705

Barry J. Maron, Martin S. Maron, Christopher Semsarian

Hypertrophic cardiomyopathy (HCM) is the most common familial heart disease with vast genetic heterogeneity. Mutations in 11 or more genes encoding proteins of the cardiac sarcomere (>1,400 variants) are responsible for, or associated with, HCM. The current power of HCM mutational analysis, albeit more limited than initially envisioned, lies most prominently in screening family members at risk for developing disease. Interfacing a heterogenous disease with the vast genetic variability of the human genome, and high frequency of novel mutations, has created unforeseen difficulties in translating complex science (and language) into the clinical arena. Major challenges rest with making reliable distinctions between pathogenic mutations and benign variants.

716

Sotirios Tsimikas, Jennifer L. Hall

Recent published studies have provided increasing evidence that lipoprotein(a) [Lp(a)] may be a potential causal, genetic, independent risk factor for cardiovascular disease (CVD). Circulating Lp(a) levels are primarily influenced by the LPA gene without significant dietary or environmental effects. Recent clinical studies have shown that genetically determined Lp(a) levels are continuously and linearly related to the risk of CVD, yet the pathophysiology of Lp(a) is poorly understood and targeted therapies to lower Lp(a) are not available. Tsimikas and Hall provide a rationale for increased basic and clinical investigational efforts to further understand Lp(a) pathophysiology and perform studies to assess whether reducing Lp(a) levels lowers CVD risk.

722

Anna Helgadottir, Solveig Gretarsdottir, Gudmar Thorleifsson, Hilma Holm, Riyaz S. Patel, Thorarinn Gudnason, Gregory T. Jones, Andre M. van Rij, Danny J. Eapen, Annette F. Baas, David-Alexandre Tregouet, Pierre-Emmanuel Morange, Joseph Emmerich, Bengt Lindblad, Anders Gottsäter, Lambertus A. Kiemeny, Jes S. Lindholt, Natzi Sakalihasan, Robert E. Ferrell, David J. Carey, James R. Elmore, Philip S. Tsao, Niels Grarup, Torben Jørgensen, Daniel R. Witte,Torben Hansen, Oluf Pedersen, Roberto Pola, Eleonora Gaetani, Hulda B. Magnadottir, Cisca Wijmenga, Gerard Tromp, Antti Ronkainen, Ynte M. Ruigrok, Jan D. Blankensteijn, Thomas Mueller, Phil Wells, Javier Corral, Jose Manuel Soria, Juan Carlos Souto, John F. Peden, Shapour Jalilzadeh, Bongani M. Mayosi, Bernard Keavney, Rona J. Strawbridge, Maria Sabater-Lleal, Karl Gertow, Damiano Baldassarre, Kristiina Nyyssönen, Rainer Rauramaa, Andries J. Smit, Elmo Mannarino, Philippe Giral, Elena Tremoli, Ulf de Faire, Steve E. Humphries, Anders Hamsten, Vilhelmina Haraldsdottir, Isleifur Olafsson, Magnus K. Magnusson, Nilesh J. Samani, Allan I. Levey, Hugh S. Markus, Konstantinos Kostulas, Martin Dichgans, Klaus Berger, Gregor Kuhlenbäumer, E. Bernd Ringelstein, Monika Stoll, Udo Seedorf, Peter M. Rothwell, Janet T. Powell, Helena Kuivaniemi, Pall T. Onundarson, Einar Valdimarsson, Stefan E. Matthiasson, Daniel F. Gudbjartsson, Guðmundur Thorgeirsson, Arshed A. Quyyumi, Hugh Watkins, Martin Farrall, Unnur Thorsteinsdottir, Kari Stefansson

Helgadottir and colleagues investigated the effects of genetic variations in the apolipoprotein (a) gene (LPA) on vascular diseases. Two LPA variants (rs10455872 and rs3798220) were examined for association with ischemic stroke, peripheral arterial disease (PAD), abdominal aortic aneurysm (AAA), venous thromboembolism (VTE), coronary artery disease (CAD), carotid intima media thickness (IMT), and angiographic CAD severity. The number of positive alleles associated with the risk of ischemic stroke due to large artery atherosclerosis, PAD, and AAA, but not with the other stroke subtypes. While the LPA variants did not associate with IMT, they did associate with the number of obstructed coronary vessels. There was no association of LPA score with VTE. These findings help to clarify the risk associated with elevated LPA levels.

730

Fen-Yu Tseng, Wen-Yuan Lin, Cheng-Chieh Lin, Long-Teng Lee, Tsai-Chung Li, Pei-Kun Sung, Kuo-Chin Huang

Tseng and colleagues evaluated the relationship between subclinical hypothyroidism (SCH) and all-cause and cardiovascular disease (CVD) mortality. SCH was defined as an elevated thyroid-stimulating hormone (TSH) level with a normal thyroxine (T4) level in this review of >100,000 Taiwanese subjects. Compared to subjects with euthyroidism, after adjustment for age, sex, body mass index, diabetes, hypertension, dyslipidemia, smoking, alcohol consumption, betel nut chewing, physical activity, income, and education level, the relative risks of deaths from all-cause and CVD among subjects with SCH were 1.30 and 1.68, respectively. These findings confirm a link between SCH and CVD death.

738

Gregory Y. H. Lip, Torben Bjerregaard Larsen, Flemming Skjøth, Lars Hvilsted Rasmussen

A “head-to-head” direct comparison of drugs is the preferred method for comparing treatments, but this is unlikley to occur for some time, if ever, for the recently introduced oral anticoagulant drugs for the prevention of stroke in patients with atrial fibrillation. Lip and colleagues instead performed an indirect comparison, using warfarin as a common comparator. There was a significantly lower risk of stroke and systemic embolism (by 26%) for dabigatran (150 mg BID) compared to rivaroxaban, but no significant differences between the other options. Major bleeding was lower with apixaban compared to dabigatran 150 mg BID (by 26%) and rivaroxaban (by 34%), but not significantly different from dabigatran 110 mg BID. These results, with the limitations of an indirect comparison, may help to guide the clinician in choosing between the new oral anticoagulants.

Editorial Comment: Christopher P. Cannon, Payal Kohli, p.747

749

Jonathan Buber, Ilan Goldenberg, Arthur Moss, Paul J. Wang, Scott McNitt, W. Jackson Hall, Michael Eldar, Alon Barsheshet, Michael Shechter

Some prior studies have suggested that statins have antiarrhythmic properties. Buber and colleagues studied the antiarrhythmic potential of statins in patients with nonischemic cardiomyopathy (NICM) enrolled in MADIT-CRT (Multicenter Automatic Defibrillator Implantation Trial with Cardiac Resynchronization Therapy). Multivariate analysis showed that statin therapy was independently associated with a 77% reduction in the risk of fast ventricular fibrillation/ventricular tachycardia (VT/VF) or death and a 46% reduction in the risk of appropriate implantable cardioverter-defibrillator shocks. The cumulative probability of fast VT/VF or death at 4 years was 11% in those treated with statins compared to 19% in those who were not. These results suggest that statins should be considered in patients with NICM at risk of life-threatening arrhythmias, but this was not a randomized controlled trial.

756

Roy Jogiya, Sebastian Kozerke, Geraint Morton, Kalpa De Silva, Simon Redwood, Divaka Perera, Eike Nagel, Sven Plein

Three-dimensional (3D) myocardial perfusion imaging with cardiovascular magnetic resonance (CMR) has previously shown good diagnostic accuracy compared to quantitative coronary angiography (QCA). In this study, Jogiya and colleagues compared 3D CMR to fractional flow reserve (FFR) measurements. Perfusion was scored on a patient and coronary territory basis. Sensitivity, specificity, and diagnostic accuracy of CMR for the detection of significant coronary artery disease (CAD) (FFR <0.75) were 90%, 91 % and 91%, on a patient basis and 79%, 92% and 88%, respectively by coronary territory. 3D myocardial perfusion CMR accurately detects functionally significant CAD as defined by FFR and provides an assessment of ischemia burden in agreement with the invasively derived Duke Jeopardy Score.

Editorial Comment: Jens Vogel-Claussen, p.766

768

Ronald J. Oudiz, Bruce H. Brundage, Nazzareno Galie‘, Hossein Ardeschir Ghofrani, Gerald Simonneau, Fady T. Botros, Melanie Chan, Anthony Beardsworth, Robyn J. Barst, for the PHIRST Study Group

Tadalafil is an oral phosphodiesterase-5 (PDE-5) inhibitor approved for treatment of pulmonary arterial hypertension (PAH). In the placebo-controlled, randomized, 16-week PHIRST (Pulmonary Arterial Hypertension and Response to Tadalafil) study, 40-mg tadalafil improved exercise capacity and delayed clinical worsening. The PHIRST-2 trial studied the long-term safety and durability of tadalafil by extending the study for another 52 weeks. The safety profile of tadalafil in PHIRST-2 was similar to that of PHIRST, with typical PDE-5 inhibitor adverse events. The improvement in 6 min walk distance achieved in PHIRST was maintained at PHIRST-2 completion. Long-term treatment with tadalafil was well tolerated and the benefits attained at 16 weeks appear to be sustained for the long term.

775

Deepanjana Das, Joseph Gawdzik, Lisa Dellefave-Castillo, Elizabeth M. McNally, Aliya Husain, Jai Raman, Marion A. Hofmann Bowman

Das and colleagues recently reported that transgenic mice engineered to express human S100A12, a pro-inflammatory protein, in aortic smooth muscle cells develop thoracic aortic aneurysms (TAA). In this paper, they examine S100A12 expression in human aortic diseases using biopsy samples obtained from patients presenting with TAA, either with dissection or for elective repair. There was a strong expression of S100A12 in inflammatory cells and in smooth muscle cells in all cases of thoracic aneurysms with type A dissection, and in approximately 25% of clinically stable TAA. Studies on cultured human aortic smooth muscle cells show a direct role of S100A12 in mediating apoptosis. Together these data demonstrate that S100A12 is up-regulated in TAAD and may contribute to the pathogenesis of TAAD.