Lifetime ADHD symptoms highly prevalent in women with cardiovascular complaints. A cross-sectional study.

Patients with Attention Deficit Hyperactivity Disorder (ADHD) are at greater cardiovascular risk. We investigated the association between ADHD symptoms and cardiovascular disease in women at a specialized Dutch cardiological clinic. Lifetime ADHD symptoms were found in 35% of women (n = 300) with cardiac complaints. Women with ADHD symptoms compared to those without were significantly younger but had no different cardiological profile. To protect women's health, further research and multidisciplinary cooperation is required to better understand the relationship between ADHD and cardiovascular disease.

Novel advances in cardiac rehabilitation : Position paper from the Working Group on Preventive Cardiology and Cardiac Rehabilitation of the Netherlands Society of Cardiology.

Cardiac rehabilitation (CR) has evolved as an important part of the treatment of patients with cardiovascular disease. However, to date, its full potential is fairly underutilised. This review discusses new developments in CR aimed at improving participation rates and long-term effectiveness in the general cardiac population. It consecutively highlights new or challenging target groups, new delivery modes and new care pathways for CR programmes. These new or challenging target groups include patients with atrial fibrillation, obesity and cardiovascular disease, chronic coronary syndromes, (advanced) chronic heart failure with or without intracardiac devices, women and frail elderly patients. Also, the current evidence regarding cardiac telerehabilitation and loyalty programmes is discussed as new delivery modes for CR. Finally, this paper discusses novel care pathways with the integration of CR in residual risk management and transmural care pathways. These new developments can help to make optimal use of the benefits of CR. Therefore we should seize the opportunities to reshape current CR programmes, broaden their applicability and incorporate them into or combine them with other cardiovascular care programmes/pathways.

Ischaemia with no obstructive coronary arteries.

Ischaemia with no obstructive coronary arteries (INOCA) is a common ischaemic heart disease with a female preponderance, mostly due to underlying coronary vascular dysfunction comprising coronary microvascular dysfunction and/or epicardial coronary vasospasm. Since standard ischaemia detection tests and coronary angiograms are not suitable to diagnose coronary vascular dysfunction, INOCA is often overlooked in current cardiology practice. Future research, including large outcome trials, is much awaited. Yet, adequate diagnosis is possible and treatment options are available and vital to reduce symptoms and most probably improve cardiovascular prognosis. This review intends to give a brief overview of the clinical presentation, underlying pathophysiology, and the diagnostic and treatment options in patients with suspected INOCA.

Recommendations on how to provide cardiac rehabilitation services during the COVID-19 pandemic.

The ongoing coronavirus disease 2019 (COVID-19) crisis is having a large impact on acute and chronic cardiac care. Due to public health measures and the reorganisation of outpatient cardiac care, traditional centre-based cardiac rehabilitation is currently almost impossible. In addition, public health measures are having a potentially negative impact on lifestyle behaviour and general well-being. Therefore, the Working Group of Cardiovascular Prevention and Rehabilitation of the Dutch Society of Cardiology has formulated practical recommendations for the provision of cardiac rehabilitation during the COVID-19 pandemic, by using telerehabilitation programmes without face-to-face contact based on current guidelines supplemented with new insights and experiences.

Cardiac telerehabilitation as an alternative to centre-based cardiac rehabilitation.

Multidisciplinary cardiac rehabilitation (CR) reduces morbidity and mortality and increases quality of life in cardiac patients. However, CR utilisation rates are low, and targets for secondary prevention of cardiovascular disease are not met in the majority of patients, indicating that secondary prevention programmes such as CR leave room for improvement. Cardiac telerehabilitation (CTR) may resolve several barriers that impede CR utilisation and sustainability of its effects. In CTR, one or more modules of CR are delivered outside the environment of the hospital or CR centre, using monitoring devices and remote communication with patients. Multidisciplinary CTR is a safe and at least equally (cost-)effective alternative to centre-based CR, and is therefore recommended in a recent addendum to the Dutch multidisciplinary CR guidelines. In this article, we describe the background and core components of this addendum on CTR, and discuss its implications for clinical practice and future perspectives.

Paraoxonase gene polymorphisms are associated with carotid arterial wall thickness in subjects with familial hypercholesterolemia.

Human serum paraoxonase (PON) is a high density lipoprotein (HDL) associated enzyme capable of hydrolyzing lipid peroxides in vitro. PON has recently attracted attention as a protective factor against oxidative modification of LDL and may therefore play an important role in the prevention of the atherosclerotic process. Two frequent mutations at the paraoxonase gene locus (PON1) are the leucine (L allele)-->methionine (M allele) and the glutamine (Q allele)-->arginine (R allele) substitutions at residues 55 and 192, respectively. We have examined the influence of these two polymorphisms on carotid atherosclerosis in familial hypercholesterolemia (FH) patients. The allele frequencies of these two polymorphisms were determined by PCR and restriction fragment analysis, for both the FH population and healthy controls. High resolution B-mode ultrasound was used to assess intima-media wall thickness (IMT) of the carotid artery. No differences were found in allele frequencies between the FH and the control population. In FH patients, the LL, LM and MM genotypes at position 55 occurred in 86 (46.0%), 78 (41.7%) and 23 (12.3%) subjects, respectively, whereas the QQ, QR and RR genotypes at position 192 were found in 90 (48.1%), 79 (42.2%) and 18 (9.6%) individuals. When both polymorphisms were considered separately, no different carotid IMTs were found between the genotype groups. However, our data did show a significant association between the various genotypes of the combined polymorphisms at position 55 and 192 of PON1 and the carotid artery IMT in FH subjects. Subjects with the homozygous wildtype LL/QQ for paraoxonase had the highest mean carotid IMTs when compared to other genotypes, combined. Multiple regression analysis demonstrated age (beta=0.34, P<0.0001), total plasma cholesterol (beta=0.17, P=0. 0109) and the LL/QQ genotype of the PON1 gene (beta=0.22, P=0.0018) to be significant risk factors for carotid atherosclerosis in subjects with FH. The LL/QQ genotype could explain 5.3% of total variance of carotid IMT. In conclusion, this is the first study to report an independent association between the combined PON1 polymorphism genotypes and carotid wall thickness. The homozygous wildtype LL/QQ for PON1 may represent an additional risk factor for carotid atherosclerosis in subjects with FH.

The effect of concentrated n-3 fatty acids versus gemfibrozil on plasma lipoproteins, low density lipoprotein heterogeneity and oxidizability in patients with hypertriglyceridemia.

We evaluated in a double-blind randomized trial with a double-dummy design in 28 patients with primary hypertriglyceridemia, the effect of gemfibrozil (1200 mg/day) versus Omacor (4 g/day), a drug containing the n-3 fatty acids eicosapentaenoic (EPA) and docosahexaenoic acid (DHA), on lipid and lipoprotein levels, low density lipoprotein (LDL) subfraction profile and LDL oxidizability. Both Omacor and gemfibrozil therapy resulted in a similar significant decrease in serum triglyceride (TG), very low density lipoprotein (VLDL) triglyceride and VLDL cholesterol concentrations and an increase in high density lipoprotein (HDL) and LDL cholesterol concentrations. The increase in LDL cholesterol was due to a significant increase in cholesterol content of the relatively buoyant LDL subfractions LDL1, LDL2 and LDL3, whereas the relative contribution of the dense LDL subfractions LDL4 and LDL5 to total LDL tended to decrease. So, both therapies resulted in a more buoyant LDL subfraction profile, reflected by a significant increase of the value of parameter K (+10.3% on Omacor vs. +26.5% on gemfibrozil therapy, gemfibrozil vs Omacor P>0.05). Cu(2+)-induced oxidation of LDL was measured by continuous monitoring of conjugated dienes. After 12 weeks of Omacor treatment LDL appeared more prone to oxidative modification in vitro than LDL after gemfibrozil treatment, as measured by the significantly decreased lag time, preceding the onset of the lipid peroxidation. In both groups the rate of oxidation did not change with therapy. The amount of dienes formed during oxidation increased significantly on Omacor treatment, but not on gemfibrozil treatment. Plasma thiobarbituric acid reactive substances were higher after Omacor and lower after gemfibrozil treatment, although not significantly. We conclude that both Omacor and gemfibrozil have favorable effects on lipid and lipoprotein concentrations and the LDL subfraction profile. However, Omacor increased the susceptibility of LDL to oxidation, whereas gemfibrozil did not affect the resistance of LDL to oxidative modification in vitro. The clinical relevance of these changes remains to be established in the light of other postulated favorable effects of n-3 fatty acids on the course of cardiovascular disease.

Differences in intima-media thickness in the carotid and femoral arteries in familial hypercholesterolemic heterozygotes with and without clinical manifestations of cardiovascular disease.

It is unknown whether the variation in severity of cardiovascular disease (CVD), seen in patients with familial hypercholesterolemia (FH), is reflected in the intima-media thickness (IMT) of carotid and femoral arteries. We measured IMT in both these arteries in 248 consecutive patients with FH, attending our Lipid Clinic. One hundred and six patients were classified as having CVD, while the remaining FH subjects had no clinical evidence of CVD. IMT measurements of 20 prespecified carotid and femoral arterial wall segments of the FH groups with and without CVD were compared. All IMTs in both groups were severely thickened with respect to normal controls. Furthermore, the highest IMTs and the largest absolute differences were observed in the common femoral artery (1.23 +/- 0.46 mm vs 1.10 +/- 0.51 mm; P = 0.006). In subjects with CVD, the distributions of IMT within tertiles for both arterial segments were opposite to those found in FH patients without CVD, (P < 0.05, for both segments). The mean IMT of, in particular, the common femoral artery is thicker in FH individuals with CVD compared with those without. Some FH patients have abnormal IMT of the femoral artery, whereas in others the carotid artery is more affected. Therefore, in FH patients, combined assessment of the carotid and femoral arterial walls provides a more accurate estimation of total atherosclerotic burden in FH.

The apolipoprotein(a) kringle IV repeats which differ from the major repeat kringle are present in variably-sized isoforms.

Elevated levels of plasma lipoprotein(a) [Lp(a)] have been correlated with the development of atherosclerosis in human populations. Apolipoprotein(a) [apo(a); the distinguishing protein component of Lp(a)] is characterized by multiple repeats of a sequence that closely resembles kringle IV of plasminogen. Variably-sized Lp(a) isoforms that are observed in the human population have been shown to occur as a result of differences in the numbers of the repeated kringle IV units in apo(a). Using PCR analysis of human liver mRNA, we have analyzed apo(a) from 10 unrelated individuals in order to determine the presence or absence of kringle IV repeat #1, and #30-#37. Based on the apo(a) cDNA sequence published for one individual, these kringles all differ to some degree in amino acid sequence from the major kringle IV repeat, which is present in a number of identically repeated copies. We found that sequences corresponding to apo(a) kringle IV repeat #1, and #30-#37 were present in all individuals studied. This suggests that the inverse relationship that has been observed between Lp(a) isoform size and plasma Lp(a) levels is mediated by different numbers of identical kringle IV repeats, by an as yet undetermined mechanism. During the course of this study, we identified a Met-->Thr polymorphism in the apo(a) kringle IV repeat #37. The calculated frequencies of the Met and Thr alleles were 0.58 and 0.42 respectively. We did not observe a correlation between the Met-->Thr substitution and either plasma Lp(a) levels, or apo(a) transcript size.

Activation of the contact system of coagulation does not contribute to the hemostatic imbalance in hypertriglyceridemia.

In vitro, triglyceride-rich lipoproteins may act as a surface to initiate the contact system of coagulation. Therefore, we studied the activation of factor XII (FXII), prekallikrein, and FXI and the generation of thrombin in 52 hypertriglyceridemic patients before and after 12 weeks of triglyceride-lowering treatment with gemfibrozil or n-3 polyunsaturated fatty acids. Thrombin generation was assessed by measuring the levels of prothrombin fragment F1+2 and thrombin-antithrombin (TAT) complexes. Contact activation was assessed by measuring FXIIa, kallikrein, and FXIa in complex with their major inhibitor, C1 inhibitor, and FXIa was also determined as part of a complex with alpha(1)-antitrypsin. Triglyceride and cholesterol levels decreased equally in both treatment groups. In the gemfibrozil group, there was a significant decrease in F1+2, while TAT complexes did not change. FXIIa- and kallikrein-C1 inhibitor complexes were elevated in 13% and 9% of the patients before treatment, respectively, and no changes were observed on triglyceride-lowering therapy. Also, no significant changes in regard to FXIa-C1 inhibitor and FXIa-alpha(1)-antitrypsin complexes were seen. FXIa-alpha(1)-antitrypsin complexes were present in 70% of the patients before therapy and were positively correlated with the level of TAT complexes. In conclusion, we did not detect an effect on activation markers of the contact coagulation system in hypertriglyceridemic patients after triglyceride-lowering therapy. Therefore, contact activation is not likely to contribute to the hypercoagulability seen in these patients.

A common mutation in the lipoprotein lipase gene (N291S) alters the lipoprotein phenotype and risk for cardiovascular disease in patients with familial hypercholesterolemia.

BACKGROUND: Recently, a mutation in the lipoprotein lipase (LPL) gene (N291S) has been reported in 2% to 5% of individuals in western populations and is associated with increased triglyceride (TG) and reduced HDL cholesterol (HDLC) concentrations. METHODS AND RESULTS: Here we report a significant alteration in biochemical and clinical phenotype in subjects with familial hypercholesterolemia (FH) who are heterozygous for this N291S LPL mutation. Sixty-four FH heterozygotes carrying the N291S mutation had significantly a higher TG level (P=.004), a higher ratio of total cholesterol to HDLC (P<.001), and lower HDLC concentrations (P=.002) compared with 175 FH heterozygotes without this LPL mutation. Moreover, the N291S mutation conferred a significantly greater risk for developing cardiovascular disease in FH heterozygotes compared with FH heterozygotes without this LPL mutation (odds ratio, 3.875; P=.006). CONCLUSIONS: These data provide evidence that a common LPL variant (N291S) significantly influences the biochemical phenotype and risk for cardiovascular disease in patients with FH.

DNA adduct formation and repair in hamster and rat tracheas exposed to benzo[a]pyrene in organ culture.

Syrian golden hamsters are much more susceptible than Wistar rats to the induction of tracheal tumors by benzo[a]pyrene (B[a]P). To investigate whether this difference is reflected in the pattern of DNA adduct induction and removal, tracheas from either species were isolated and exposed to B[a]P (5 micrograms/ml) in organ culture. At various time-points B[a]P-DNA adducts were quantified by 32P-postlabeling; unscheduled DNA synthesis (UDS) and cell proliferation were determined by [3H]thymidine incorporation during the 18 h before sampling. In an induction-repair experiment tracheas were exposed to B[a]P for 2 days, and cultured for another 4 days without B[a]P. After 2 days of exposure total B[a]P-DNA adduct levels were 10 times higher in hamster compared to rat tracheas. In hamster tracheas one major adduct was formed (95%), namely the adduct between (+)-anti-benzo[a]pyrene diolepoxide and deoxyguanosine (BPDE-N2dG). In rat tracheas BPDE-N2dG comprised approximately 60% of the total B[a]P-DNA adduct level. The other major adduct found in rat tracheas is probably derived from interaction of syn-BPDE and deoxyadenosine. During exposure to B[a]P in hamsters the adduct level increased to 36 +/- 19 adducts/10(6) nucleotides (add/10(6)n) on day 2. Two days after removal of B[a]P the B[a]P-DNA adduct level had decreased to 60% of that on day 2; there was no further decrease in the B[a]P-DNA adduct level, despite considerable cell proliferation at the end of the 6 day culture period. UDS increased during exposure to B[a]P and decreased after removal of B[a]P. In rats removal of B[a]P did not lead to a decrease in the B[a]P-DNA adduct level, which agreed with the observed absence of UDS. In a second experiment tracheas were exposed to B[a]P continuously for 15 days. In hamster tracheas the total B[a]P-DNA adduct level increased from 11 +/- 0.7 add/10(6)n after 1 day of exposure to 105 +/- 2 add/10(6)n after 15 days; also UDS increased with increasing exposure until day 11. Cell proliferation was low at the end of the culture period. In rat tracheas no progressive increase in the B[a]P-DNA adduct level was seen, UDS was not increased and cell proliferation had increased significantly at the end of the exposure period. The extent of adduct induction in the trachea of the two species corresponded with the different susceptibilities to B[a]P-induced tumor formation.

A frequent mutation in the lipoprotein lipase gene (D9N) deteriorates the biochemical and clinical phenotype of familial hypercholesterolemia.

The D9N substitution is a common mutation in the lipoprotein lipase (LPL) gene. This mutation has been associated with reduced levels of HDL cholesterol and elevated triglycerides (TG) in a wide variety of patients. We investigated the influence of this D9N mutation on lipid and lipoprotein levels and risk for cardiovascular disease (CVD) in patients with familial hypercholesterolemia (FH). A total of 2091 FH heterozygotes, all of Dutch extraction, were screened for the D9N mutation using standard polymerase chain reaction techniques, followed by specific enzyme digestion. A total of 94 FH subjects carried the D9N mutation at a carrier frequency of 4.5%. Carriers of other common LPL mutations, such as the N291S and the S447X were excluded. Clinical data on 80 FH individuals carrying the D9N were available and were compared with a FH control group matched for age, sex, and body mass index (n=203). Analysis revealed significantly higher TG (P=0.01) and lower HDL-cholesterol levels (P=0.002). Dyslipidemia was more pronounced in D9N carriers with higher body mass index. Moreover, FH patients carrying this common LPL mutation were at higher risk for CVD, (odds ratio=2.8; 95% CI, 1.43 to 5.32; P=0.002). The common D9N LPL mutation leads to increased TG and decreased HDL plasma levels in patients with FH. These effects are most apparent in those FH heterozygotes with an increased body mass index. Furthermore, this mutation, present in 4.5% of Dutch FH heterozygotes, leads to increased risk for CVD.

Two common mutations (D9N, N291S) in lipoprotein lipase: a cumulative analysis of their influence on plasma lipids and lipoproteins in men and women.

We assessed the effect of two common mutations in the lipoprotein lipase gene (LPL), D9N and N291S, which have been shown to modulate plasma lipids in a wide spectrum of patients. A total of 1114 men and 1 144 women from the Framingham Offspring Study (FOS) were analyzed for these two LPL variants. Subsequently, the association with fasting plasma lipids and risk of coronary artery disease (CHD) was determined. We extended our study by calculating weighed means of lipids and lipoproteins in carriers and non-carriers for these LPL mutations in patients with genetic dyslipidemias, CHD patients and healthy controls. In the FOS sample, the D9N and N291S alleles were associated with lower high-density lipoprotein-cholesterol (HDL-C) (delta = - 0.07 mmol/ 1, p = 0.03) and a trend towards increased triglycerides (delta = 0.25 mmol/ 1, p = 0.07). In women, a trend towards the high triglyceride, low HDL-C phenotype was evident (delta = - 0.02 mmol/1 for HDL-C and delta = 0.14 mmol/l for triglycerides, respectively). Cumulative analysis of other studies of male carriers of the D9N and N291S revealed higher levels of triglycerides (D291N; 2.60(1.85) mmol/l vs. 1.62(1.18) mmol/l: p < 0.0001) (D9N; 1.94 (1.19) mmol/l vs. 1.74(1.17) mmol/l: p < 0.001) and lower HDL-C (N291S; 1.04(0.32) mmol/l vs. 1.15(0.28) mmol/l: p < 0.0001) (D9N; 1.08(0.24) mmol/l vs. 1.16(0.28) mmol/l: p < 0.0001). In females, results differed with higher TG levels (N291S; 1.70(0.99) mmol/l vs. 1.10(0.63) mmol/l: p < 0.001) (D9N; 1.08(0.76) mmol/l vs. 0.96(0.51) mmol/l: p < 0.01) and lower HDL-C levels (N291S; 1.27(0.33) mmol/l vs. 1.51(0.32) mmol/l: p < 0.0001); however, the HDL-C levels for D9N carriers were similar to non-carriers (D9N; 1.52(0.29) mmol/l vs. 1.53(0.35) mmol/l: p = 0.83). Our data provide evidence that common variants of the LPL gene are significant modulators of lipid and lipoprotein levels in both men and women.