A physician who has crossed many frontiers and has changed direction a number of times 

in European Heart Journal (2017), 38(37), 27992800

The Plasma Membrane Calcium ATPases and Their Role as Major New Players in Human Disease.

in Physiological Reviews (2017), 97(3), 1089-1125

The Ca2+ extrusion function of the four mammalian isoforms of the plasma membrane calcium ATPases (PMCAs) is well established. There is also ever-increasing detail known of their roles in global and local ... [more ▼]

The Ca2+ extrusion function of the four mammalian isoforms of the plasma membrane calcium ATPases (PMCAs) is well established. There is also ever-increasing detail known of their roles in global and local Ca2+ homeostasis and intracellular Ca2+ signaling in a wide variety of cell types and tissues. It is becoming clear that the spatiotemporal patterns of expression of the PMCAs and the fact that their abundances and relative expression levels vary from cell type to cell type both reflect and impact on their specific functions in these cells. Over recent years it has become increasingly apparent that these genes have potentially significant roles in human health and disease, with PMCAs1-4 being associated with cardiovascular diseases, deafness, autism, ataxia, adenoma, and malarial resistance. This review will bring together evidence of the variety of tissue-specific functions of PMCAs and will highlight the roles these genes play in regulating normal physiological functions and the considerable impact the genes have on human disease. [less ▲]

Effect of renal artery revascularization upon cardiac structure and function in atherosclerotic renal artery stenosis: cardiac magnetic resonance sub-study of the ASTRAL trial.

in Nephrology Dialysis Transplantation (2016)

BACKGROUND: Cardiac abnormalities are frequent in patients with atherosclerotic renovascular disease (ARVD). The Angioplasty and Stenting for Renal Artery Lesions (ASTRAL) trial studied the effect of ... [more ▼]

BACKGROUND: Cardiac abnormalities are frequent in patients with atherosclerotic renovascular disease (ARVD). The Angioplasty and Stenting for Renal Artery Lesions (ASTRAL) trial studied the effect of percutaneous renal revascularization combined with medical therapy compared with medical therapy alone in 806 patients with ARVD. METHODS: This was a pre-specified sub-study of ASTRAL (clinical trials registration, current controlled trials number: ISRCTN59586944), designed to consider the effect of percutaneous renal artery angioplasty and stenting on change in cardiac structure and function, measured using cardiac magnetic resonance (CMR) imaging. Fifty-one patients were recruited from six selected ASTRAL centres. Forty-four completed the study (medical therapy n = 21; revascularization n = 23). Full analysis of CMR was possible in 40 patients (18 medical therapy and 22 revascularization). CMR measurements of left and right ventricular end systolic (LV and RVESV) and diastolic volume (LV and RVEDV), ejection fraction (LVEF) and mass (LVM) were made shortly after recruitment and before revascularization in the interventional group, and again after 12 months. Reporting was performed by CMR analysts blinded to randomization arm. RESULTS: Groups were well matched for mean age (70 versus 72 years), blood pressure (148/71 versus 143/74 mmHg), degree of renal artery stenosis (75 versus 75%) and comorbid conditions. In both randomized groups, improvements in cardiac structural parameters were seen at 12 months, but there were no significant differences between treatment groups. Median left ventricular changes between baseline and 12 months (medical versus revascularization) were LVEDV -1.9 versus -5.8 mL, P = 0.4; LVESV -2.1 versus 0.3 mL, P = 0.7; LVM -5.4 versus -6.3 g, P = 0.8; and LVEF -1.5 versus -0.8%, P = 0.7. Multivariate regression also found that randomized treatment assignment was not associated with degree of change in any of the CMR measurements. CONCLUSIONS: In this sub-study of the ASTRAL trial, renal revascularization did not offer additional benefit to cardiac structure or function in unselected patients with ARVD. [less ▲]

Plasma membrane calcium ATPases (PMCAs) as potential targets for the treatment of essential hypertension.

in Pharmacology and Therapeutics (2016), 159

The incidence of hypertension, the major modifiable risk factor for cardiovascular disease, is increasing. Thus, there is a pressing need for the development of new and more effective strategies to ... [more ▼]

The incidence of hypertension, the major modifiable risk factor for cardiovascular disease, is increasing. Thus, there is a pressing need for the development of new and more effective strategies to prevent and treat hypertension. Development of these relies on a continued evolution of our understanding of the mechanisms which control blood pressure (BP). Resistance arteries are important in the regulation of total peripheral resistance and BP; changes in their structure and function are strongly associated with hypertension. Anti-hypertensives which both reduce BP and reverse changes in resistance arterial structure reduce cardiovascular risk more than therapies which reduce BP alone. Hence, identification of novel potential vascular targets which modify BP is important. Hypertension is a multifactorial disorder which may include a genetic component. Genome wide association studies have identified ATP2B1, encoding the calcium pump plasma membrane calcium ATPase 1 (PMCA1), as having a strong association with BP and hypertension. Knockdown or reduced PMCA1 expression in mice has confirmed a physiological role for PMCA1 in BP and resistance arterial regulation. Altered expression or inhibition of PMCA4 has also been shown to modulate these parameters. The mechanisms whereby PMCA1 and 4 can modulate vascular function remain to be fully elucidated but may involve regulation of intracellular calcium homeostasis and/or comprise a structural role. However, clear physiological links between PMCA and BP, coupled with experimental studies directly linking PMCA1 and 4 to changes in BP and arterial function, suggest that they may be important targets for the development of new pharmacological modulators of BP. [less ▲]

Angiotensin receptor neprilysin inhibition compared with enalapril on the risk of clinical progression in surviving patients with heart failure.

in Circulation (2015), 131(1), 54-61

BACKGROUND: Clinical trials in heart failure have focused on the improvement in symptoms or decreases in the risk of death and other cardiovascular events. Little is known about the effect of drugs on the ... [more ▼]

BACKGROUND: Clinical trials in heart failure have focused on the improvement in symptoms or decreases in the risk of death and other cardiovascular events. Little is known about the effect of drugs on the risk of clinical deterioration in surviving patients. METHODS AND RESULTS: We compared the angiotensin-neprilysin inhibitor LCZ696 (400 mg daily) with the angiotensin-converting enzyme inhibitor enalapril (20 mg daily) in 8399 patients with heart failure and reduced ejection fraction in a double-blind trial. The analyses focused on prespecified measures of nonfatal clinical deterioration. In comparison with the enalapril group, fewer LCZ696-treated patients required intensification of medical treatment for heart failure (520 versus 604; hazard ratio, 0.84; 95% confidence interval, 0.74-0.94; P=0.003) or an emergency department visit for worsening heart failure (hazard ratio, 0.66; 95% confidence interval, 0.52-0.85; P=0.001). The patients in the LCZ696 group had 23% fewer hospitalizations for worsening heart failure (851 versus 1079; P<0.001) and were less likely to require intensive care (768 versus 879; 18% rate reduction, P=0.005), to receive intravenous positive inotropic agents (31% risk reduction, P<0.001), and to have implantation of a heart failure device or cardiac transplantation (22% risk reduction, P=0.07). The reduction in heart failure hospitalization with LCZ696 was evident within the first 30 days after randomization. Worsening of symptom scores in surviving patients was consistently more common in the enalapril group. LCZ696 led to an early and sustained reduction in biomarkers of myocardial wall stress and injury (N-terminal pro-B-type natriuretic peptide and troponin) versus enalapril. CONCLUSIONS: Angiotensin-neprilysin inhibition prevents the clinical progression of surviving patients with heart failure more effectively than angiotensin-converting enzyme inhibition. CLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrials.gov. Unique identifier: NCT01035255. [less ▲]

Angiotensin-neprilysin inhibition versus enalapril in heart failure.

in The New England journal of medicine (2014), 371(11), 993-1004

BACKGROUND: We compared the angiotensin receptor-neprilysin inhibitor LCZ696 with enalapril in patients who had heart failure with a reduced ejection fraction. In previous studies, enalapril improved ... [more ▼]

BACKGROUND: We compared the angiotensin receptor-neprilysin inhibitor LCZ696 with enalapril in patients who had heart failure with a reduced ejection fraction. In previous studies, enalapril improved survival in such patients. METHODS: In this double-blind trial, we randomly assigned 8442 patients with class II, III, or IV heart failure and an ejection fraction of 40% or less to receive either LCZ696 (at a dose of 200 mg twice daily) or enalapril (at a dose of 10 mg twice daily), in addition to recommended therapy. The primary outcome was a composite of death from cardiovascular causes or hospitalization for heart failure, but the trial was designed to detect a difference in the rates of death from cardiovascular causes. RESULTS: The trial was stopped early, according to prespecified rules, after a median follow-up of 27 months, because the boundary for an overwhelming benefit with LCZ696 had been crossed. At the time of study closure, the primary outcome had occurred in 914 patients (21.8%) in the LCZ696 group and 1117 patients (26.5%) in the enalapril group (hazard ratio in the LCZ696 group, 0.80; 95% confidence interval [CI], 0.73 to 0.87; P<0.001). A total of 711 patients (17.0%) receiving LCZ696 and 835 patients (19.8%) receiving enalapril died (hazard ratio for death from any cause, 0.84; 95% CI, 0.76 to 0.93; P<0.001); of these patients, 558 (13.3%) and 693 (16.5%), respectively, died from cardiovascular causes (hazard ratio, 0.80; 95% CI, 0.71 to 0.89; P<0.001). As compared with enalapril, LCZ696 also reduced the risk of hospitalization for heart failure by 21% (P<0.001) and decreased the symptoms and physical limitations of heart failure (P=0.001). The LCZ696 group had higher proportions of patients with hypotension and nonserious angioedema but lower proportions with renal impairment, hyperkalemia, and cough than the enalapril group. CONCLUSIONS: LCZ696 was superior to enalapril in reducing the risks of death and of hospitalization for heart failure. (Funded by Novartis; PARADIGM-HF ClinicalTrials.gov number, NCT01035255.). [less ▲]

Plasma membrane calcium ATPase isoform 4 inhibits vascular endothelial growth factor-mediated angiogenesis through interaction with calcineurin.

in Arteriosclerosis, thrombosis, and vascular biology (2014), 34(10), 2310-20

OBJECTIVE: Vascular endothelial growth factor (VEGF) has been identified as a crucial regulator of physiological and pathological angiogenesis. Among the intracellular signaling pathways triggered by VEGF ... [more ▼]

OBJECTIVE: Vascular endothelial growth factor (VEGF) has been identified as a crucial regulator of physiological and pathological angiogenesis. Among the intracellular signaling pathways triggered by VEGF, activation of the calcineurin/nuclear factor of activated T cells (NFAT) signaling axis has emerged as a critical mediator of angiogenic processes. We and others previously reported a novel role for the plasma membrane calcium ATPase (PMCA) as an endogenous inhibitor of the calcineurin/NFAT pathway, via interaction with calcineurin, in cardiomyocytes and breast cancer cells. However, the functional significance of the PMCA/calcineurin interaction in endothelial pathophysiology has not been addressed thus far. APPROACH AND RESULTS: Using in vitro and in vivo assays, we here demonstrate that the interaction between PMCA4 and calcineurin in VEGF-stimulated endothelial cells leads to downregulation of the calcineurin/NFAT pathway and to a significant reduction in the subsequent expression of the NFAT-dependent, VEGF-activated, proangiogenic genes RCAN1.4 and Cox-2. PMCA4-dependent inhibition of calcineurin signaling translates into a reduction in endothelial cell motility and blood vessel formation that ultimately impairs in vivo angiogenesis by VEGF. CONCLUSIONS: Given the importance of the calcineurin/NFAT pathway in the regulation of pathological angiogenesis, targeted modulation of PMCA4 functionality might open novel therapeutic avenues to promote or attenuate new vessel formation in diseases that occur with angiogenesis. [less ▲]

The tumour suppressor Ras-association domain family protein 1A (RASSF1A) regulates TNF-alpha signalling in cardiomyocytes.

in Cardiovascular research (2014), 103(1), 47-59

AIMS: Tumour necrosis factor-alpha (TNF-alpha) plays a key role in the regulation of cardiac contractility. Although cardiomyocytes are known to express the TNF-alpha receptors (TNFRs), the mechanism of ... [more ▼]

AIMS: Tumour necrosis factor-alpha (TNF-alpha) plays a key role in the regulation of cardiac contractility. Although cardiomyocytes are known to express the TNF-alpha receptors (TNFRs), the mechanism of TNF-alpha signal transmission is incompletely understood. The aim of this study was to investigate whether the tumour suppressor Ras-association domain family protein 1 isoform A (RASSF1A) modulates TNF-alpha signalling in cardiomyocytes. METHODS AND RESULTS: We used RASSF1A knockout (RASSF1A(-/-)) mice and wild-type (WT) littermates in this study. Acute stimulation with a low dose of TNF-alpha (10 microg/kg iv) increased cardiac contractility and intracellular calcium transients' amplitude in WT mice. In contrast, RASSF1A(-/-) mice showed a blunted contractile response. Mechanistically, RASSF1A was essential in the formation of the TNFR complex (TNFRC), where it functions as an adaptor molecule to facilitate the recruitment of TNFR type 1-associated death domain protein and TNFR-associated factor 2 to form the TNF-alpha receptor complex. In the absence of RASSF1A, signal transmission from the TNF-alpha receptor complex to the downstream effectors, such as cytoplasmic phospholipase A2 and protein kinase A, was attenuated leading to the reduction in the activation of calcium handling molecules, such as L-type Ca(2+) channel and ryanodine receptors. CONCLUSION: Our data indicate an essential role of RASSF1A in regulating TNF-alpha signalling in cardiomyocytes, with RASSF1A being key in the formation of the TNFRC and in signal transmission to the downstream targets. [less ▲]

The mammalian Ste20-like kinase 2 (Mst2) modulates stress-induced cardiac hypertrophy.

in The Journal of biological chemistry (2014), 289(35), 24275-88

The Hippo signaling pathway has recently moved to center stage in cardiac research because of its key role in cardiomyocyte proliferation and regeneration of the embryonic and newborn heart. However, its ... [more ▼]

The Hippo signaling pathway has recently moved to center stage in cardiac research because of its key role in cardiomyocyte proliferation and regeneration of the embryonic and newborn heart. However, its role in the adult heart is incompletely understood. We investigate here the role of mammalian Ste20-like kinase 2 (Mst2), one of the central regulators of this pathway. Mst2(-/-) mice showed no alteration in cardiomyocyte proliferation. However, Mst2(-/-) mice exhibited a significant reduction of hypertrophy and fibrosis in response to pressure overload. Consistently, overexpression of MST2 in neonatal rat cardiomyocytes significantly enhanced phenylephrine-induced cellular hypertrophy. Mechanistically, Mst2 positively modulated the prohypertrophic Raf1-ERK1/2 pathway. However, activation of the downstream effectors of the Hippo pathway (Yes-associated protein) was not affected by Mst2 ablation. An initial genetic study in mitral valve prolapse patients revealed an association between a polymorphism in the human MST2 gene and adverse cardiac remodeling. These results reveal a novel role of Mst2 in stress-dependent cardiac hypertrophy and remodeling in the adult mouse and likely human heart. [less ▲]

Pacing-induced cardiomyopathy: pathophysiological insights through matrix metalloproteinases.

in Heart failure reviews (2013)

Pacing-induced ventricular dysfunction and pacing-induced cardiomyopathy (PiCMP) are recognized complications of chronic right ventricular pacing. Alterations in myocardial perfusion and sympathetic ... [more ▼]

Pacing-induced ventricular dysfunction and pacing-induced cardiomyopathy (PiCMP) are recognized complications of chronic right ventricular pacing. Alterations in myocardial perfusion and sympathetic innervation contribute to the development of pacing-induced heart disease. However, it is unlikely that these are the only processes involved. Matrix metalloproteinases (MMPs) are proteolytic enzymes that degrade the collagenous extracellular matrix and play a central role in left ventricular remodelling during the development of heart failure. While the pathophysiological mechanisms and altered MMP expression that occur in chronic pressure overload, ischaemic and non-ischaemic dilated cardiomyopathy have been defined, those that occur in the clinical setting of pacing-induced ventricular dysfunction and PiCMP have not been reported. Here we review the clinical epidemiology of pacing-induced ventricular dysfunction and discuss how data derived from animal models provide insight into how changes in MMP expression and function contribute to the development of PiCMP. The review concludes by exploring pacing strategies that may be used to prevent pacing-induced ventricular dysfunction. [less ▲]