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These interact accordingly with the endothelial receptors and the smooth muscle cells that migrate to the intima Pathogenetic and Immunological Paradigm of Atherosclerotic Plaque 5 and are able to secrete collagen fibres. Still to be clarified is the simultaneous appearance of the adhesion and endothelial molecules that diffuse and represent traffic signals for the migration of the leucocytes from the lumen to the vessel walls. The NF-kB system [7] is made of heterodimeric proteins caught in the cytoplasm, linked to a kB inhibitor IkB , and it has been documented that the various risk factors that increase the production of the adhesion molecules act to start the oxidative stress, producing reactive species of the O2 superoxide anion and peroxide H.

The reactive oxygen species H2O2, O2 cause degradation of the NF inhibitors, making them available to interaction with the promoter region of the genes for adhesion molecule synthesis Fig. Early events of the atherosclerotic process 6 G. Corno Fig. This causes early degradation of the fibrous component which, associated with reduced production of the fibrotic component, causes degradation of the fibrous cap and thus a fissuring or rupture of the plaque Fig.

Furthermore, the increased endothelial production of PAI1 reduces the spontaneous fibrinolytic activity. The interaction between the CD40L of platelet production and the CD40 expressed on the endothelial cells and on the macrophages is involved in the pathogenesis of atherosclerosis, provoking a complex of inflammatory reactions with endothelial production of VCAM-1, ICAM-1, E-selectin, MCP1 and production of reactive oxygen species from macrophage activation, legitimating the role of CD40L inflammatory marker as predictive criteria risk for cardiovascular events [10].

The platelet activation is preceded by recruitment and activation of polymorphonuclear neutrophils PMNs , despite their apparent insignificance in coronary atherogenesis, has been shown an increased degranulation within the coronary circulation in acute coronary syndrome. One of the principal mediators secreted on PMN activation is myeloperoxidase, which displays potent pro-atherogenic proper t ies [11].

Myeloperoxidase can oxidise LDL cholesterol, amplifying and perpetuating foam cell formation, activate metalloproteinase, and consume endotheliumderived nitric oxide. Corno 8 Conclusions Inflammation plays a key role in atherosclerosis. A number of different biomarkers of inflammation are measurable in blood. These include cytokines, chemokines, soluble adhesion molecules, and acute-phase reactants. The first three of these groups of molecules are not routinely available in clinical laboratories. In contrast, however, C-reactive protein is readily measurable, and numerous clinical studies have demonstrated its usefulness as a marker of atherosclerotic risk [12, 13].

Given its pro-inflammatory properties, myeloperoxidase, produced by the activated PMNs, could be utilised as a marker and mediator of vascular inflammation, confirming the importance of activated PMNs in the physiopathology of the acute coronary syndrome. The different combinations of immunocompetent cells macrophage—monocytes and T lymphocytes , of the vascular wall cells, of atheronecrotic material, and of fibrous material regulated by cytokines and growth factors produced by the same cells, allow us to say that every plaque is different from the next.

This hypothesised physiopathological and pathogenetic paradigm is a useful reference point for therapeutic strategies and prevention. References 1. Transition of blood from monocytes into foam cells in fatty lesions. Lab Invest — Jander S, Sitzer M, Schumann R et al Inflammation in light grade carotid stenosis: a possible role for macrophages and T cells in plaque destabilisation, Stroke — Pathogenetic and Immunological Paradigm of Atherosclerotic Plaque 9. Prostaglandin dependent regulation and role in metalloproteinase-2 activation.

Circulation — Baldus S, Heeschen C, Meinertz T et al Myeloperoxidase serum levels predict risk in patients with acute coronary syndromes. Circulation — Ridker PM, Rifai N, Rose L et al Comparison of C-reactive protein and lowdensity lipoprotein cholesterol levels in the prediction of first cardiovascular events.

PIROLA Clinicians have become increasingly sophisticated in their application of cardiac biomarkers in the management of acute coronary syndromes. In the s, clinical investigators first reported that proteins released from necrotic cardiac myocytes could be detected in the serum and could aid in the diagnosis of acute myocardial infarction.

The ensuing 40 years witnessed progressive improvement in the cardiac tissue-specificity of biomarkers of myocardial necrosis and a corresponding enhancement in the clinical sensitivity and specificity of their use for establishing the diagnosis of acute myocardial infarction. In recent years, novel biochemical markers have been demonstrated to play a pivotal role in diagnosis, risk stratification, and guidance of treatment of acute coronary syndromes, complex clinical conditions with multiple causes: as such, treatment is likely to be most effective when directed at the underlying cause of the disease.

Five principal causes of acute coronary syndromes have been described: 1 plaque rupture with acute thrombosis, 2 progressive mechanical obstruction, 3 inflammation, 4 secondary unstable angina, and 5 dynamic obstruction coronary vasoconstriction [1]. It is rare that any of these contributors exists in isolation. However, patients with acute coronary syndromes may vary substantially with respect to the mixture of contributions from each of these major mechanisms and are likely to benefit from different therapeutic strategies [1].

Pirola vascular disease. With the emergence of novel, sensitive biomarkers of inflammation, myocyte necrosis, vascular damage, and haemodynamic stress, it is becoming possible to characterise non-invasively the participation of different contributors in any individual patient. There is solid evidence from numerous studies that the unstable patient with elevated troponins has a nine-fold increased risk for myocardial infarction or death in the next 30 days [2].

Over the past decade, the emergence of convincing evidence for the value of cardiac troponin in guiding therapy has dramatically accelerated the integration of cardiac biomarkers into clinical decision making for patients with acute coronary syndromes. Concurrently, advances in our understanding of the pathogenesis and consequences of acute coronary atherothrombosis have stimulated the development of new biomarkers and created the opportunity for an expanded role of multiple biomarkers, some old and others new, in the classification and individualisation of treatment for acute coronary syndromes [5—7].

For example, detection of cardiac troponin in the blood of patients with non-ST-elevation acute coronary syndromes is not only indicative of myocardial necrosis, but is also associated with the presence of intracoronary thrombus and distal embolisation of platelet microaggregates [8].

These pathobiological links to elevated levels of cardiac troponin are likely to underlie, at least in part, the value of this biomarker in targeting potent antithrombin and antiplatelet therapy. Inflammation has an essential role in the pathogenesis of atherosclerosis [9] and is also a consequence of myocardial damage. Elevated markers of inflammatory activity are associated with an increased risk of future cardiovascular events in healthy individuals [10, 11] and in patients with stable [12] and unstable coronary artery disease [13—16]. High-sensitivity testing for C-reactive protein CRP has emerged as a convenient tool for detecting low-level systemic inflammation that portends a higher risk of developing atherothrombotic vascular disease [17] and poor short- and long-term prognosis in patients after acute coronary syndromes [14, 16].

Although the precise mechanistic links between inflammation and risk in acute coronary syndromes are not conclusively established, it is plausible that elevated levels of circulating markers of inflammation reflect an intensification of focal inflammatory processes that destabilise vulnerable plaques [17]. Moreover, growing evidence implicates CRP as a mediator, in addition to a marker, of atherothrombosis [18].


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However, many practical aspects of optimising the sampling protocols in Biomarkers in Acute Coronary Syndromes 13 the emergency unit and combining troponin measurements with other markers in the clinical routine setting still need to be clarified. The timing of the second test has not yet been clearly defined. The European Society of Cardiology ESC recommends repeating troponin testing 6—12 h after arrival in the emergency unit [4]. The American version asks for a repeat test 8—12 h after the onset of pain — a minor, but sometimes decisive difference in perception in the work-up of the individual patient [3].

Previous studies before the era of troponins had suggested a h rule-out strategy [19]. Troponins have helped to shorten and to improve the diagnostic work-up. A prospective study using troponin T and troponin I bedside tests proposed an interval of 6 h to identify high-risk patients [20]. The new consensus documents have therefore based the new definition of myocardial infarction on biochemical grounds — a choice that was guided by the advent of new markers of myocardial necrosis, such as cardiac troponins [23—25].

The superior clinical value of troponin comes from its higher sensitivity to smaller myocardial injury and its virtually total specificity for cardiac damage [26]. Despite the ability to detect quantitatively smaller degrees of myocardial necrosis, cardiac troponins need 4—10 h after symptom onset to appear in serum, at about the same time as CKMB elevations become detectable, and peak at L.

Pirola 14 12—48 h, then remaining abnormal for several days [27]. In applying the results of cardiac troponin testing to the defining of myocardial infarction, one should keep in mind that these markers actually reflect myocardial necrosis but do not indicate its mechanism. Thus, an elevated value in the absence of clinical evidence of ischaemia should prompt a search for other causes of cardiac damage. Measurement of cardiac troponin provides a valuable diagnostic test for myocardial infarction only when used together with other clinical information.

Ideally, three measurements of cardiac troponin are suggested, with a sampling frequency of hospital admission, 6 and 12 h later, to demonstrate changing values. From the point of view of risk definition, too, troponin measurements can be used less than optimally [28—30]. The data are clear and have shown for many years that the predictive accuracy of troponin measurements requires more than one measurement [2, 24, 31]. Thus, markers that rise earlier than troponin might be more predictive than a solitary admission troponin value, but not more predictive if an additional troponin value is included in the analysis.

In some situations where immediate events are the outcomes of interest, such a strategy might be reasonable [7]. Braunwald E Unstable angina: an etiologic approach to management. Circulation — Ottani F, Galvani M, Nicolini FA et al Elevated cardiac troponin levels predict the risk of adverse outcome in patients with acute coronary syndromes. Circulation — Galvani M, Ottani F, Oltrona L et al N-terminal pro-brain natriuretic peptide on admission has prognostic value across the whole spectrum of acute coronary syndromes. Circulation — Biomarkers in Acute Coronary Syndromes 7.

Am Heart J — Morrow DA Troponins in patients with acute coronary syndromes: biologic, diagnostic, and therapeutic implications. Cardiovascular Toxicology — Ross R Atherosclerosis — an inflammatory disease. Production of Creactive protein and risk of coronary events in stable and unstable angina. Prognostic influence of increased fibrinogen and C-reactive protein levels in unstable coronary artery disease.

Markers of myocardial damage and inflammation in relation to long-term mortality in unstable coronary artery disease. Predictive value of C-reactive protein and troponin T in patients with unstable angina: a comparative analysis. Circulation — Lee TH, Juarez G, Cook EF et al Ruling out acute myocardial infarction: a prospective multicenter validation of a hour strategy for patients at low risk.

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N Engl J Med — Anonymous Nomenclature and criteria for diagnosis of ischemic heart disease. Circulation — Hamm CW Acute coronary syndromes. The diagnostic role of troponins. Circulation — Heeschen C, Dimmeler S, Fichtlscherer S et al Prognostic value of placental growth factor in patients with acute chest pain. STEMI is associated with a high rate of mortality, morbidity, and heart failure.

The past 10 years have seen a great fight against infarctions. Historically, the weapon of choice to battle infarctions is thrombolysis, which, in the first 12 h after the onset of symptoms, has demonstrated improvement in survival; the first trials to show this were ISIS 2 and GISSI 2 [1, 2].

After streptokinase SK , the first drug used, new drugs were developed that are more fibrinospecific. Alteplase co-administered with aspirin and heparin [3, 4] demonstrated better performance in safety and effectiveness [5] than SK, whereas others e. Randomised studies give us important information about better medical therapy, and also about pathophysiology and picking new research directions.

The importance of time led to the development of tenecteplase TNK , which is more rapid, more fibrinospecific, and, due to its resistance to PAI-1, has a longer half-life and is thus easier to use single bolus. In ASSENT 2 these drugs demonstrated no difference in day mortality versus alteplase, with fewer non-cerebral haemorrhagic complications [6]. TNK can also be used in association with enoxaparin no detrimental effect versus intravenous heparin in patients less than 75 years in age.


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The reasons for this are late U. Chiarella et al. An increasingly used intervention for revascularisation in STEMI is angioplasty percutaneous coronary intervention, PCI , called primary when done in first 12 h from symptom onset. In a recent meta-analysis, fibrinoly tic therapy all drugs together has been shown to be inferior to catheter-based intervention in reducing death, non-fatal reinfarction, or stroke [8]. But not all authors agree with these results, and these data need confirmation with new controlled studies [9, 10].

Result from these trials gave a new importance to time from onset of symptoms to treatment. Paradoxically, fibrinolytic agents may systemically activate platelets. Fibrinolysis generates plasmin, which degrades the fibrin component of the clot and exposes a highly active platelet-rich core. Thus, studies were done on the association between fibrinolytic drugs and platelet inhibitors to enhance clot lysis and prevent additional platelet aggregation on the surface of the clot [12].

This association showed a little more IRA patency in early angiographic follow-up, a reduction of in-hospital reinfarction, and a need for early PCI. However, this association did not show a beneficial effect on mortality, and bleeding complications increased in older people [13, 14]. The aim of successful reperfusion strategies — medical or mechanical or both together — is to quickly restore the oxygen supply of the myocytes.

To do this in the best way, restoring IRA patency is very important but is not sufficient. Data from trials have demonstrated that mortality at 1 month is related to IRA patency on arrival in the catheterisation laboratory. Studies by Braunwald et al. Another important study by Braunwald et al. However, Percutaneous transluminal coronary angioplasty PTCA and stent placement carry the risk of mobilising thrombotic and thrombogenic material, causing distal embolisation and microcirculatory impairment, which may limit the myocardial salvage gained by these techniques.

Percutaneous revascularisation techniques are being developed with interesting tools [18]. For example, during primary PCI, pretreatment with the Xsizer catheter system demonstrated, in a small number of patients, improved epicardial flow and accelerated ST segment resolution compared with conventional PCI alone [18]. Another device, PercuSurge demonstrated a substantially higher rate of immediate final TFG 3 flow in epicardial vessels and increased the integrity of the microvasculature [19].

A good way to restore flow in the infarct area epicardial vessels and microvessels is a combined pharmaco-invasive approach that starts pharmacological reperfusion as soon as possible, followed by PCI to consolidate the results and prevent reinfarction [20]. An important subject for study will be the correct pharmacological therapy TNK, platelet inhibitor, or both?

The ongoing trials on combined PCI will give important information on how to improve flow restoration. As a high-volume, full-time catheterisation laboratory cannot be developed in every hospital, an interhospital net would be useful for sending high-risk patients high TIMI risk score to a centre that has one. In conclusion, the new challenge is to find the right treatment combined treatment, fibrinolysis alone, or PCI alone for every STEMI patient on the basis of time from onset of angina to treatment, haemorrhagic risk, response to treatment, and the availability of resources.

Lancet — GISSI-2 A factorial randomised trial of alteplase versus streptokinase and heparin versus no heparin among patients with acute myocardial infarction. Lancet —71 The GUSTO Investigators An international randomised trial comparing four thrombolytic strategies for acute myocardial infarction. Lancet — Topol EJ Toward a new frontier in myocardial reperfusion therapy. Circulation — Keeley EC, Boura JA, Grines CL Primary angioplasty versus intravenous thrombolytic therapy for acute myocardial infarction: a quantitative review of 23 randomised trials.

Letter to the editor. Lancet — Melandri G Primary angioplasty or thrombolysis for acute myocardial infarction? Circulation — Giugliano RP, Sabatine MS, Gibson CM et al Combined assessment of thrombolysis in myocardial infarction flow grade, myocardial perfusion grade, and ST-segment resolution to evaluate epicardial and myocardial reperfusion.

Am J Cardiol —, A5-A6 Beran G, Lang I, Schreiber W et al Intracoronary thrombectomy with the XSizer catheter system improves epicardial flow and accelerates ST-segment resolution in patients with acute coronary syndrome: a prospective, randomized, controlled study. Circulation — Wu CJ, Yang CH, Fang CY et al Six-month angiographic results of primary angioplasty with adjunctive PercuSurge GuardWire device support: evaluation of the restenotic rate of the target lesion and the fate of the distal balloon occlusion site.

Although conventional antithrombotic therapy e. Cavallini and subsequently approved for clinical use. Boersma et al. A small reduction in the odds of death or myocardial infarction MI in the active treatment arm was observed Patients were treated in a medical stabilisation phase for a minimum of 48 h before possible angiography. The benefits of tirofiban in higher risk patients from PRISM-PLUS were observed in several subgroups, notably including patients with diabetes [9], patients with impaired renal function [10], and in the elderly [11].

In general, the higher the level of risk of the patients, the greater the benefits from the use of the drug, as shown in the study by Morrow et al. This early hazard appears to be the result of a thrombin-mediated and platelet-dependent process that is initiated by mechanical plaque disruption and culminates in thrombus formation at the site of vessel injury.

Distal embolisation of atherothrombotic debris into the 26 C. Cavallini coronary microcirculation may also occur as a complication of the unstable plaque. In contrast, the FRISC II study showed a significant and clinically relevant decrease in death and MI at 6-month [17] and 1-year [18] follow-up in patients randomised to an early invasive strategy.

An invasive strategy appears to limit the increased risk conferred by raised levels of troponin Tn. More recently, the results of the third Randomised Intervention Trial of unstable Angina RITA study suggested that routine early invasive management was effective in reducing refractory or severe angina among patients at moderate risk of death after NSTE-ACS, but no reduction was seen in new MI [20]. Identification of subsets of patients with different risk profiles is crucial in order to select the most appropriate therapy in each case.

The patients considered to be at high risk on the basis of clinical, electrocardiographic, and biochemical characteristics benefit more from an aggressive strategy that includes powerful antithrombotic therapy and early angiography with revascularisation, if feasible. On the other hand, low risk patients need to be identified in order to avoid unnecessary resource use and the risks deriving from an unjustified aggressive approach. Risk stratification is a dynamic process Tirofiban and NSTE-ACS:The Current Perspective 27 that starts at the time of admission and is continuously updated with new information obtained during the subsequent hospital stay.

However, immediate risk stratification is the most important step for the appropriate management of these patients, since the probability of events is highest in the very early phase of the disease and progressively decreases thereafter. Two different models of risk stratification have been developed. The first is based on the simple, dichotomous description of a series of variables, whose presence, even when isolated, is sufficient to identify high risk patients.

This method is currently suggested by the ESC guidelines. The second takes into account the prognostic information derived from a number of clinical, electrocardiographic, and biochemical parameters, analysed in a comprehensive manner [21]. These models have the advantage of allowing the identification of patients at the highest risk of events. ISAR-COOL compared routine invasive management among a high risk NSTE-ACS patient population treated either with prolonged medical stabilisation with the combination of heparin, aspirin, clopidogrel, and tirofiban for a mean of 86 h or by proceeding directly to the catheterisation laboratory within the first 24 h mean 2.

Cavallini 28 These results suggest that the benefits of early invasive therapy may outweigh those of prolonged pharmacological pretreatment. However, whether a strategy of immediate coronary angiography within hours of presentation leads to a significant clinical benefit in comparison with the overall accepted intervention within 48 h is unknown, and a larger randomised trial testing the two strategy will be needed. As adjunctive therapies improve, lessening the risk associated with invasive cardiac procedures, we may well be moving to an era of rapid risk assessment and triage, initial medical stabilisation with very potent antithrombotic medications, and rapid transfer to cardiac centres of excellence for diagnostic and therapeutic procedures within 48 h of presentation.

This should allow to patients admitted to peripheral hospitals to have access to the same type of care as those patients directly admitted to tertiary centres. A unified systematic approach to NSTE-ACS that incorporates all evidence-based therapies and interventions would be expected to maximise the positive impact of such strategies on long-term clinical outcome. Lancet —16 30 C. Cavallini Randomized Intervention Trial of unstable Angina. JAMA — With increasing prevalence of DM, the burden of cardiovascular disease associated with this condition will increase dramatically [5].

Diabetic patients are at an increased risk of cardiovascular events as compared with non-diabetic patients. In a study by Haffner et al. On the basis of these data, the risk of subsequent coronary events for patients with diabetes but without previous MI is the same as non-diabetic patients with previous MI [4].

In the setting of both ST-elevation MI and non-ST elevation acute coronary syndromes ACS , diabetic patients suffer increased mortality as compared to non-diabetic patients. Bovenzi et al. Notably, mortality was highest among those treated with insulin. Undoubtedly less known is the fact that fibrinolysis saved 37 lives per patients with diabetes at 35 days, compared with 15 per patients without diabetes [13]. Thus, the absolute benefit of fibrinolytic therapy is more than doubled for diabetics.

Despite its tremendous benefit, however, patients with diabetes were less likely to receive fibrinolytic therapy [14], as evidenced in the Survival and Ventricular Enlargement SAVE Study [15]. In this trial, of the patients enrolled, fibrinolytic therapy was administered to Diabetic patients undergoing a percutaneous coronary intervention PCI exhibited similar angiographic success rates to non-diabetic patients, but showed a trend toward higher in-hospital mortality rates, higher rates of urgent revascularisation, and greater incidence of acute coronary occlusions [15].

In a recent study, diabetes mellitus was associted with higher incidences of death, AMI, and repeated revascularisation at long-term follow-up after a primary PCI [16]. Therefore, the optimal strategy for coronary revascularisation in diabetic patients remains to be determined. Re-stenosis and Platelet Function The addition of stent implantation to balloon angioplasty in diabetic patients is feasible, with favourable procedural and in-hospital success rates. However, long-term outcomes after stenting remain worse because of a higher incidence of major adverse cardiac events and, above all, the re-stenosis rate compared with that in non-diabetic patients [17].

In a recent pooled analysis of several major recent stent trials, Cutlip et al. Considering the higher rate of re-stenosis and the current prevalence of diabetes among patients who undergo PCI e. Thus, reduction of the restenosis rate among diabetic patients will have a major favourable impact on the global outcome of catheter-based coronary interventions. There is ample evidence that platelets of diabetic patients are larger and hyper-reactive, showing increased adhesion and aggregation and increased 34 F.

In fact, diabetes is characterised by elevated concentrations of procoagulant factors, including fibrinogen, von Willebrand factor, and factor VII, with decreased concentration of antithrombotic factors including antithrombin III and protein C [21]. Tissue factor, which is the most potent trigger of the coagulation cascade [22], is increased in patients with DM [23].

Recently, Sambola et al. These observations highlight the concept of high-risk blood in the pathophysiology of diabetic atherosclerosis leading to coronary thrombosis. Moreover, in patients with type 2 diabetes, there is an association between glycaemic control and blood thrombogenicity. Osende et al. Importance of Pre-procedural Glycaemic Control Recently, a growing body of evidence has shown an association between optimal glycaemic control and improvement in major cardiovascular events [26].

In a meta-analysis of 95 patients who were observed for In a study by Khaw et al. These findings are supported by the fact that pre-procedural hyperglycaemia is known to induce vascular endothelial cell damage, excessive extracellular matrix formation, and increased cellular proliferation [25, 29], which could progressively contribute to the adverse outcomes after stent implantation.

Conversely, recent studies identified poor glycaemic control as a significant predictor of angiographic re-stenosis without any impact on mortality [20, 30]. These results are in accordance with a study by Corpus et al. By multivariate analysis, poor glycaemic control was a major independent predictor of TVR.

Hyperglycaemia might be associated with impaired microvascular function after AMI, resulting in a larger infarct size and worse functional recovery [32]. A total of consecutive patients with a first AMI were studied by intracoronary myocardial contrast echocardiography after successful reperfusion within 24 h after symptom onset. Another meta-analysis of three placebo-controlled abciximab trials, demonstrated a reduction of mortality from 4.

A sub-study of the EPISTENT trial about the outcomes of diabetic patients demonstrated that abciximab, irrespective of revascularisation strategy stent or balloon angioplasty , resulted in a significant reduction in the 6-month death or MI rate: Angiographic re-stenosis was also greatly reduced in diabetics randomised to stenting No beneficial effects were apparent with abciximab in diabetic patients at 1 year [36].

Despite the improved outcomes with stenting in patients with diabetes, 1-year mortality remained increased in diabetic patients who received stents compared with non-diabetics 8. Thus, the combination of abciximab with stenting has been hypothesised to be the optimal percutaneous revascularisation strategy [38], not only for reducing TVR but also for improving survival to the level of placebo-treated non-diabetic patients in elective PCI [33, 38]. By contrast, the ISAR-SWEET study [39] randomised to abciximab or placebo diabetic patients who underwent an elective PCI with bare metal stents after pre-treatment with a mg loading dose of clopidogrel at least 2 h before the procedure.

The incidence of death or MI at 1 year was 8. In patients with DM, clopidogrel has been shown to be superior to aspirin in reducing recurrent ischaemic events [40]. The PCI-CURE study demonstrated that a strategy of clopidogrel pre-treatment followed by longterm therapy is beneficial in reducing cardiovascular events [41]. An analysis of the multi-centre, randomised, double-blind CAPRIE study showed that clopidogrel provided even greater reductions than aspirin in the risk of recurrent ischaemic events in diabetic patients [42].

Moreover, recent evidence demonstrates that a loading dose of mg clopidogrel leads to more rapid platelet inhibition than a dose of mg [43] and may obviate the need for abciximab during elective PCI in patients at low to intermediate risk [44]. Drug-Eluting Stents and Intracoronary Brachytherapy The advent of drug-eluting stents DES is a remarkable improvement in preventing re-stenosis in coronary arteries after coronary angioplasty. However, the use of DES in diabetic patients undergoing coronary stent placement cannot be considered standard of care until larger trials confirm its safety and efficacy in this patient population.

The mechanism by which brachytherapy reduces re-stenosis reduction of intimal hyperplasia could potentially be useful in diabetics treated with Acute Coronary Syndromes and Diabetes: How Much Can We Intervene? Recent studies demonstrate that the effectiveness of brachytherapy in reducing re-stenosis in the context of intra-stent re-stenosis is especially high in diabetics [48].

These results have inspired the design and execution of studies in which brachytherapy is applied with angioplasty in de novo lesions in diabetics. Conclusions Diabetes is a source of significant morbidity and mortality resulting from long-term micro- and macrovascular complications after coronary angioplasty in patients with ACS. Optimal pre-procedural glycaemic control and inhibition of intimal hyperplasia would reduce or impede re-stenosis, resulting in better clinical results.

JAMA — Haffner SM, Lehto S, Ronnemaa T et al Mortality from coronary heart disease in subjects with type 2 diabetes and in nondiabetic subjects with and without prior myocardial infarction. JAMA — Bolognese L, Carrabba N, Santoro GM et al Angiographic findings, time course of regional and global left ventricular function, and clinical outcome in diabetic patients with acute myocardial infarction treated with primary percutaneous transluminal coronary angioplasty.

A serial intravascular study. J Am Coll Cardiol — Kornowski R, Fuchs S Optimisation of glycemic control and restenosis prevention in diabetic patients undergoing percutaneous coronary interventions. Blood —8 Zumbach M, Hofmann M, Borcea V et al Tissue factor antigen is elevated in patients with microvascular complications of diabetes mellitus. J Am Coll Cardiol — Muhlestein JB, Anderson JL, Horne BD et al Effect of fasting glucose levels on mortality rate in patients with and without diabetes mellitus and coronary artery disease undergoing percutaneous coronary intervention.

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Am Heart J — Coutinho M, Gerstein HC, Wang Y et al The relationship between glucose and incident cardiovascular events: a metaregression analysis of published data from 20 studies of 95, individuals followed for Am Heart J — Corpus RA, George PB, House JA et al Optimal glycemic control is associated with a lower rate of target vessel revascularisation in treated type II diabetic patients undergoing elective percutaneous coronary intervention. Lancet — Jarvis B, Simpson K Clopidogrel: a review of its use in the prevention of atherothrombosis.

N Engl J 40 Circulation — Williams DO Intracoronary brachytherapy. Past, present and future. Numerous improvements have expanded the spectrum of therapeutic options, e. Despite such innovative procedures, however, it is not possible to effectively treat angina pectoris symptomatology for all patients. If coronary revascularisation is not feasible — either by catheter intervention or by surgical placement of a bypass — and if the patient still suffers serious symptoms despite optimal anti-angina medication, the patient is said to suffer from refractory angina pectoris. Categorisation of the severity of an angina pectoris symptom complex normally takes place in accordance with the classification of the Canadian Cardiovascular Society CCS [1], which was developed on the basis of the NYHA classification of stages of heart failure.

CCS IV characterises an inability to perform any type of bodily activity without discomfort. Patients with refractory angina pectoris CCS III—IV are highly symptomatic under everyday conditions, which results in massive restriction of physical functional activity. Many patients additionally report social isolation, since friends and family members consider frequently occurring angina pectoris attacks as particularly problematic, if not to say life-threatening.

These chronically ill patients, on the whole, experience significant diminution of their quality of life. Theres et al. Since no exact epidemiological surveys have been conducted on this topic, it is difficult to estimate the number of patients suffering from refractory angina pectoris. On the basis of Scandinavian data [2], Mannheimer et al. Mukherjee et al. Various treatment concepts have by now been developed and introduced into clinical work: these include intermittent urokinase therapy [5], transmyocardial laser revascularisation [6—8], and external counterpulsation [9].

Chester, of Britain, has developed a highly promising interdisciplinary approach to pain therapy for patients suffering from refractory angina pectoris, and has published his results on the Internet under www. Only recently, the Working Group for Refractory Angina Pectoris of the European Cardiovascular Society has published an overview on refractory angina pectoris, in which it recommends neurostimulation as therapeutic alternative: two techniques are transcutaneous electrical nerve stimulation TENS and spinal cord stimulation SCS [3].

Numerous studies have demonstrated that this adjuvant therapy was associated with reduction in the frequency of attacks, and with increase in exercise capability. The present article presents the procedure of neurostimulation for patients with refractory angina pectoris, with discussion on the indications, therapeutic mechanisms, and published results of studies concerning effectiveness and safety.

Indications The indication for application of TENS or for implantation of a spinal cord stimulator may follow from interdisciplinary procedures, e. As initial step, however, all necessary efforts should be undertaken to exclude secondary causes of angina pectoris e. In addition to optimisation of medical therapy, primary attention should be directed to the question of whether revascularisation by catheter interven- Spinal Cord Stimulation in Refractory Coronary Artery Disease:The Last Resort? For patients who have already undergone repeated cardiac catheter intervention procedures or bypass surgery, risk—benefit assessment will be necessary for continuation of invasive therapy.

From the point of view of coronary anatomy, candidates for SCS implantation will primarily be found among those patients for whom diffuse alterations in coronary vessels that extend into the vascular periphery have rendered bypass surgery or catheter intervention inadvisable or impossible.

Implantation of such a system may also prove worth considering among patients listed for heart transplantation in conjunction with ischaemic cardiomyopathy and refractory angina pectoris. Further experience could likewise be profitably gained here in the context of controlled studies. As part of patient preparation, and on an intraoperative basis, investigation is also essential to determine the possibility of interference with already implanted pacemaker or cardioverter—defibrillator systems.

One potential danger here is back-coupling of stimulation pulses from the neurostimulator to the sensing circuitry of the pacemaker system. This phenomenon can lead to inhibition of the pacemaker system and, in turn, to asystole among pacemaker users. Use of a pacemaker, however, does not automatically represent an absolute contraindication [11, 12]. Whatever the case, it is essential that the patient be sufficiently trained in the use of a neurostimulator.

Since the system is controlled by the patient as needed, and is activated according to pre-set time sequences, a basic understanding of its functioning is necessary. The TENS technique is used in patients who cannot immediately decide on implantation of a neurostimulator system.

TENS therapy can be considered as a test phase for patients who demonstrate typical angina pectoris symptoms with the associated coronary findings, but for whom there is no definitive evidence of ischaemia. If these patients are identified as responders on the basis of reduction in their anginal symptom complex, definitive treatment with an SCS system is recommended.

The procedure for establishing the indication is shown in the flow diagram in Figure 1. The scope of this present article will not allow treatment of differential therapeutic application of other methods: e. Interested readers may consult the work of Chester www. Indication for neuromodulation for patients with the refractory angina pectoris complex Therapeutic Mechanisms Although neurostimulation has successfully been applied in specialised centres in Europe for more than 15 years now, the highly complex physiological and biochemical foundations of its therapeutic mechanisms have not yet been fully elucidated.

The hypothesis currently considered most probable [14] is that, subsequent to diminution of pain, down-regulation of sympathicotonia, and consequently of myocardial oxygen demand, takes place in conjunction with optimisation of microcirculation Fig. Anti-nociceptive Effect In Melzack and Wall published their so-called gate control theory in the pioneering publication on this topic [15]. Since then, many standard works on pain therapy have cited their work. This theory postulated segmental pain inhibition induced by neurostimulation, under the assumption that selective activation of sensitive afferent fibres initially occurs as a result of regionally applied electrical stimuli, with slowly increasing intensity of stimulation below the threshold of pain [15, 16].

Melzack and Wall also postulated that this phenomenon leads in the dorsal horn of the spinal cord the gate to subsequent presynaptic inhibition of nociceptive afferents A and C fibres , and consequently to local analgesia [15, 17]. Myocardial ischaemia Myocardial ischaemia Angina pectoris Angina pectoris 45 Neurostimulation Sympathetic activation Sympathetic activation Increase of the double product Increase of the double product i. Breakthrough of the chain of pain: neurostimulation leads to reduction in pain symptoms and, in turn, to diminution of sympathetic activity, accompanied by subsequent reduction in the frequency of occurrence of myocardial ischaemia episodes.

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  7. Louis, United States of America. International Conference on Clinical 4. Most evidence on the relation between nutrition and CVD is based onobservational studies; randomized clinical trials estimating the impact ofdiet on endpoints are scarce. The nutrients of interest with respect to CVD are fatty acids which mainlyaffect lipoprotein levels , minerals which mainly affect BP , vitamins andfibre. For prevention of CVD, the types of fatty acids consumed are more importantthan the total fat content.

    The same has notbeen clearly shown for replacement with carbohydrates and monounsaturatedfatty acids MUFAs. The polyunsaturated fattyacids can be divided into two subgroups: omega-6 fatty acids, mainly fromplant foods, and omega-3 fatty acids, mainly from fish oils and fats. They do not changeserum cholesterol levels and, with currently available cardioprotectivetherapies, it is debatable whether they exert a favourable effect onall-cause, CAD, and stroke mortality. The trans fatty acids, a subclass of unsaturated fatty acids, have been shownto be especially harmful due to their unfavourable impact on both totalcholesterol increase and HDL-C decrease.

    These fatty acids are formedduring industrial processing hardening of fats and are present in, forexample, margarine and bakery products. The impact of dietary cholesterol on serum cholesterol levels is weakcompared with that of the fatty acid composition of the diet. Whenguidelines are followed to lower saturated fat intake, this usually alsoleads to a reduction in dietary cholesterol intake. Although the relation between saltintake and BP remains controversial, the totality of evidence warrants saltreduction as an important way to prevent CAD and stroke.

    Salt reduction can be achieved by making different dietary choices fewerprocessed foods, more basic foods and the reformulation of foods loweringsalt content see Chapter 3c. Potassium has favourable effects on BP. The main sources of potassium arefruits and vegetables. An inverse statistically significant associationexists between potassium intake and the risk of incident stroke [RR 0. Many case—control and prospective observational studies have observed inverseassociations between levels of vitamin A and E and the risk of CVD. However,intervention trials have failed to confirm these observational studies.

    Also, for the B vitamins B6, folic acid and B12 and vitamin C, trials haveshown no beneficial effects. Therefore, conclusions about vitamin Dsupplementation [type of supplement D2 or D3 , dosage and duration] for CVprevention cannot yet be drawn. Although themechanism has not been elucidated completely, it is known that a high fibreintake reduces postprandial glucose responses after carbohydrate-rich mealsand lowers total cholesterol and LDL-C levels. Prospective cohort studies have shown a protective effect of theconsumption of fruits and vegetables on CVD, but RCTs are scarce.

    The protective effect of fish on CVD is attributed to the n-3 fatty acidcontent. Especially in the rangeof no or very low intake, risk is increased. The public health impact ofa small increase in fish consumption in the general population istherefore potentially large. For fish oil, three randomized controlled prevention trials have beenpublished.

    A recent meta-analysis of 20trials, mostly prevention of recurrent CV events and mostly using fishoil supplements, showed no benefit of fish oil supplementation on CVoutcomes. Drinking three or more alcoholic beverages per day is associated withelevated CVD risk. Results from epidemiological studies suggest a lowerrisk of CVD occurring with moderate one to two units per day alcoholconsumption compared with non-drinkers. This association appears not tobe explained by special characteristics of abstainers, although thepotential for residual confounding and reverse causality cannot be fullyexcluded.

    Moreover, a recent Mendelian randomization study includinganalyses from 59 epidemiological studies has shed doubt on anybeneficial effect of moderate alcohol consumption, suggestingthat the lowest risks for CV outcomes were in abstainers and that anyamount of alcohol is associated with elevated BP and BMI. Sugar-sweetened soft drinks are the largest single food source ofcalories in the US diet and are important in Europe. Regular consumption of soft drinks has been associated withoverweight, metabolic syndrome and type 2 DM. Substitution ofsugar-sweetened soft drinks with artificially sweetened drinks resultedin less weight gain in children over an month period.

    Regularconsumption of sugar-sweetened beverages i. The cholesterol-lowering effect is in addition to thatobtained with a low-fat diet or use of statins. Further cholesterolreduction can be obtained with higher doses of phytosterols. Studying the impact of a total dietary pattern theoretically shows the fullpreventive potential of diet since it yields a combined estimate of theimpact of several favourable dietary habits. The Mediterranean dietcomprises many of the nutrients and foods that have been discussedpreviously: high intake of fruits, vegetables, legumes, wholegrain products,fish and unsaturated fatty acids especially olive oil ; moderateconsumption of alcohol mostly wine, preferably consumed with meals and lowconsumption of red meat, dairy products and saturated fatty acids.

    The biggest challenge in dietary prevention of CVD is to develop moreeffective strategies to make people change their diet bothquantitatively and qualitatively and to maintain that healthy dietand a normal weight.

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    Both overweight and obesity are associated with an increased risk of CVDdeath and all-cause mortality. Achieving and maintaining a healthy weight has a favourable effect onmetabolic risk factors BP, blood lipids, glucose tolerance and lowerCV risk. There is evidence thatoptimal weight in elderly is higher than in the young andmiddle-aged.

    In many countries, favourable trends in major risk factors such as bloodcholesterol, BP and smoking prevalence have been observed, translating intoreduced CV mortality. However, BMI has greatly increased in all countriesover recent decades, resulting in a concomitant increase in the prevalenceof type 2 DM. In the USA, it has been projected that if obesity trends from to continue, obesity will increasingly offset the positive effectsof declining smoking rates. Body fat stored in the abdomen intra-abdominal fat carries a higher risk than subcutaneous fat.

    Several measures of body fatness are available see Table D in the web addenda. Most data are available for BMI, waist:hipcircumference ratio and simple waist circumference. The optimal level formeasurement of waist circumference is midway from the lower rib margin tothe anterior superior iliac crest, in the standing position.

    The WHOthresholds for waist circumference are the most widely accepted in Europe. Based on these thresholds, two action levels are recommended:. These thresholds have been calculated based on Caucasians, and it is apparentthat different cut-offs for anthropometric measurements are required indifferent races and ethnicities.

    Some studies argue that a specific subgroup of obeseindividuals is resistant to metabolic complications such as arterialhypertension and insulin resistance. However, MHO individuals present ahigher all-cause mortality compared with normal weight metabolically healthyindividuals. At the population level, obesity is associated with CVD risk. However, amongthose with established CAD, the evidence is contradictory.

    However, this evidence should not bemisinterpreted to recommend higher target BMIs for those with establishedCVD since reverse causality may be operating. Cardiorespiratory fitnessmight influence relationships between adiposity and clinical prognosis inthe obesity paradox. Normal weight unfit individuals have a higher risk ofmortality than fit individuals, regardless of their BMI.

    Overweight andobese fit individuals have mortality risks similar to normal weight fitindividuals. Although diet, exercise and behaviour modifications are the mainstaytherapies for overweight and obesity, they are often unsuccessful forlong-term treatment. A recent meta-analysis indicates that patientsundergoing bariatric surgery have a reduced risk of MI, stroke, CV eventsand mortality compared with non-surgical controls. Knowledge and implementation of effective strategies to achieveweight loss and maintain a long-term healthy weight. Identification of the relative roles of diet, exercise and behaviourmodification in the management of overweight and obese people.

    Whileaccepting the simplicity of this approach and that it could beuseful in some settings, there is better scientific support for thethree targets matched to level of risk. It should be noted that the evidence for patients withCKD is less strong. The crucial role of dyslipidaemia, especially hypercholesterolaemia, in thedevelopment of CVD is documented beyond any doubt by genetic, pathology,observational and intervention studies.

    In blood plasma, lipids such as cholesterol and triglycerides circulate aslipoproteins in association with various proteins apolipoproteins. Themain carrier of cholesterol in plasma LDL-C is atherogenic. The role oftriglyceride-rich lipoproteins is currently under active investigation:chylomicrons and large very-low-density lipoproteins VLDLs appear not tobe atherogenic, but very high concentrations of these triglyceride-richlipoproteins can cause pancreatitis.

    Most cholesterol is normally carried in LDL-C. Over a wide range of plasmacholesterol concentrations, there is a strong and graded positiveassociation between total as well as LDL-C and risk of CVD. The evidence that reducing plasma LDL-C reduces CVD risk is unequivocal; theresults of epidemiological studies and trials with and without statins usingangiographic or clinical endpoints confirm that the reduction of LDL-C is ofprime concern in the prevention of CVD.

    Every 1. Apolipoprotein B apoB; the main apoprotein of atherogenic lipoproteins levels have also been measured in outcome studies in parallel withLDL-C. Hypertriglyceridaemia is a significant independent CVD risk factor, but theassociation is far weaker than for hypercholesterolaemia. There are, however, no randomized trials to providesufficient evidence to derive target levels for triglycerides.

    This lipidpattern is also characterized by the presence of small, dense, atherogenicLDL particles. Lipoprotein a [Lp a ] is a low-density lipoprotein to which an additionalprotein called apolipoprotein a is attached. There is norandomized intervention study showing that reducing Lp a decreases CVDrisk. Apolipoprotein A1 apoA1 is the major apoprotein of high-densitylipoprotein. It is beyond doubt that the apoB:apoA1 ratio is one of thestrongest risk markers. Since the measurement of apolipoproteins is not available toall physicians in Europe, is more costly than currently used lipid variablesand only adds moderately to the information derived from currently appliedlipid parameters, its use is not recommended.

    Direct methods may beless sensitive to plasma triglyceride levels. However, recent data showthat the direct methods may also be biased when triglyceride levels arehigh. Also, the values obtained with the different direct methods arenot necessarily identical, especially for low and high LDL-C values. Non-HDL-C comprises the cholesterol in low-density lipoprotein,intermediate-density lipoprotein, remnant and VLDL, thus capturing allthe information regarding pro-atherogenic lipoproteins.

    Therefore, it is certainly abetter measure than calculated LDL-C for patients with increased plasmatriglyceride concentrations, but also has an additional advantage of notrequiring patients to fast before blood sampling. There is evidence fora role of non-HDL-C as a treatment target.

    This parameter, however, is not suggested as apredictor or main target for therapy and further population data andclinical studies are awaited. The presence of dyslipidaemias secondary to other conditions must be excludedbefore beginning treatment, as treatment of underlying disease improveshyperlipidaemia without requiring antilipidaemic therapy.

    This isparticularly true for hypothyroidism. Secondary dyslipidaemias can also becaused by alcohol abuse, DM, Cushing's syndrome, diseases of the liver andkidneys and several drugs e. If possible, these patients should bereferred for specialist evaluation. In general, RCTs are the ideal evidence base for decisional thresholds andtreatment goals.

    For treatment goals, this requires RCTs randomly allocatingsubjects to different lipid goal levels. However, most evidence in terms oftreatment goals is derived from observational studies and from post hocanalyses of RCTs and meta-regression analyses thereof randomly allocatingdifferent treatment strategies and not treatment goals. Hence,recommendations reflect consensus based on large-scale epidemiological dataand RCTs comparing treatment regimens, not on RCTs comparing different lipidgoal levels. In the past, an LDL-C of 2.

    This goal remains reasonable for most patientswho have an indication for LDL-C-lowering therapy based on calculation ofthe CV risk see section 2. In addition, this is a secondary goal in people with elevatedtriglycerides. There are no differences in the relative reductionbetween men and women and between younger and older age or between thosewith and without DM. Possible intervention strategies as a function of totalcardiovascular risk and low-density lipoprotein cholesterollevel.

    Note that risk stratification isnot applicable in familial hypercholesterolaemia, where drugtreatment is recommended, and that, in this table, drugtreatment may be considered at risks lower than the generictreatment thresholds indicated in paragraph 2. If baseline LDL-C in this category is alreadybelow the target level of 1. If patients with CKD already on ahypolipidaemic therapy enter end-stage renal disease, the therapy may bemaintained.

    The currently available lipid-lowering drugs include inhibitors of3-hydroxymethylglutaryl-coenzyme A reductase statins , fibrates, bileacid sequestrants anion exchange resins , niacin nicotinic acid ,selective cholesterol absorption inhibitors e. Response to all therapy varies widely among individuals and thereforemonitoring the effect on LDL-C levels is recommended. Data indicate that combination therapy with ezetimibe also brings a benefitthat is in line with the Cholesterol Treatment Trialists' CTT Collaboration meta-analysis supporting the notion that LDL-C reduction iskey to the achieved benefit independent of the approach used.

    Increased levels of liver enzymes in plasma occur occasionally during statintherapy, and in most cases are reversible. Routine monitoring of liverenzyme values is not indicated. Because statins are prescribed on a long-termbasis, possible interactions with other drugs deserve particular andcontinuous attention, as many patients will receive pharmacological therapyfor concomitant conditions. In general, the safety profile of statins is acceptable, and earlierobservations that lipid-lowering treatment may contribute to an increase innon-CV mortality e.

    For non-statin treatments, selective cholesterol absorption inhibitors e. They arerecommended as combination therapy with statins in selected patients when aspecific goal is not reached with the maximal tolerated dose of astatin. Bile acid sequestrants also decrease total cholesterol and LDL-C but arepoorly tolerated and tend to increase plasma triglyceride concentrations. They are therefore not recommended for routine use in CVD prevention. In those rare patients with severe primaryhypertriglyceridaemia, specialist referral must be considered. Whether this approach results in thepredicted reduction in CV events is being addressed in large outcome trials;preliminary evidence suggests that this is the case.

    Patients with dyslipidaemia, particularly those with established CVD, DM orasymptomatic high-risk individuals, may not always reach treatment goals,even with the highest tolerated statin dose. Therefore, combinationtreatment may be needed. It must be stressed, however, that the onlycombination that has evidence of clinical benefit one large RCT is that ofa statin combined with ezetimibe. Combinations of niacin and a statin increase HDL-C and decrease triglyceridesbetter than either of these drugs alone, but flushing is the main adverseeffect of niacin, which may affect compliance.

    Furthermore, there is noevidence of clinical benefit for this combination. Fibrates, particularly fenofibrate, may be useful, not only for decreasinghigh triglyceride concentrations and increasing low HDL-C, but for loweringLDL-C further when used with a statin. There is limited evidence for thiscombination in terms of a reduction in CVD events. Other drugsmetabolized through cytochrome P should be avoided when this combinationis prescribed.

    Fibrates should preferably be taken in the morning andstatins in the evening to minimize peak dose concentrations and decrease therisk of myopathy. Patients have to be instructed about warning symptoms myalgia , even though such adverse effects are very rare. Gemfibrozilshould not be added to a statin treatment, because of the high potential forinteractions. If target levels cannot be reached even on maximal doses of lipid-loweringtherapy or drug combinations, patients will still benefit from treatment tothe extent that the dyslipidaemia has been improved. In these patients,increased attention to other risk factors may help to reduce total risk.

    Whether functional foods and food supplements with a lipid-loweringeffect can safely reduce the risk of CVD. Lifestyle management to aid weight control by sustainable dietary changesand increased PA levels should be central in the management of patientswith type 2 DM. Intensive management of hyperglycaemia reduces the risk of microvascularcomplications and, to a lesser extent, the risk of CVD.

    However, targetsshould be relaxed in the elderly, frail, those with long-duration DM andthose with existing CVD. Intensive treatment of BP in DM, with a target of mmHg systolic forthe majority, reduces the risk of macrovascular and microvascularoutcomes. A lower SBP target of mmHg further lessens the risks forstroke, retinopathy and albuminuria and should be applied to selectedpatients. Recent evidence points to sizeable reductions in CVD mortality in DMpatients via improvements in risk factor management, although theincreasing worldwide DM prevalence will create major challenges.

    Moreshould be done to prevent DM. Clear reductions have occurred inCVD death rates in DM consistent with better management of risk factors,although the increasing prevalence of DM continues to create pressures on allhealth care systems. The targets, especially the glycaemic and in some cases lipids, should be lessstringently implemented in older people with DM, those with a longer duration ofDM, those with evidence of CVD and the frail.

    Except for glucose management, prevention of CVD follows the same generalprinciples as for people without DM. Many treatmenttargets are more stringent for patients with DM. Typically, patients with type 2DM have multiple CVD risk factors, each requiring treatment according toexisting guidelines. The ESC and European Association for the Study of Diabetes scientificstatements advocate lifestyle management as a first measure for theprevention and management of DM.

    Several dietary patterns can be adopted where thepredominance of fruits, vegetables, wholegrain cereals and low-fat proteinsources is more important than the precise proportions of total energyprovided by the major macronutrients. Salt intake should be restricted. Specific dietary recommendations include limiting saturated and trans fatsand alcohol intake, monitoring carbohydrate consumption and increasingdietary fibre.

    A Mediterranean-type diet is acceptable, where fat sourcesare derived primarily from monounsaturated oils. A combination of aerobic and resistance exercise training is effective in theprevention of the progression of DM and for the control of glycaemia. Littleis known about how to promote and sustain PA; however, reinforcement byhealth care providers to patients to find sustainable ways to increase PA iscrucial. Smoking increases the risk of DM, CVD and premature death andshould be strongly discouraged see section 3a.

    This recommendationreflects greater lifetime vascular risk trajectories in these individuals. However, a proportion of DM patients at 40—50 years of age may have a low 10year risk of CVD due to normal BP and lipid levels and being non-smokers,and in such cases there remains a role for physician judgement. The UK Prospective Diabetes Study UKPDS established the importance ofintensive glucose lowering with respect to CVD risk reduction in newlydiagnosed patients with DM but not treated with modern BP- or lipid-loweringtherapies, with the best evidence to support metformin, leading to itsposition as first-line therapy.

    Three trials were conducted to see if CVevents could be reduced further with more intensive glycaemia treatment andlower target HbA1c levels. The results prompted concerns about the safety of intensiveglucose lowering and the appropriateness of pursuing tight glucose control,particularly in older people with DM and in those with existing CVD. Moreresearch on understanding the trial results is needed.

    Hypertension is more common in patients with type 2 DM compared with thegeneral population. Combination treatment is commonly needed to lower BP effectively in DM. AnACE-I or an angiotensin receptor blocker ARB , where tolerated, shouldalways be included as first-line therapy because of the evidence of superiorprotective effects against initiation or progression of nephropathy. While the most common lipid abnormality in type 2 DM is elevated triglycerideand low HDL-C, trials examining possible CVD benefits of lipid mainlytriglyceride lowering with fibrates in DM have not been positive.

    Patients with type 1 or type 2 DM have an increased tendency to developthrombotic phenomena. The role of aspirin in patients without CVD remains unproven. A meta-analysisof six RCTs found no statistically significant reduction in the risk ofmajor CV events or all-cause mortality when aspirin was compared withplacebo or no aspirin in people with DM and no pre-existing CVD.

    In patients with DM and hypertension,microalbuminuria—even below the current threshold values—predicts CV events,and a continuous relationship between CV as well as non-CV mortality andurinary protein:creatinine ratios has been reported. Microalbuminuria can bemeasured from spot urine samples due to inaccuracy in sampling, 24 h ornight-time urine collection is discouraged by indexing the urinary albuminconcentration to the urinary creatinine concentration 2. There is a need to examine whether a type 2 DM CV risk score based oneither 10 year or lifetime risk helps to improve targeting ofpreventative therapies and leads to a reduction in CV risk or a gainin lifetime years free from disease.

    Further trial data are needed to establish if the empagliflozinoutcome findings hold for other classes of SGLT2 inhibitors and tobetter understand the mechanisms of benefit. More research on the benefits of glucagon-like peptide 1 GLP-1 receptor agonists on CVD risk is needed and trials are due to bereported in subsequent years. Key messages Type 1 DM is the result of a lack of insulinproduction in the pancreas, confirmed by absent or virtually absentC-peptide levels. Type 1 DM should be suspected in any patientwho progresses to insulin within the first year of diagnosis. A largecontemporary study in Scotland observed a relative risk for CVD events of2.

    The presence of proliferative retinopathy andautonomic neuropathy also signalled an elevated CVD risk. CVD and mortality risks have decreased in type 1 DM patients butremain unacceptably elevated in those with very poor glycaemiccontrol or any evidence of kidney disease. Intensive management of hyperglycaemia in DM reduces the risk ofmacrovascular complications and premature mortality; a target of6.

    The Diabetes Control and Complications Trial DCCT established theimportance of tight glucose control to lessen the risks of bothmicrovascular and macrovascular disease. A 27 year follow-up of this trialshowed that 6. The use of insulin analogues, insulin pumps and continuousglucose monitoring to improve glycaemic control while minimizinghypoglycaemia is the subject of intense research, as is the use of agents e. The CTT suggested lipid lowering with statins is as equally effective in type1 patients as in type 2.

    Younger patients with multiple risk factors orevidence of end organ damage albuminuria, low eGFR, proliferativeretinopathy or neuropathy should be considered for statin therapy. As morepatients with type 1 DM are living to older age, SBP targets may need to berelaxed mmHg in some to avoid side effects. Further studies are needed on metformin and GLP-1 receptor agonistsin subgroups of patients with type 1 DM to determine whether theyimprove glycaemic control, aid in weight reduction and improveclinical outcomes. There is a need for a CVD risk score in type 1 DM to better guideinitiation of preventative therapies in younger patients.

    High BP is a leading risk factor for disease burden globally, accounting for9. The risk of death from either CAD or stroke increases progressivelyand linearly from BP levels as low as mmHg systolic and 75 mmHgdiastolic upwards, although for absolute risk the curves flatten in thelower BP ranges. Office BP is recommended for screening and diagnosis of hypertension, whichshould be based on at least two BP measurements per visit and on at leasttwo visits. If BP is more markedly elevated or accompanied by targetorgan damage, other CV factors or established CV or renal disease, repeatedBP measurements are required within a shorter period in order to maketreatment decisions.

    Auscultatory or oscillometric semi-automatic sphygmomanometers should bevalidated and checked periodically. If feasible, automated recording of multiple BP readings inthe office, with the patient seated in an isolated room, might be consideredas a means of improving reproducibility and matching office BP values closerto those provided by daytime ambulatory BP monitoring ABPM or home BPmeasurements HBPMs. The following general principles and remarks should be taken into account: i the procedure should be adequately explained to the patient, with verbaland written instructions; ii interpretation of the results should takeinto account that the reproducibility of out-of-office BP measurements isreasonably good for 24 h, day and night BP averages, but less so for shorterperiods; iii ABPM and HBPM provide somewhat different information on thesubject's BP status and risk, and the two methods should thus be regarded ascomplementary rather than competitive; iv devices should be validated andregularly calibrated, at least every 6 months.

    Clinical indications for the use of out-of-office blood pressuremeasurements home blood pressure measurement, ambulatory bloodpressure measurement. Laboratory tests should include haemoglobin, fasting plasma glucose HbA1c ifnot fasting and serum tests for total cholesterol, HDL-C, triglycerides,potassium, uric acid, creatinine and calculated renal function andthyrotropin in postmenopausal women. Urinalysis should includealbumin:creatinine ratio, dipstick test, sediment and quantitativeproteinuria if the dipstick test is positive.

    Echocardiography andfundoscopy can be considered. The decision to start pharmacological treatment depends not only on the BPlevel but also on total CV risk, outlined in section 2. The decision to start antihypertensive treatment depends on the BP level andtotal CV risk. Lifestyle changes are recommended in all patients withsuboptimal BP, including masked hypertension. Prompt initiation of drugtreatment is recommended in individuals with grade 3 hypertension with anylevel of CV risk.

    Lifestyle changes only with close BP monitoring should be the recommendationin young individuals with isolated moderate elevation of brachialSBP andin individuals with high-normal BP who are at low or moderaterisk. Drug treatment may also be considered in white coathypertensive patients with a higher CV risk because of metabolicderangements or in the presence of organ damage. Lifestyle interventions, weight control and regular PA alone may besufficient for patients with high-normal and grade 1 hypertension, andshould always be advised for patients receiving BP-lowering drugs, asthese may reduce the dosage of BP-lowering drugs needed to achieve BPcontrol.

    The lifestyle intervention specific to hypertension is saltrestriction. At the individual level, effective salt reduction is by nomeans easy to achieve. As a minimum, advice should be given to avoidadded salt and high-salt food. As the BP-lowering effect of increasedpotassium has been well documented in the DASH diet rich in fruits,vegetables and low-fat dairy products with a reduced content of dietarycholesterol as well as saturated and total fat , patients withhypertension should generally be advised to eat more fruits andvegetables and to reduce their intake of saturated fat andcholesterol.

    The large number of randomized trials of BP-lowering therapy, both thosecomparing active treatment vs. Some aspects should be considered for each of theBP-lowering drug groups. Thiazide diuretics also have dyslipidaemic and diabetogenic effects,particularly when used in high doses. Evidence concerning the benefits of other classes of agents is much morelimited. All of these agents have frequentlybeen used as added drugs in trials documenting CV protection and canthus be used for combination treatment in addition to the recommendedcombinations see below.

    Drugs with 24 h efficacy are preferred. Simplification of treatmentimproves adherence to therapy, and effective 24 h BP control isprognostically important in addition to office BP control. Long-actingdrugs also minimize BP variability, which may offer protection againstprogression of organ damage and the risk of CV events. Any all-purpose ranking of drugs for general BP lowering is infeasibleand no evidence is available that different choices should be made basedon age or sex except for caution in using ACE-Is and ARBs in women ofchildbearing age because of possible teratogenic effects.

    Combination treatment is needed to control BP in most patients. Theaddition of a drug from another class should thus be regarded as arecommended treatment strategy unless the initial drug needs to bewithdrawn because of side effects or the absence of any BP-loweringeffects. The extra BP reduction from combining drugs from two differentclasses is approximately five times greater than doubling the dose ofone drug andmay reduce the side effects associated with either drug.

    The combinationof two drugs may also offer advantages for treatment initiation,particularly in patients at very high risk in whom early BP controlmay be desirable. Trial evidence of outcome reduction has been obtained,particularly for the combination of a diuretic with an ACE-I, an ARB ora calcium antagonist. The most rational combinations appear to bea blocker of the renin—angiotensin system, a calcium antagonist and adiuretic at effective doses. There are only a few randomized clinical trials comparing different treatmenttargets.

    Hence any recommendation on target levels largely derives fromobservational studies and post hoc analyses of RCTs, which have mostlycompared different treatment regimens and reported achieved BP levels. Nevertheless, it should beconsidered that DBP values between 80 and 85 mmHg are generally safe andwell tolerated. Post hoc analyses of large-scale trials e. However, significantly higher rates of serious adverse events, hypotension,syncope, electrolyte abnormalities and acute kidney injury or failure, butnot injurious falls, were observed in the intensive-treatment group.

    Thefact that the study was open label in a strategy close to usual care withfrequent visits may have helped to adjust the antihypertensive treatment ifserious side effects occurred and thus minimized the risk of events. Large meta-analyses confirm that treatment is highly beneficial in theelderly hypertensive patient.

    Infrail elderly patients, it is recommended to be careful and reach adecision based on monitoring of the clinical effects of treatment. Resistant hypertension isassociated with a high risk of CV and renal events.

    Emerging Pathologies in Cardiology

    In these patients, physiciansshould check whether the drugs included in the existing multiple drugregimen have any BP-lowering effect and withdraw them if their effect isabsent or minimal. In the case of drug treatment ineffectiveness i. Generally, BP-lowering therapy should be maintained indefinitely. Cessationof therapy in hypertensive patients is mostly followed by the return of BPto pretreatment levels.

    This may be particularly the case if BPcontrol is accompanied by healthy lifestyle changes. A reduction ofmedications should be made gradually and the patient should be checkedfrequently because of the risk of reappearance of hypertension. Patient follow-up should be carried out by the health care team, which shouldinclude physicians, nurses and pharmacists in a concerted activity, althoughwide variations exist in the organization of health care systems acrossEurope.

    In some countries, the task relies more on physicians, while inothers, specially educated and trained nurses play a more prominent role. Once the target is reached, a visit interval of a few months is reasonable;there is no difference in BP control between 3 and 6 month intervals. Theregression of asymptomatic organ damage occurring during treatment reflectsthe treatment-induced reduction of morbid and fatal CV events; however, acost-effectiveness analysis in which signs of organ damage should best beassessed in the follow-up has never been done.

    The optimal office BP values i. The optimal out-of-office home and ambulatory BP targets andwhether the treatment strategies based on control of out-of-officeBP provide an advantage over strategies based on conventional office BP control. Antiplatelet therapy is not recommended in individuals free from CVD, dueto the increased risk of major bleeding.

    Prevention in individuals without overt CV or cerebrovascular disease wasinvestigated using long-term aspirin vs. A risk reduction from 0. The risk of vascular mortality was not changed bytreatment with aspirin. In a recent Japanese study, patients 60—85years of age presenting with hypertension, dyslipidaemia or DM wererandomized to treatment with mg aspirin or placebo. In individualswith multiple risk factors, clopidogrel in combination with aspirin vs. In a meta-analysis of 16 trials comprising 17 individuals, theAntithrombotic Trialists' Collaboration, aspirin treatment was associatedwith serious vascular events in 6.