Unstable angina pectoris I20.0

The term "unstable angina pectoris" has been used since 1971. Eugene Braunwald introduced a classification of unstable AP for the first time in 1989 (see "Classification" below), which has been widely accepted and recognized worldwide (Weber 2004).

Unstable AP is part of the acute coronary syndrome.

According to ACC / AHA 2007 the unstable AP is defined as follows:

• AP at rest, which lasts longer (> 20 min)
• Newly appeared AP with at least severity level CCS III (see CCS classification)
• AP already known, but increasing in duration, frequency and intensity (at least CCS III)
• AP already known to occur at a reduced load level (at least CCS III) (Pinger 2019)

By definition, the unstable Ap runs without myocardial necrosis (Kasper 2015).

Unstable angina pectoris belongs to the acute coronary syndrome along with STEMI and NSTEMI. NSTEMI and unstable AP are together also called"Non- ST- Elevation Acute Coronary Syndrome" (NSTE- ACS).

The further differentiation of NSTE- ACS into NSTEMI and unstable AP is based on the detection of troponin elevation (Roffi 2015).

The unstable AP is divided into

• primarily unstable AP

This means any firstangina with at least severity CCS III [Pinger 2019])

• Secondary unstable Ap

These include an AP with increasing severity, duration and frequency of the seizures, a resting AP, the post-infarction AP, etc. (Herold 2020).

Eugene Braunwald formulated the classic idea of unstable AP in 1989 according to severity, clinical circumstances and possible medication. C. W. Hamm modified it in 2000:

• Severity I: newly occurring AP < 2 months with a pronounced intensity, which occurs at least 3 x / d or known AP, which increases in frequency and already occurs at significantly lower exposure
• Severity II: AP that occurred in the last month but not within the last 48 h at rest.
• Severity III: AP which has occurred at rest within the last 48 hours.

• Severity A: Secondary AP occurring as a result of fever, infections, tachyarrhythmia absoluta, hypotension, anemia or hyperthyroidism.
• Severity B: Primary unstable AP
• Severity level C: Unstable AP that occurs within 2 weeks of an infarction.

• Severity 1: AP with no or little medication
• Severity 2:AP under standard medication
• Severity 3: AP under maximum therapy including i. v. nitro administration (Pinger 2019/ Braunwald 1989/Hamm 2000)

• Silent myocardial ischaemia: In almost all patients with unstable AP, so-called "silent myocardial ischaemia" occurs in addition, and is painless. Exclusively painless ischemias are found in about 5% of patients with coronary stenosis. These are often diabetics or smokers. These silent ischemias represent a considerable risk factor for the occurrence of a myocardial infarctionin the following years. Whether these infarctions can be prevented or reduced by drug treatment of silent ischemias is unknown (Stierle 2017).

The group of unstable angina pectoris also includes the following special forms of AP:

• Prinzmetal angina (Barmeyer 2010)
• Angina nocturna (in the literature this is partly classified as stable AP and partly as unstable AP)

In Germany, between 350,000 to 400,000 patients are found annually with an acute coronary syndrome without ST elevation (Pinger 2019).

Associated non-cardiac diseases:

• Iron deficiency (serum ferritin and transferrin saturation): Iron deficiency has significant prognostic significance. In one study, iron deficiency was shown to have a high prevalence to acute coronary syndrome (ACS). 29.1% of patients with ACS (including 42.8% women) had low levels. The risk of cardiovascular mortality and nonfatal myocardial infarction was increased by 73% in these patients during a 4-year follow-up period (Zeller 2018).

In unstable AP, in addition to progressive stenosing coronary sclerosis, plaque ruptures or plaque erosions with activation of coagulation and thrombus formation are in the foreground. Sometimes there is also an embolization of the thrombi and also vasospasms (Pinger 2019). The primary cause of AP is an imbalance between oxygen supply and oxygen demand, which can be caused by:

• a thrombus formation on a coronary plaque
• an erosion of the coronary arterial endothelium
• dynamic constrictions (e.g. due to coronary spasm)
• severe mechanical constrictions (e.g. due to coronary sclerosis)
• Increased myocardial oxygen demand for e.g.
  • Fever
  • Tachycardia
  • Thyrotoxicosis
  • severe anaemia (Arntz 2002)
  • Hypotension (Arntz 2002; Kasper 2015)

The following mechanisms can be found:

• first, there is a rupture of an atherosclerotic plaque
• various degrees of additional thrombosis develop
• distal embolization occurs (Stierle 2017)

Pathophysiology: In an AP-attack the perfusion pressure decreases in the poststenotic area of the coronary artery. The end-diastolic ventricular pressure, on the other hand, increases. This initially leads to a disturbance of the blood flow in the inner layer of the myocardium and, in the case of transmural hypoperfusion, to a deterioration of the pumping function of the affected ventricle (Herold 2020).

The following changes are the cause of AP:

Increased coronary resistance:

• this can be caused by major vasal factors such as:
  • Macroangiopathy > 90%.
  • Microangiopathy (small vessel disease)
  • Coronary spasms (can be triggered by cocaine, among other things)
  • Coronary anomalies
  • arteriovenous coronary fistulas
  • congenital myocardial bridges
• and by additional myocardial factors such as:
  • Heart Hypertrophy
  • Increased end-diastolic pressure in the ventricles
  • Tachycardia / Tachyarrhythmia in atrial fibrillation
  • arterial hypertension

As soon as tachycardia and hypertension exceed a critical limit due to the increase in heart work, an angina pectoris attack occurs.

Extracoronary factors. These can be cardiac factors such as:

• hypertrophic cardiomyopathy
• Aortic valve defects (e.g. due to severe left ventricular hypertrophy in aortic valve stenosis [Kasper 2015])
• Rhythm disturbances
• and extracardiac factors such as:
  • Increased oxygen demand (Neurath 2015) in case of e.g. fever, hyperthyreosis, physical exertion etc.
  • Decreased oxygen supply, e.g. in anaemia, high altitude, lung diseases, sleep apnoea syndrome, CO poisoning, etc.
  • Increased blood viscosity in cases of erythropoietin doping, hyperfibrinogenemia, multiple myoma, polycythemia vera, etc. (Herold 2020).

Unstable AP can typically be triggered by:

• physical stress (more isometric than dynamic)
• emotional strain
• stressful meals
• physical cold (Stierle 2017)

Spontaneous course: The transition from an unstable AP to a NSTEMI is usually smooth with longer lasting and stronger pain, often accompanied by increasing vegetative symptoms (Stierle 2017)

The symptoms of unstable angina pectoris can occur progressively under stress, at rest and also during sleep (Kasper 2015). The symptoms are predominantly:

• retrosternal localized pain with radiation in
  • the neck / nape of the neck
  • Lower jaw
  • Teeth
  • Shoulder area
  • both (!) arms (with focus on the ulnar sides of the forearms), which can radiate into the ulnar fingertips
  • Pain in the epigastrium (rarely also below the navel)
• typically the region of the trapezius muscle remains painless (pain in this area is typical of pericarditis) (Kasper 2015)

However, these typical symptoms may be absent in:

• diabetes mellitus
• Renal insufficiency
• Women
• older patients > 75 years
• Currently undergoing heart surgery
• At present according to heart transplantation (Herold 2020)

Here there are rather unspecific symptoms, such as

• Nausea
• Shortness of breath
• Swindle
• Pain in the epigastrium (Herold 2020)

Cardio CT - Multi-layer computed tomography (MSCT) / Dual-source computed tomography (DSCT)

With the MSCT, which was clinically introduced in 1998, up to 64 layers can be recorded simultaneously. Up to now, restrictions have mainly existed in cases of increased heart rate, stents and severe coronary calcifications (Mahnken 2007).

A further development is the DSCT with two tube detector systems, which has been in use since 2006 (Luhmann 2009). Both examination methods are suitable for patients with a low to medium pre-test probability (see coronary heart disease under "Diagnosis") of coronary heart disease. The sensitivity is almost 100 %, as is the negative predictive value.

In contrast to conventional invasive cardiac catheters, this method can also be used to visualize the vessel walls and thus non-calcified (so-called soft plaques), mixed and calcified plaques. The radiation exposure of 1 mSv is significantly lower than that of the invasive heart catheter with 5 mSv - 12 mSv.

The limitations of these methods - compared to an invasive heart catheter - are found in:

• Cardiac arrhythmias
• a calcium score of > 400 (Herold 2020)

Cardiac catheterization: Coronary angiography is rarely appropriate for low to moderate probability of NSTEMI- ACS (Pinger 2019).

In contrast, coronary angiography is recommended within the first 48 hours at the latest in the case of a demonstrably unstable AP, in order to be able to carry out therapeutic steps such as a PCI or surgical intervention in good time (Lapp 2014).

In the case of unstable AP,:

• 85 % significant stenoses
• 50 % intracoronary thrombus formation
• 15 % no evidence of stenosing coronary heart disease (Schunkert 1999)

Troponin T and Troponin I: Troponin does not rise in unstable angina pectoris (Herold 2020). The value is ≤ 0.01 (Stierle 2017). Troponin should be determined immediately upon admission and 6 - 9 h after onset of symptoms. If there is a clinically high suspicion of NSTEMI , it is recommended to check again after 12 - 24 h (Pinger 2019) if the value has been negative so far.

Patients with a negative CK- MB show an increase in troponin in approx. 15 % - 20 %. In such cases one speaks of troponin positive unstable angina, also known as "minor myocardial damage". Since the ESC / ACC consensus in 2000, this situation is considered a myocardial infarction in the sense of a NSTEMI (Pinger 2019).

Copeptin: According to new ESC guidelines, Copeptin should be determined in combination with troponin for rapid infarction exclusion (Kasper 2017).

CK- MB and CK (an increased CK- MB- value with normal CK indicates a bad prognosis)

For prognostic reasons, it should be further determined:

• serum titans (see "Associated non-cardiac diseases" under "Occurrence")
• Transferrin saturation
• Creatinine clearance
• BNP (Pinger 2019)

The diagnosis of the disease underlying angina pectoris - coronary artery disease - is described in detail there. Here, only a few criteria, especially important for unstable AP, are highlighted.

Inspection and palpation: When describing the pain during an AP attack, the patient typically clenches the fist in the middle of the sternum - also known as the so-called Levine sign, the hand is placed flat on the sternum or both hands, fingertips facing each other are placed on the sternum from the lateral side to indicate the belt-like tightness. Sensitivity for cardiac pain is approximately 80%, specificity is approximately 49% (Edmondstone 1995).

Resting ECG: In about 50% of patients, no changes are seen on the ECG. Otherwise, ST-segment elevation, possibly followed by ST-segment depression, may be present (Stierle 2014). All types of disorders of depolarization or repolarization are also possible. The specificity of the resting ECG with regard to an unstable AP must be considered very low overall (Pinger 2019).

Exercise ECG: Persistent unstable angina is an absolute contraindication for exercise ECG (Pinger 2019).

Echocardiography: Echocardiography can provide information about the function of the left ventricle. In addition, certain differential diagnoses such as aortic dissection, aortic valve stenosis, pulmonary embolism, etc. can be excluded (Achenbach 2012).

Stressechocardiography: If the diagnosis remains unclear based on the examinations performed up to this point, stress examinations to provoke ischemia are recommended - after stabilization of the patient. These include, for example, stress echocardiography or myocardial scintigraphy (Herold 2020). Because unstable AP is among the contraindications for stress testing, a decision on whether to perform it should be made on a case-by-case basis. The sensitivity of stress echocardiography with dynamic stress is between 80%-85%, and the specificity is between 80%-88% (Pinger 2019). Coronary stenoses are only detectable when they are already significant, i.e., constrict more than 50 % of the vessel lumen (Völler 2000).

NSTEMI: the differentiation between a NSTEMI and an unstable AP is only possible by the determination of troponin (Giannitsis 2007).

The so-called "big five" of thoracic pain are:

1. Acute coronary syndrome

2. pulmonary embolism

3. aortic dissection

4. boerhaave syndrome (spontaneous rupture of the esophagus after strong vomiting)

5. tension pneumothorax (Herold 2019 / 2020)

For detailed information on further differential diagnostic clarification see acute coronary syndrome

Since unstable angina pectoris is an emergency, the acute disease requires immediate inpatient treatment (Paumgartner 1999).

• lysis is not (yet) indicated
• Acetylsalicylic acid (e.g., with asisol 500 mg i.v.)
• Full heparinization with low molecular weight heparin (e.g. enoxaparin sodium 60 - 100 mg /day s. c.)
• Glycoprotein receptor IIa / IIIa antagonists (e.g., abciximab: initial bolus of 0.25 mg/kg bw i. v., followed by 0.125 µg/kg bw/ min, max. 10 µg/min for 12 - 24 h [Stierle 2017])
• Nitrates: i.v. glycerol trinitrate- infusion 1 mg - 5 mg / h.
• O2 via nasal probe
• Pain therapy with 2 mg - 10 mg morphine slowly i. v.
• early administration of a beta-blocker (e.g. with esmolol i.v.) favors the further course of the disease
• no calcium channel blockers (absolute contraindication) (Wehling 2005)

In further course:

• Iron carboxymaltose i. v. in case of existing iron deficiency (see above "Occurrence": Associated non-cardiac diseases) (Zeller 2018).

An unstable AP is the indication for surgery (Kasper 2015).

The surgical treatment consists in revascularization of the stenosed vessels. The two standard procedures are percutaneous catheter intervention (PTCA or PCI [percutaneous coronary intervention] in the Anglo-Saxon-speaking world) and coronary bypass surgery (ACVB or CABG [coronary artery bypass graft]). (Stierle 2017)

For detailed information on both procedures see coronary heart disease

The risk of acute coronary syndrome, to which unstable AP belongs, can be determined by means of the so-called Grace- Score(https://www.outcomes-umassmed.org/risk_models_grace_orig.aspx).

With a score of:

• < 108 the risk of dying in hospital is < 1 %.
• between 109 - 140 the risk of dying in hospital is 1 % - 3 %
• > 140, the risk of dying in the octopus house is > 3 % (Herold 2020)

The 30-day mortality for the unstable AP is 4.5 % and after 6 months 8.6 % (Stierle 2017).

The serious risks in the further course of an unstable AP include acute myocardial infarction and sudden cardiac death. These events occur every year:

• myocardial infarction 14 % - 22 %
• sudden cardiac death 8 % - 18 % (Barmeyer 2010)

In the case of a history of renal insufficiency, mortality is also significantly increased:

Creatinine clearance: < 30 ml / min at 16

30 - 60 ml / min at 6

> 60 ml / min at 2 % (Pinger 2019)

Notes: According to recent studies, asprosin (a biochemical marker discovered in 2016 for diabetes mellitus and other conditions) is a marker for predicting the severity of unstable angina pectoris (Yuan 2020 / Acara 2017).

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