The relevance of tissue angiotensin-converting enzyme: manifestations in mechanistic and endpoint data

Angiotensin-converting enzyme (ACE) is primarily localized (>90%) in various tissues and organs, most notably on the endothelium but also within parenchyma and inflammatory cells. Tissue ACE is now recognized as a key factor in cardiovascular and renal diseases. Endothelial dysfunction, in response to a number of risk factors or injury such as hypertension, diabetes mellitus, hypercholesteremia, and cigarette smoking, disrupts the balance of vasodilation and vasoconstriction, vascular smooth muscle cell growth, the inflammatory and oxidative state of the vessel wall, and is associated with activation of tissue ACE. Pathologic activation of local ACE can have deleterious effects on the heart, vasculature, and the kidneys. The imbalance resulting from increased local formation of angiotensin II and increased bradykinin degradation favors cardiovascular disease. Indeed, ACE inhibitors effectively reduce high blood pressure and exert cardio- and renoprotective actions. Recent evidence suggests that a principal target of ACE inhibitor action is at the tissue sites. Pharmacokinetic properties of various ACE inhibitors indicate that there are differences in their binding characteristics for tissue ACE. Clinical studies comparing the effects of antihypertensives (especially ACE inhibitors) on endothelial function suggest differences. More comparative experimental and clinical studies should address the significance of these drug differences and their impact on clinical events

Systemic and cardiac neuroendocrine activation and severity of myocardial ischemia in humans

AbstractObjectives. The purpose of this study was to assess the effect of different degrees of ischemia on circulating and cardiac neurohormones and vasotone.Background. Neuroendocrine activation and subsequent systemic vasoconstriction may complicate ischemia. Whether this relates to severity of ischemia and subsequent cardiac dysfunction, and whether neurohormonal balance in the ischemic area changes, is unknown.Methods. Fifty-six normotensive patients with coronary artery disease were evaluated during incremental atrial pacing. On the basis of ST segment changes, patients were classified in a nonischemic (n = 11) or ischemic group (n = 45), the latter patients were subsequently classified as lactate (n = 28) or nonlactate (n = 17) producing, to identify neurohormonal changes in the effluent of the ischemic myocardium.Results. Angina occurred in 55%, 82% and 82% of patients in the nonischemic, lactate- and nonlactate-producing groups, respectively. Baseline hemodynamic variables and neurohormones were comparable in all groups, as were heart rate, rate-pressure product and coronary hemodynamic variables during pacing. In lactate producers, contractility did not improve, relaxation deteriorated, left ventricular filling pressure increased and cardiac output decreased pacing, indicating more severe ischemia compared with that in nonlactate producers. Neurohormenes did not change in the nonischemic group. In contrast, arterial and coronary venous catecholamines increased significantly more in lactate producers than in nonlactate producers (arterial norepinephrine by 68% vs. 36%, respectively). Moreover, arterial angiotensin II increased in lactate producers from a baseline mean ± SEM of 6.8 ± 0.9 to 9.7 ± 1.6 pmol/liter (p < 0.05), accompanied by a sustained 23% increase in systemic resistance and arterial pressures. In lactate producers, baseline net cardiac norepinephrine release changed to net uptake during pacing (−0.05 ± 0.02 vs. 0.06 ± 0.05 nmol/min, p < 0.05). Epinephrine uptake increased in all patients with ischemia, albeit more in lactate producers.Conclusions. Circulating catecholamines and renin-angiotensin levels are activated, and systemic vasotone is increased in relation to the degree of ischemia. Cardiac epinephrine uptake increases, whereas net baseline norepinephrine release from the ischemic myocardium changes to net uptake. Modulation of this neurohormonal activation may provide an alternative mode to limit ischemia

The Cardioprotective Effects of the Angiotensin-Converting Enzyme Inhibitor Perindopril in Patients With Stable Coronary Artery Disease Are Not Modified by Mild to Moderate Renal Insufficiency Insights From the EUROPA Trial

ObjectivesThis study sought to examine whether the cardioprotective effects of angiotensin-converting enzyme (ACE) inhibitor therapy by perindopril are modified by renal function in patients with stable coronary artery disease.BackgroundA recent study reported that an impaired renal function identified a subgroup of patients with stable coronary artery disease more likely to benefit from ACE inhibition therapy. In light of the growing interest in tailored therapy for targeting medications to specific subgroups, remarks on the consistency of the treatment effect by ACE inhibitors are highly important.MethodsThe present study involved 12,056 patients with stable coronary artery disease without heart failure randomized to perindopril or placebo. Estimated glomerular filtration rate (eGFR) was calculated using the abbreviated Modification of Diet in Renal Disease equation. Cox regression analysis was used to estimate multivariable-adjusted hazard ratios.ResultsThe mean eGFR was 76.2 (±18.1) ml/min/1.73 m2. During follow-up, the primary end point (cardiovascular death, nonfatal myocardial infarction, or resuscitated cardiac arrest) occurred in 454 of 5,761 patients (7.9%) with eGFR ≥75 and in 631 of 6,295 patients (10.0%) with eGFR <75. Treatment benefits of perindopril were apparent in both patient groups either with eGFR ≥75 (hazard ratio 0.77; 95% confidence interval 0.64 to 0.93) or eGFR <75 (hazard ratio 0.84; 95% confidence interval 0.72 to 0.98). We observed no significant interaction between renal function and treatment benefit (p = 0.47). Using different cutoff points of eGFR at the level of 60 or 90 resulted in similar trends.ConclusionsThe treatment benefit of perindopril is consistent and not modified by mild to moderate renal insufficiency

Long term improvement in global left ventricular function after early thrombolytic treatment in acute myocardial infarction

The effect of reperfusion achieved by early intracoronary streptokinase in acute myocardial infarction on left ventricular function was studied in 533 patients enrolled in a prospective randomised multicentre study. Two hundred and sixty four patients were allocated to conventional treatment and 269 patients to thrombolysis. At the end of the procedure patency of the infarct related vessel was achieved in 198 (85%) of 234 patients in whom coronary angiography was performed. The median interval from onset of symptoms till the angiographic documentation of patency was 200 minutes. Data were analysed according to the original treatment allocation. Global left ventricular ejection fraction was determined by radionuclide angiography in 418 patients within two days of admission, in 361 patients after two weeks, and in 307 patients after three months. Global left ventricular function remained unchanged throughout the observation period in the control group, whereas it improved during the first two weeks in patients allocated to thrombolytic treatment. Improved function in these patients persisted up to three months after the infarction. Global left ventricular ejection fraction was significantly better in the thrombolysis group than in the control group at two days, two weeks, and at three months. In patients with anterior myocardial infarction the left ventricular ejection fraction was 9% better than in the control group at two weeks and at three months. In the patients with inferior myocardial infarction differences between the two treatment groups were smaller because of photon attenuation within the body. Angiographic evidence suggested that the improvement in function seen after thrombolysis is indeed associated with the patency of the infarct related artery

Prediction of absolute risk reduction of cardiovascular events with perindopril for individual patients with stable coronary artery disease - results from EUROPA

BACKGROUND: Angiotensin-converting-enzyme inhibition reduces the risk of cardiovascular events at a group level. Presumably, the absolute effect of treatment varies between individuals. We sought to develop multivariable prediction scores to estimate individual treatment effect of perindopril in patients with stable coronary artery disease (sCAD). METHODS: In EUROPA trial participants, we estimated the individual patient 5-year absolute risk reduction (ARR) of major adverse cardiovascular events(MACE) by perindopril. Predictions were based on a new Coxproportional-hazards model with clinical characteristics and an external risk score in combination with the observed relative risk reduction. Second, a genetic profile modifying the relative efficacy of perindopril was added. The individual patient ARR was defined as the difference in MACE risk with and without treatment. The group level impact of selectively treating patients with the largest predicted treatment effect was evaluated using net benefit analysis. RESULTS: The risk score combining clinical and genetic characteristics estimated the 5-year absolute treatment effect to be absent or adverse in 27% of patients. On the other hand, the risk score estimated a small 5-year ARR of ≤2% (NNT5≥50) in 20% of patients, a modest ARR of 2-4% (NNT5 25-50) in 26%, and a large ARR of ≥4% (NNT5≤25) in 28%. The external risk score yielded similar predictions. Selective prediction-based treatment resulted in higher net benefit compared to treat everyone at any treatment threshold. CONCLUSION: A prediction score combining clinical characteristics and genetic information can quantify the ARR of MACE by perindopril for individual patients with sCAD and may be used to guide treatment decisions. TRIAL REGISTRATION NUMBER: ISRCTN37166280

Desmosomal protein degradation as an underlying cause of arrhythmogenic cardiomyopathy

Arrhythmogenic cardiomyopathy (ACM) is an inherited progressive cardiac disease. Many patients with ACM harbor mutations in desmosomal genes, predominantly in plakophilin-2 (PKP2). Although the genetic basis of ACM is well characterized, the underlying disease-driving mechanisms remain unresolved. Explanted hearts from patients with ACM had less PKP2 compared with healthy hearts, which correlated with reduced expression of desmosomal and adherens junction (AJ) proteins. These proteins were also disorganized in areas of fibrotic remodeling. In vitro data from human-induced pluripotent stem cell-derived cardiomyocytes and microtissues carrying the heterozygous PKP2 c.2013delC pathogenic mutation also displayed impaired contractility. Knockin mice carrying the equivalent heterozygous Pkp2 c.1755delA mutation recapitulated changes in desmosomal and AJ proteins and displayed cardiac dysfunction and fibrosis with age. Global proteomics analysis of 4-month-old heterozygous Pkp2 c.1755delA hearts indicated involvement of the ubiquitin-proteasome system (UPS) in ACM pathogenesis. Inhibition of the UPS in mutant mice increased area composita proteins and improved calcium dynamics in isolated cardiomyocytes. Additional proteomics analyses identified lysine ubiquitination sites on the desmosomal proteins, which were more ubiquitinated in mutant mice. In summary, we show that a plakophilin-2 mutation can lead to decreased desmosomal and AJ protein expression through a UPS-dependent mechanism, which preceded cardiac remodeling. These findings suggest that targeting protein degradation and improving desmosomal protein stability may be a potential therapeutic strategy for the treatment of ACM