinical HCM is characterized by impaired relaxation but preserved systolic strain. In contrast, both diastolic and longitudinal systolic abnormalities are present in overt disease despite normal ejection fraction. We propose that diastolic dysfunction is an early consequence of sarcomere mutations, whereas systolic dysfunction results from mutations combined with subsequent pathological remodeling. Identifying mechanistic pathways triggered by these mutations may begin to reshape the clinical paradigm for treatment, based on early diagnosis and disease prevention.

An 11-year-old girl sitting in the kitchen suddenly complained of dizziness. Seconds later, she collapsed and had cardiac arrest. Cardiopulmonary resuscitation was initiated immediately but was unsuccessful, despite prolonged efforts. The girl was previously healthy and had never experienced any cardiac or muscular symptoms. At autopsy, the gross examination was normal. The heart weighed 230 g; the chamber sizes, wall thicknesses, and myocardial appearance were normal. Microscopic examination of the right ventricular myocardium showed marked fibrofatty replacement (Figures 1 and 2⇓). No replacements were found in the left ventricular myocardium or in the skeletal musculature. On this basis, it was concluded that the cause of death was arrhythmogenic right ventricular cardiomyopathy (ARVC). Figure 1. Biopsy from the right ventricular free wall showing fibrofatty replacement. Hematoxylin-eosin stain, magnification ×25. …

Friedreich ataxia (FA) is an autosomal recessively inherited neurodegenerative disease that most often presents in childhood or in young adulthood. A substantial proportion of patients with FA also develop a cardiomyopathy that usually presents as left ventricular hypertrophy (FA-CM). The mean life expectancy is significantly reduced to ≈40 years, and ≈60% of patients with FA die from cardiac causes.1,2 The prevalence of FA is 0.1 to 4.7:100 000, and an estimated 9000 Americans are affected.3 The potential ability to reduce disease progression or even to reverse FA-CM by antioxidants underscores the importance of early identification of the disease and the development of clinically identifiable markers of cardiac involvement. In the current issue of Circulation, the Mitochondrial Protection With Idebenone in Cardiac or Neurological Outcome (MICONOS) study group investigated such markers.4 Article see p 1626 Early identification of FA as the cause of a newly identified cardiomyopathy depends on the cardiologist's ability to identify the extracardiac manifestations of FA. These include progressive limb ataxia and weakness, dysarthria, nystagmus, and loss of proprioception and may also include scoliosis, diabetes mellitus, and impaired vision and hearing. A majority will lose the ability to walk and require wheelchairs. Cardiac involvement is rarely found in other inherited ataxias.5 However, the phenotype is highly variable, and in some patients the first manifestation is cardiomyopathy.3 On the other hand, the pediatrician's or neurologist's knowledge about cardiac involvement and the importance of early referral for cardiac assessment is equally important. In 1996, Durr et al6 reported that FA in most cases is caused by expansion of the DNA triplet intron repeat (GAA) in the FXN gene. This reduces the transcription and expression of the mitochondrial inner membrane protein, frataxin, which may reduce the density of respiratory chain enzyme complexes and …

In a search for a nonsurgical intervention to control intracranial hypertension during craniotomy, the authors studied the effects of dihydroergotamine on mean arterial blood pressure (MABP), intracranial pressure (ICP), cerebral perfusion pressure (CPP), cerebral blood flow (CBF), and cerebral metabolism in patients who underwent craniotomy for supratentorial brain tumors. Twenty patients were randomized to receive either dihydroergotamine 0.25 mg intravenously or placebo as a bolus dose during craniotomy. Anesthesia was induced with thiopental/fentanyl/atracurium, and maintained with isoflurane/N2O/fentanyl at normocapnia. After removal of the bone flap and exposure of intact dura, ICP was measured subdurally and dihydroergotamine/placebo was administered. Intracranial pressure and MABP were measured continuously. Cerebral blood flow (after intravenous administration of 133Xe) and arteriojugular venous difference of oxygen (AVDO2) were measured before, and 30 minutes after, dihydroergotamine/placebo administration. Cerebral metabolic rate of oxygen (CMRO2) was calculated. After administration of dihydroergotamine, a significant increase in MABP from 74 to 87 mm Hg (median) and CPP from 65 to 72 mm Hg (median) were found. Simultaneously to the increase in MABP, a significant increase in ICP from 9.5 to 11.5 mm Hg (median) was disclosed, whereas no significant differences in CBF, AVDO2, or CMRO2 were found. Intracranial pressure was significantly higher after dihydroergotamine than after placebo. In conclusion, no ICP decreasing effect of a bolus dose of dihydroergotamine was found when administered to patients with brain tumors during isoflurane/N2O anesthesia. Corresponding increases in MABP and ICP suggest that abolished cerebral autoregulation might explain why dihydroergotamine was associated with an ICP increase.

Abstract —Aldosterone upregulates the Na + -K + pump in kidney and colon, classical target organs for the hormone. An effect on pump function in the heart is not firmly established. Because the myocardium contains mineralocorticoid receptors, we examined whether aldosterone has an effect on Na + -K + pump function in cardiac myocytes. Myocytes were isolated from rabbits given aldosterone via osmotic minipumps and from controls. Electrogenic Na + -K + pump current, arising from the 3:2 Na + :K + exchange ratio, was measured in single myocytes using the whole-cell patch clamp technique. Treatment with aldosterone induced a decrease in pump current measured when myocytes were dialyzed with patch pipette solution containing Na + in a concentration of 10 mmol/L, whereas there was no effect measured when the solution contained 80 mmol/L Na + . Aldosterone had no effect on myocardial Na + -K + pump concentration evaluated by vanadate-facilitated [ 3 H]ouabain binding or by K + -dependent paranitrophenylphosphatase activity in crude homogenates. Aldosterone induced an increase in intracellular Na + activity. The aldosterone-induced decrease in pump current and increased intracellular Na + were prevented by cotreatment with the mineralocorticoid receptor antagonist spironolactone. Our results indicate that hyperaldosteronemia decreases the apparent Na + affinity of the Na + -K + pump, whereas it has no effect on maximal pump capacity.